Clinical Genetics 1985: 27: 535-542

Autoimmune polyendocrinopathy - candidosis - ,ectodermal dystrophy

(APECED): autosomal recessive inheritance

PEKKA AHONEN Children’s Hospital, University of Helsinki, Finland

A genetic analysis was made of 58 patients and their 42 families with APECED (autoimmune polyendocrinopathy - candidosis - ectodermal dystrophy). APECED is characterized by hypo- parathyroidism, primary adrenocortical failure and chronic mucocutaneous candidosis, but none of its components is constant. Other endocrine deficiencies can occur as well and also dystrophy of dental enamel and nails. The proportion of affected siblings was 0.147+0.034 (S.D.) when corrected for truncate single ascertainment, 0.246 0.019 when corrected for a priori truncate complete ascertainment and 0.240 k0.047 when corrected for a posteriori trunc- ate complete ascertainment. The male/female ratio was 1.04. The results are compatible with autosomal recessive transmission. No heterozygous manifestations of the gene were found. The gene is enriched in isolated subpopulations in central and eastern Finland. APECED is part of the “Finnish heritage of disease”.

Received 28 September 1984, accepted for publication I3 February 1985

Key words: APECED; autoimmune; autosomal recessive; chronic mucocutaneous candidosis; hypoparathyroidism; polyendocrinopathy; primary adrenocortical failure.

Two distinct autoimmune polyendocrinopa- thies are known: Schmidt’s complex* (Car- penter et al. 1964) or autoimmune polyglan- dular syndrome 2 (Neufeld & Blizzard 1980) and autoimmune polyendocrinopathy ~

candidosis - ectodermal dystrophy (APE- CED, Perheentupa 1980). Schmidt’s com- plex was initially described as a combi- nation of hypothyroidism and primary ad- renocortical failure (Schmidt 1926) but includes, potentially, the thyrogastric com- plex (Graves’ disease or atrophic thyroiditis

* Originally named syndrome, this variable complex does not fit the present definition of the word syndrome: a set of symptoms and signs.

and pernicious anemia), insulin dependent diabetes mellitus (IDDM), primary ovarian atrophy, vitiligo, alopecia, myasthenia gra- vis (Eisenbarth et al. 1978) and possibly hypophysitis (Klaer & Nnrrgaard 1969, Gleason et al. 1978, Goudie & Pinkerton 1962).

Hypoparathyroidism and chronic muco- cutaneous candidosis have not been re- ported in Schmidt’s complex but they are the most consistent components of APE- CED. APECED is a highly variable combi- nation of hypoparathyroidism, chronic mu- cocutaneous candidosis (Thorpe & Hanley 1929), primary adrenocortical failure (Whi- taker et al. 1956), IDDM (Soderlund 1938),

536 A H O N E N

pernicious anemia (Walsh & Murray 1953, Whitaker et al. 1956, Drury 1970), primary gonadal failure (Craig et al. 1955, Golon- ka & Goodman 1968, Richman et al. 1975), primary atrophic thyroiditis (Craig et al. 1955), hepatitis (Craig et al. 1955), vitiligo (Perlmutter et al. 1956), alopecia (Sutphn et al. 1943), intestinal malabsorption (Walsh & Murray 1953, Morse et al. 1961), keratopa- thy (Pohjola 1962), hypoplasia of dental enamel (Myllarniemi & Perheentupa 1978) and nail dystrophy (Perheentupa et al. 1978). The ectodermal manifestations of the disease are independent of the endocrinopa- thies (Perheentupa et al. 1978). APECED has appeared under several different names: “familial hypoparathyroidism, hypoadre- nocorticism and superficial moniliasis” (Whitaker et al. 1956), “candida endocrin- opathy” (Wells et al. 1972), “juvenile fam- ilial endocrinopathy” (Drury 1970), “juven- ile autoimmune polyendocrinopathy” (Brun & Cortet 1980), “Whitaker’s syn- drome” (Brun & Cortet 1980), “familial candidiasis endocrinopathy” (Arulanan- tham et al. 1979), “autoimmune polyglan- dular syndrome, type 1” (Neufeld et al. 1980), “polyglandular autoimmune disease, type 1” (Neufeld & Blizzard 1980) and most recently “polyglandular failure, type 1” (Eisenbarth & Rassi 1983). The name APECED indicates the three independent groups of components of the disease.

