Autoimmune polyendocrinopathy associated with ring chromosome 18

J Pediatr Endocr Met 2011;24(9-10):847–850 © 2011 by Walter de Gruyter • Berlin • Boston. DOI 10.1515/JPEM.2011.320

Patient report

Autoimmune polyendocrinopathy associated with ring chromosome 18

Nina Jain 1, *, Pamela J. Reitnauer 2 , Kathleen W. Rao 3 , Arthur S. Aylsworth 3,4 and Ali S. Calikoglu 1

1 Division of Pediatric Endocrinology , University of North Carolina Children’s Hospital, Chapel Hill, NC , USA 2 Pediatrics , Moses H. Cone Memorial Hospital, Greensboro, NC , USA 3 Division of Genetics and Metabolism , University of North Carolina Children’s Hospital, Chapel Hill, NC , USA 4 Department of Genetics , University of North Carolina, Chapel Hill, NC , USA

Abstract

Phenotypic and clinical features of individuals with ring chro-mosome 18 [r(18)] vary with the extent of deletion of the short (18p-) or long arm (18q-). Most patients with r(18), therefore, demonstrate a clinical spectrum of both 18p- and 18q- dele-tions. Short stature, microcephaly, mental and motor retarda-tion, craniofacial dysmorphism and extremity abnormalities are the most commonly reported features in patients with r(18). Abnormalities of chromosome 18, especially 18p- syndrome, are often reported with autoimmune thyroid disease and growth hormone defi ciency, but reports of endocrine abnormalities asso-ciated with r(18) are rare. Here, we report a case of an African-American female with hyperthyroidism, type 1 diabetes mellitus, vitiligo and IgA defi ciency associated with a r(18) chromosome complement. This patient additionally had mild intellectual dis-ability and dysmorphic features. Karyotype analysis showed a de novo ring chromosome 18 (deletion 18q23-18qter and deletion 18p11.3-18pter). Although this unique association of autoim-mune polyglandular endocrinopathy with ring chromosome 18 could be coincidental, we speculate that a gene or genes on chro-mosome 18 might play a role in the autoimmune process.

Keywords: autoimmune polyendocrinopathy; ring Ch18; type 1 diabetes mellitus.

* Corresponding author: Nina Jain, MD, Assistant Professor, Department of Pediatrics, Division of Pediatric Endocrinology, CB # 7039, 3341 MBRB, University of North Carolina, Chapel Hill, NC 27599-703, USA Phone: + 1 9199664435 , Fax: + 1 9199662423 ,E-mail: [email protected] Received June 21, 2011; accepted July 31, 2011; previously published online September 8, 2011

Introduction

The patient was a 20-year-old African-American female who was the 2820 g product of a full-term pregnancy complicated by maternal cocaine and alcohol abuse. Her postnatal medical history was notable for growth failure, chronic diarrhea due to lactose intolerance, eczema, non-anion gap metabolic acido-sis, hypotonia and developmental delay. She was referred to Pediatric Endocrinology at the University of North Carolina at 3.5 years of age with a voracious appetite, growth failure and thyroid function tests indicating hyperthyroidism.

Phenotypic features

Initial physical exam was notable for minor dysmorphic fea-tures including short stature, microcephaly with bilateral epi-canthal folds and telecanthus, posteriorly rotated ears with a small right preauricular pit, fl at nasal bridge, fl attened phil-trum, and micrognathia. She was generally hypotonic with normal deep tendon refl exes. Her stature remained well below the third percentile throughout childhood and her adult height was signifi cantly short at 139.4 cm.

Thyroid disease

When she presented at age 3.5 years, laboratory analy-sis included a serum thyroxine (T4) of 16.5 µ g/dL (nor-mal range: 4.5 – 11.5 µ g/dL), triiodothyronine (T3) of 337.5 ng/dL (normal range: 98 – 186 ng/dL), and undetectable TSH. Antimicrosomal, antithyroglobulin antibodies and thyroid stimulating immunoglobulin were negative. 123 I thyroid scan showed an enlarged thyroid gland with diffusely increased radionuclide uptake. Methimazole treatment was initiated with a satisfactory response. Within 2 months, however, the patient developed a severe skin rash and treatment was changed to propylthiouracil (PTU). During PTU treatment she again developed a severe skin rash and elevated liver enzymes. Because of hypersensitivity to antithyroid medica-tions, she underwent ablation of thyroid tissue by radioactive iodine at 4 years of age. Following radioactive iodine treat-ment, she became hypothyroid and euthyroid status was sub-sequently maintained with levothyroxine replacement.

