help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2008-1210
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints, Permissions and Rights
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hemminki, K.
Right arrow Articles by Sundquist, K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hemminki, K.
Right arrow Articles by Sundquist, K.
Related Collections
Right arrow Adrenal and Hypertension
Right arrow Neuroendocrinology and Pituitary
Right arrow Autoimmunity
Right arrow Calcium and Bone Metabolism
The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 12 4755-4758
Copyright © 2008 by The Endocrine Society

Familial Risks for Hospitalization with Endocrine Diseases

Kari Hemminki, Xiaochen Shu, Xinjun Li, Jianguang Ji, Jan Sundquist and Kristina Sundquist

Division of Molecular Genetic Epidemiology (K.H.), German Cancer Research Center, D-69120 Heidelberg, Germany; and Center for Family and Community Medicine (K.H., X.S., X.L., J.J., J.S., K.S.), Karolinska Institute, 141 83 Huddinge, Sweden

Address all correspondence and requests for reprints to: K. Hemminki, Division of Molecular Genetic Epidemiology, German Cancer Research Center, Im Neuenheimer Feld 580, D-69120 Heidelberg, Germany. E-mail: k.hemminki{at}dkfz.de; or X. Shu, Center for Family and Community Medicine, Karolinska Institute, 141 83 Huddinge, Sweden. E-mail: xiaochen.shu{at}ki.se


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Familial clustering of a disease is an indicator of a possible heritable cause. In the era of genome scans, the consideration of data on heritability should be important in the assessment of the likely success of the scans.

Object: The objective of the study was to carry out a family study on nonthyroid endocrine diseases to search familial clustering of these diseases beyond the known syndromes.

Design and Setting: The Swedish Multigeneration Register on 0- to 72-yr-old subjects was linked to the Hospital Discharge Register from years 1964 to 2004.

Main Outcome Measure: Standardized incidence ratios were calculated for offspring of affected parents and siblings by comparing with those whose relatives had no hospitalization for nonthyroid endocrine diseases.

Results: A total of 11,948 hospitalized cases and 443 familial cases were identified. The familial standardized incidence ratios were increased for parathyroid, pituitary, and adrenal hyperfunctions and hypofunctions, some findings consistent with known syndromes, most clearly that for adrenal cortical hypofunction showing recessive inheritance described for autoimmune polyendocrine syndrome 1. The sibling risks were very high for many diseases, but some of these affecting young individual may be due to bias caused by selective hospitalization. A high sibling risk observed for anterior pituitary hypofunction may represent a yet-unknown recessive syndrome.

Conclusions: To our knowledge this is a first population-based study on nonthyroid endocrine diseases. The results call for further studies to sort out the challengingly high sibling risk for many individual nonthyroid endocrine diseases, whether they are due to bias or possible recessive effects.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
Non-thyroid endocrine diseases constitute hypersecretory and hyposecretory subtypes, most of which are diagnosed as sporadic disease. The reasons for familial nonthyroid endocrine diseases include several known syndromes, many of which present with an associated hypertrophy or tumors or with autoimmune conditions; examples include {alpha}-subunit pituitary tumors and adrenal adenoma in Cushing’s syndrome (1, 2). Our interest in nonthyroid endocrine diseases was kindled through our review of familial risks of all major diseases based on the Swedish Multigeneration Register and the Hospital Discharge Register (3). The sibling relative risk for nonthyroid endocrine diseases was highest of the surveyed disease subtypes (3). In the present analysis we wanted to examine what disease subtypes constitute hospitalized nonthyroid endocrine diseases and how high the related familial risks are. We cover familial nonthyroid endocrine diseases of the parathyroid, pituitary, adrenal and some other glands as they are reported in the hospital discharges from year 1969 onwards. To discern known syndromes we cover also tumors of the thyroid and other organs in family members.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
A nonthyroid endocrine diseases research database was constructed by linking several national Swedish registers. In the Multigeneration Register, persons born in Sweden in 1932 and later (second generation) were linked to their parents (first generation), registered shortly after birth. Families could be defined by linking all the children to their parents. Siblingships could be defined only for the second generation. Linkages were carried out to national census data to obtain individual socioeconomic status. The final links were made by adding individual data from the Hospital Discharge Register that is an administrative database recording all discharges after a minimal stay of 1 night with dates of hospitalization and discharge diagnoses since 1964 with a complete nationwide coverage since 1986. All linkages were performed by the use of the individual national identification number. Each individual was entered only once, for his first appearance with a defined diagnosis. More than 11.5 million individuals in More than 3.5 million families were included in this database; 8.9 million individuals belonged to the second generation, which had reached age 72 yr (4).