The disease is rare and most reports have been of single patients or sibships but some larger series have been reported, which were based on serologic studies (Blizzard et al. 1966, Irvine 1972) and on inquiries among endocrinologists (Spinner et al. 1968, Neu- feld & Blizzard 1980). The condition has only been found in the offspring of unaffec- ted parents (Eisenbarth & Rassi 1983) and in both sexes although a clear predominance has been noted in the female (Brun & Cortet 1980, Fanconi 1969, Neufeld & Blizzard 1980). Autosomal recessive inheritance has,

however, been postulated (Spinner et al. 1968), and a preliminary report on a series of Finnish patients has supported this (Per- heentupa et al. 1978). APECED is, like many other rare autosomal recessive dis- eases, enriched in the Finnish population as part of the “Finnish heritage of disease” (Norio et al. 1973, Nevanlinna 1980). The aim of this study was to define its mode of inheritance by making a genetic analysis of all 58 presently-known Finnish patients and their 42 families.

Material and Methods

Collection of the series: The series was col- lected by inquiries to hospital departments of internal medicine and pediatrics through- out Finland about patients with hypopara- thyroidism, primary adrenocortical failure, chronic mucocutaneous candidosis or com- binations of these. All endocrinologists and pediatric endocrinologists were also con- tacted and a search was made of Finnish medical literature for published case re- ports. Further information was obtained from private physicians who had managed some of the patients. The hospital records of all patients thus found were obtained for establishing a definitive diagnosis. When- ever possible, the patient was also seen at this hospital and examined by Jaakko Per- heentupa, M.D. and myself. Forty-nine pa- tients as well as 44 siblings and 56 parents were examined at this hospital.

Evident patients: Criterion for inclusion in this category was the presence of at least two of the following components, clearly documented by a physician: 1) chronic mu- cocutaneous candidosis, 2) hypoparathyro- idism (subnormal Ca and supranormal in- organic phosphate concentrations in serum, excluding renal failure), 3) primary adren- ocortical failure (primary cortisol (Leisti et al. 1983) and/or aldosterone deficiency). For

A P E C E D : A U T O S 0 M A L R E C E S S I V E 537

S i b s h i p

1

3 4 . 5 0 6 0 7 .I 8 .O 9 a.

2 ; 0

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12 om 13 00 14 n o 15 0 8 10 .O 17 0.r 18 o r 0 19 O D 8 20 0.D 21 8 0.

11 ;:

Sibship

22 0.. 2 3 00.

27 O O M 2 8 0 0 0 8 2 9 00.0 30 00110 31 8 U 0 0 32 0 0 0 8 0 3 3 00.00 3 4 0-.000 3 5 n0.w 36 00.HOO 37 oa..u. 38 8 0 O . H

living siblings known to be free of all symp- toms and signs, and deceased siblings with- out any history suggestive of APECED.

Genealogical studies: Dates and places of birth for the eight great-grandparents of each patient were established from the population registers. This was possible for all families except one, in which only the mother’s side was known. In two other sib- ships, the families provided us with the in- formation regarding two of the great-grand- parents who could not be found in registers.

Fig. 1. Sibships with APECED. 0 unaffected, evi- dently affected, E3 probably affected, 8 possibly affec- ted, JZ’ stillborn, Hdeceased. Aspects of these families have been reported pre- viously: (2) Soderlund 1938; (21) Pohjola 1962; (30) Visakorpi 8 Gerber 1963; (33) lkkala et al. 1964, Siurala et al. 1968; (38) Hiekkala 1964; (42) lkkala et ai. 1964, Siurala et al. 1968, Jarvinen & Latvalahti 1958.

siblings of an index case, one component was sufficient.

Probable patients: One brother in a sibship of four evident patients (sibship 38, Fig. 1) was included in this category. He had died suddenly at the age of six years after six months of salt craving, headaches, malaise, vomiting, diarrhea and hyperpigmentation. No autopsy had been performed.

Possible patients: Two siblings (sibship 42) who had died in childhood were included as possible patients in the absence of specific evidence, because of a history compatible with death from APECED (vomiting and convulsions).

Unaflected siblings: These were siblings examined at this hospital who did not have indication of the disease, as well as all other

-\

Fig. 2. Birthplaces of the presumed heterozygotes’ (patients’ parents’) grandparents on the map of Fin- land. If all originated from the same parish, this Is marked by a full size square. Otherwise a small squa- re, a half square or a three-quarter square is used, as appropriate. It is evident that three-quarters of these fractions of a square refer to persons who were not heterozygotes. The map also shows the main water routes, which were the routes of immigration to the east and center of the country (Lipsanen-Nyman, un- published observations).