Neurodevelopmental assessment

She had moderate mental retardation with a total develop-mental motor quotient (DMQ) with Peabody Developmental

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848 Jain et al.: Autoimmune polyendocrinopathy associated with ring chromosome 18

Motor Scales of < 69 at 3.7 years of age. This is greater than two standard deviations below the mean of 100 (SD:15).

Dermatologic fi ndings

At 9.5 years of age, she developed a large (8 cm in diameter) hypopigmented lesion on the left orbital area consistent with vitiligo. She continued to develop additional lesions consis-tent with vitiligo in different parts of the body.

Type 1 diabetes mellitus

At 10 years of age, she presented with diabetic ketoacido-sis, which was successfully treated with insulin, intravenous fl uid and electrolyte replacement. Islet cell antibodies were absent; anti-insulin antibodies were positive. She has been maintained on insulin therapy.

Immunoglobulin abnormality

Analysis at 10 years of age revealed immunoglobulin A (IgA) defi ciency (IgA < 7 mg/dL) with normal IgG (1790 mg/dL) and IgM (87 mg/dL) levels.

As an adult, the patient continued to suffer from morbid obesity with central adiposity. Secondary sexual characteris-tics, including axillary and pubic hair distribution, developed normally. She menstruates regularly. Blood pressures have remained within the normal range. She has done well on insu-lin and thyroid hormone replacement.

The clinical and laboratory evaluation to detect other potential autoimmune conditions including endocrinopathies, such as adrenal insuffi ciency and hypoparathyroidism have been negative. She did not develop adrenal antibodies.

Cytogenetic analysis

A peripheral blood karyotype showed a structurally abnormal chromosome 18. The chromosome 18 was in the form of a ring with breakpoints in the short arm, at p11.3 and in the long arm at q23 (Figure 1 ).

Discussion

Our patient has several organ-specifi c autoimmune diseases including hyperthyroidism, type 1 diabetes mellitus, and

vitiligo. She does not demonstrate any evidence of adrenal insuffi ciency and adrenal antibodies have remained negative. Similarly, there has been no evidence of hypoparathyroidism. Her fi ndings are consistent with type III autoimmune poly-glandular syndrome (APS). Patients with type III APS have the same clinical features as type II APS, but without any evi-dence of adrenal failure (1) .

The autoimmune polyglandular syndromes classifi ca-tion depends on the association of one or more autoimmune endocrinopathies with other endocrine and non-endocrine abnormalities. Three types of APS have been delineated. Type I APS, also known as autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy (APECED), is defi ned by the presence of at least two of the following diseases: chronic mucocutaneous candidiasis, acquired hypoparathy-roidism and idiopathic or autoimmune adrenal insuffi ciency. In addition, many other organ-specifi c diseases may occur simultaneously. Type I APS is an autosomal recessive disor-der due to mutation(s) in the autoimmune regulator (AIRE) gene (1) .

The criteria for type II APS include the occurrence of two or more of the following: primary adrenal insuffi ciency, hyperthyroidism or primary hypothyroidism, type 1 diabe-tes mellitus, primary hypogonadism, myasthenia gravis and celiac disease. Vitiligo, alopecia, and pernicious anemia occur with increased frequency relative to the general population. APS type II is a complex disease that is occasionally familial with more than one generation affected, and where major his-tocompatibility genes are thought to play an important role. APS type III, like APS type II, is a multifactorial disorder, with variable clinical presentation and no evidence of adrenal insuffi ciency (1) .

Autoimmune diseases are prevalent in patients with chro-mosome 18 abnormalities. The unique profi le of this associa-tion suggests that certain genes or gene groups on chromosome 18 may have specifi c functions in immune regulation. Further studies on patients with deletions or duplications of chromo-some 18 should be helpful in recognizing those genes and defi ning their functions.