538 A H O N E N

Geographic distribution of the great-grand- parents: The birthplaces of the great-grand- parents were marked on the map (Fig. 2). According to the autosomal recessive hy- pothesis, both parents of a patient must be heterozygotes as well as one of their four grandparents. If all four grandparents were born in the same parish, then this parish was a very likely location of the presumed gene.

Calculation of the proportion of aflected sibs: This was calculated by correction for trunc- ate ascertainment according to established methods (Nee1 & Schull 1954, Li 1961).

Results

Subjects: There were altogether 147 siblings in 42 sibships (Fig. 1). Of these 147, 56 were evident patients, one was a probable patient and two were possible. Thus the most prob- able number affected was 58 (all evident and probable cases plus half the possible cases (Norio 1966)). One sibship included five affected sibs, three three affected sibs, six two affected sibs and 32 one affected sib. Six sibships were single.

Sex ratio: The male/female ratio of the evi- dent and probable patients was 29/28 = 1.04.

Consanguinity: In one sibship (19) the parents were second cousins. One patient (sibship 3) was the niece of another (sibship 18).

Geographic distribution of great-grand- parents: The squares showing the birth- places of the great-grandparents were dis- tributed over a wide area but this did not include the southwestern and northern parts of the country. There were definite areas of accumulation widely spaced in the south, east and northwest of the southern half of

the country. The eastern area was clearly associated with the large Saimaa chain of lakes (Fig. 2).

Proportion of aflected sibs: The six single sibships were excluded as being uninforma- tive, thus leaving 36 sibships and 52 pa- tients. The apparent proportion of affected sibs was 52/141=0.37. However, this did not take into account the totally unaffected sibships born of two heterozygous parents. After correction for this error, the pro- portion was 0.246 kO.019 (S.D.), assuming a priori truncate complete ascertainment, 0.240 0.047, assuming aposteriori truncate complete ascertainment, and 0.147 kO.034, assuming truncate single ascertainment.

Heterozygous manifestations: All the exam- ined parents were healthy, with no candid- osis or ectodermal dystrophy. One mother had pernicious anemia with high titers of circulating thyroid antibodies and another had alopecia. All the non-affected siblings studied were free of endocrinopathies, ecto- dermal dystrophy and candidosis. One sib- ling had had unilateral optic nerve atrophy since seven years of age (sibship 13) and another had developed iridocyclitis at 31 years of age (sibship 38).

Discussion

Proportion of aflected siblings: Theoreti- cally, a condition inherited as an autosomal recessive is present in 0.25 of the offspring of a large number of heterozygous matings. However, this pertains only to populations based on ascertainment of the heterozygous parents. This was not the case with our series, as we were not aware of any marker of heterozygosity for the assumed gene. Consequently, sibships without affected children were not included at all (truncate ascertainment) and ascertainment was probably the more likely the greater the

A P E C E D : A U T O S O M A L R E C E S S I V E 539

number of affected sibs in the sibship (in- complete truncate ascertainment). Correc- tion was made by established mathematical calculations, applying two different me- thods for truncate complete ascertainment and one for truncate single ascertainment. The corrected proportions of affected chil- dren thus obtained agree with the theoreti- cal proportion of 0.25 with a range from 0.147 (truncate single ascertainment) to 0.246 (a priori truncate complete ascertain- ment). Steinberg (1959) has suggested that the hypothesis of autosomal recessive in- heritance can be accepted if

bi + & I > 0.25 > bo- dbo

where bl and bo are the calculated pro- portions of affected children, assuming truncate complete and single ascertainment, respectively, and d b l and dbo their standard errors. The present results fulfilled Stein- berg’s criteria, as by inserting my numer- ical values: 0.246 + 0.019 = 0.265 > 0.25 > 0.1 13 ~0.147-0.034.

Ascertainment: Complete ascertainment means that the study sample includes sib- ships with numbers of affected sibs in the same proportion as the population from which the sample is collected. However, this sample probably does not represent com- plete ascertainment for several reasons. Firstly, as stated above, all unaffected sib- ships born of two heterozygous parents were not known. Secondly, some sibs who were homozygous for the APECED gene may have remained unrecognized as even a first single manifestation of APECED may only appear late. As a result of this some sibships may have been excluded from the series and some sibs in the sample, who were considered healthy may manifest the disease in later life. Thirdly, a number of affected families may have remained unre- cognized due to death of affected offspring from hypoparathyroidism, primary adre-

nocortical failure, IDDM, fulminant hep- atic failure, or, perhaps, a severe infection due to the immune defect. Finally, the prob- ability of a patient being included here was greater the more affected siblings he or she had. The degree of ascertainment in this series is therefore probably somewhere be- tween incomplete and complete and cannot be determined exactly. The proportions of affected sibs calculated assuming complete ascertainment differ less from the theoreti- cal value of 0.25 than does the proportion calculated assuming single ascertainment (which is a special case of incomplete ascer- tainment). This suggests that the ascertain- ment was closer to complete than incom- plete.

Geographic distribution: Most of the ances- tors originated from central and eastern Finland (Fig. 2). These areas were only in- habitated in the 16th century and the popu- lation was not subject to any significant genetic influx or efflux until the second half of this century. The population today, as then, consists of subpopulations isolated by distance and population density, each rep- resenting offspring of a small group of orig- inal settlers. The gene frequencies in such subpopulations can differ greatly from that of the general population due to gene en- richment and loss. The gene for APECED appears to have been common in the orig- inal population as it is enriched in several subpopulations. If it had been rare the en- richment would be seen in a few subpopula- tions only. This is the case of Salla disease (Renlund et al. 1983). Western Finland, and especially the southwestern corner which is the oldest inhabited area of the country is only rarely a likely location of the gene. The subpopulations in this area have not been as strongly isolated as in the eastern regions. Thus it can be assumed that no subpopula- tions with very high gene frequencies were formed. Alternatively, the gene may have

540 A H O N E N

been lost from the southwestern population due to efflux during the habitation of east- ern and central Finland, but as the emi- grants represented only a small fraction of the southwestern population, this is less likely.

Sex ratio: The male to female ratio in this series was 1.04, which is in accord with au- tosomal recessive inheritance. A preponder- ance for females, of 1:2, has been reported by Fanconi (1969), and Brun & Cortet (1980), and of 4:3 by Neufeld et al. (1980). These studies were based on reported cases from the literature, the latter ones on an inquiry among U.S. pediatric endocrinolo- gists (41 cases) and a literature survey (65 cases). They probably reflect the more se- vere nature of the disease in females (Ahonen, Perheentupa and Myllarniemi, unpublished observations), which makes re- porting of affected females and their treat- ment by a subspecialist more likely. Our series is only slightly biased in this way as it was collected by inquiry at virtually all the hospitals in the country and only two sibships were included via a survey of the literature (sibships 2 and 33, Fig. 1). Thus the ratio obtained here can be considered more reliable than the previous estimates.

Consanguinity: The degree of consanguinity in this series was low. The large number of observed homozygotes probably reflects the fact that in isolated subpopulations many inhabitants are distant relatives. Cousin marriages are rare among Finns, as they were prohibited by law until 1872, and even after revision of the law common opinion has not favoured them (Norio 1966).

Heterozygous manifestations: No manifes- tations possibly linked with APECED were observed in the parents, except autoimmune disease. The observed frequency of autoim- mune diseases did not significantly exceed

the expected frequency. Pernicious anemia, circulating thyroid antibodies and alopecia are common conditions in the general popu- lation with frequencies of 0.13-1 (Grunnet et al. 1970, Mosbech 1952), 6 4 2 (Gordin et al. 1979) and 10 (Dawber 1970, Grunnet et al. 1970) per thousand, respectively.

Theoretically, two-thirds of the healthy siblings were heterozygotes, but no hetero- zygote manifestations were found among them. Some new evident patients were diag- nosed during the family studies, but the di- agnosis was always easily established (for criteria see Material and Methods). At pre- sent it remains unclear whether optic nerve atrophy and iridocyclitis, seen in two other- wise healthy siblings, represent the sole manifestations of the disease in these per- sons, or whether they are heterozygous manifestations or not related to the disease. Both conditions have been found among APECED patients (Merenmies, Ahonen, Perheentupa and Tarkkanen, unpublished observations) and as ocular manifestations are often present for years before endocri- nopathies develop, these patients must be followed closely to detect any life-threaten- ing endocrinopathy at an early stage.

Acknowledgments

I am indebted to Professors B.-A. Lamberg and J. K. Visakorpi, and to Doctors R. Pelkonen, 0. Westphal, C.-G. Johansson and H. Turtola, for allowing me to study their patients. I am grateful to Prof. J. Per- heentupa for his guidance throughout t h s study. The study was supported by the Foundation for Pediatric Research.

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Address: Pekka Ahonen, M.D. Children’s Hospital University of Helsinki SF-00290 Helsinki Finland