Autoimmune thyroiditis has been frequently associated with both short- and long-arm deletions of chromosome 18 (2 – 5) . Vitiligo has previously been reported as a fi nd-ing in a patient with 18p- (6) . Insulin dependent diabetes has also been described in association with chromosome 18 abnormalities. Kistenmacher et al. reported a child with autoimmune thyroiditis and IDDM in association with 18p-syndrome. Gordon et al. (7) reported another case with dystonia, hypothyroidism and insulin dependent dia-betes mellitus associated with an 18q terminal deletion [46XX,del(18)(q22.2)].

A case similar to ours was reported by Dacou-Voutetakis et al. (8) with autoimmune thyroiditis at a very young age and subsequent development of insulin-dependent diabetes mel-litus. Both that case and ours have breakpoints in the short arm at p11.3 and in the long arm at q23, suggesting that the polyendocrinopathy may be related to the relatively larger size of the material deleted from both short and long arms of chromosome 18. Figure 1 Patient karyotype.



Jain et al.: Autoimmune polyendocrinopathy associated with ring chromosome 18 849

In the last 10 years, multiple linkage studies have identifi ed the IDDM6 locus, located on 18q21, to be associated with multiple autoimmune diseases including IDDM, Graves ’ s dis-ease, rheumatoid arthritis, and systemic lupus erythematosus (9, 10) . More recently, an association of a non-synonymous single nucleotide polymorphism (SNP) rs763361/Gly307Ser in the immune response gene CD226 on chromosome 18q22 with type 1 diabetes (T1D) was reported (11) . Further stud-ies by the same group provided evidence for association of Gly307Ser allele mutation in exon 7 of CD226 predisposing individuals to type 1 diabetes, multiple sclerosis and possibly autoimmune thyroid disease (12) .

Ring defects of chromosome 18 have also been reported in association with multiple endocrine abnormalities, including both congenital and autoimmune disease. Growth hormone defi ciency has been detected in two patients with r(18) (13, 14) as well as congenital hypothyroidism (15) , acquired hypo-thyroidism (8, 16) , and congenital hypoparathyroidism (17) .

IgA defi ciency has also been described in patients with both 18q and 18p deletions (18 – 20) . As of yet, however, no specifi c gene on chromosome 18 has been linked specifi cally to IgA defi ciency.

The increased incidence of autoimmune disorders in IgA defi ciency is well known (21) and suggests an association of autoimmune endocrine disorders with IgA defi ciency. Seven percent to 36 % of patients with IgA defi ciency exhibit some form of autoimmune disorder (22) . It has been suggested that IgA serves as a “silent housekeeper”. IgA secretions protect mucosal surfaces, including linings of the respiratory, gastrointestinal and genitourinary tract from exposure to and penetrance by certain antigens. In the absence of IgA, defective antigen clearance may result in immune complex deposition in organs causing infl amma-tion and tissue destruction, thus contributing to autoimmu-nity (23) . Another theory suggests that immune dysfunction may be the primary mechanism. As the production of IgA is T-cell-dependent, dysfunctional T-cells may be responsible for IgA defi ciency as well as increased autoimmunity due to autoreactive T-cells escaping thymic destruction (23) . We believe that IgA defi ciency in our patient is a coinci-dence and it is unlikely that IgA defi ciency played a pri-mary role in her developing APS. Rather her chromosomal anomalies are more likely the cause of her multiple autoim-mune disorders.

Considering this patient ’ s constellation of symptoms, we speculate that while a break with reattachment to the ring formation has been identifi ed at 18q23, it is likely that genetic mutation extends to the more proximal region includ-ing 18q21 and the site of the IDDM6 locus and/or CD226. Mutation may include small deletions and/or rearrangements which may not be readily identifi ed with traditional karyo-typing methods. While linkage studies have previously asso-ciated IDDM6 gene anomalies with IDDM and Graves ’ s disease (10) , the additional presence of IgA defi ciency sug-gests that this patient has other, not identifi ed, chromosomal mutations on chromosome 18 which are associated with IgA defi ciency. The presence of IgA defi ciency may also serve as a “second hit”, allowing exposure to antigens in individuals

with genetic predisposition to autoimmunity. These theories need to be further studied.

Patients with chromosome 18 abnormality should be closely followed for endocrine problems, particularly autoimmune thyroid disorders and IDDM.

References

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Autoimmune polyendocrinopathy associated with ring chromosome 18