Nonthyroid endocrine diseases were retrieved from hospital discharges using the appropriate disease codes. Person-years were calculated from start of follow-up on January 1, 1969, first immigration year or birth year, whichever was later, until hospitalization/diagnosis of disease, death, emigration, or closing date on December 31, 2004, whichever was earlier. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated for familial risks as the ratio of observed to expected number of cases. The expected number of cases was calculated for age (5 yr groups), sex, period (5 yr groups), region, and socioeconomic status-specific standard incidence rates (5, 6). Separate familial risks were calculated for offspring whose parents were affected (sibling not affected), siblings (parents not affected), and offspring whose parents and at least another sibling were affected.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The numbers of the covered nonthyroid endocrine diseases cases, median years of diagnosis, and median ages of diagnosis are shown in Table 1Go. Hyperparathyroidism and anterior pituitary hypofunction were the most common diagnoses, and they also included the largest numbers of familial cases. Even adrenal cortical dysfunction was diagnosed in more than 1000 patients. The median age at diagnosis was always lower in familial compared with sporadic patients. The differences were particularly large for posterior pituitary hypofunction (familial age 3 yr, sporadic age 32 yr) and adrenal cortical hyperfunction (familial age 4 yr, sporadic age 32 yr).


View this table:
[in this window]
[in a new window]

  		TABLE 1. Number of cases with and without family history and median year and age at diagnosis

 
Significant familial risks for individual nonthyroid endocrine diseases subtypes are shown in Table 2Go. The SIR was 3.91 for concordant hyperparathyroidism between offspring and parents, and it was 7.88 among siblings. In multiplex families (sibling and parent as probands, data not shown), the SIR was 210 (n = 31, 95% CI 142–298); in three multiplex families, there were three affected siblings each; among 31 affected siblings in the multiplex families, eight were diagnosed with parathyroid adenoma and two with insulinoma; among 28 parents, 10 were diagnosed with parathyroid adenoma and five with insulinoma. No increase in thyroid tumors was noted. For hyperparathyroidism in siblings, an association was noted with hypoparathyroidism (SIR 7.06). Offspring hyperparathyroidism was also increased when parents were diagnosed with adrenal cortical hyperfunction (SIR 4.52). Familial risks were increased for concordant hypoparathyroidism when parents (SIR 24.90) or siblings (333.01) were probands. Hypoparathyroidism in one sibling associated with adrenal cortical hypofunction in another sibling (SIR 34.56).


View this table:
[in this window]
[in a new window]

  		TABLE 2. SIRs for nonthyroid endocrine diseases in offspring when parents and siblings were used as probands

 
The SIR was 9.24 for concordant anterior pituitary hyperfunction between offspring and parents (Table 2Go); there was a significant increase in pheochromocytomas in these families. Anterior pituitary hyperfunction was also increased in offspring when parents were diagnosed with hyperparathyroidism (SIR 2.22). Familial risks were increased for concordant anterior pituitary hypofunction among siblings (37.90). Only one of 114 affected siblings was diagnosed with cancer (nervous system) and no more than six cancers (esophagus, breast, and thyroid, two each) were diagnosed in 114 parents. A discordant sibling risk of 20.60 was found for fraternal testicular hypofunction. Adrenal cortical hyperfunction showed a high familial risk for offspring of affected parents (SIR 8.94) and siblings (249.28). Hyperfunction in one sibling also associated with hypofunction in another (SIR 26.92). Also, concordant adrenal cortical hypofunction showed a high familial risk for offspring of affected parents (SIR 8.27) and siblings (51.85). In siblings adrenal cortical hypofunction associated with hypoparathyroidism (SIR 22.58) and adrenal cortical hyperfunction (SIR 18.58).

We analyzed familial risks, even for other types of nonthyroid endocrine diseases, but because of the small numbers, the results were not tabulated. The only familial association for posterior pituitary dysfunction was the increase sibling risk for concordant hypofunction (n = 6, SIR 100, 95% CI 36–220). Concordant adrenomedullary hyperfunction showed a SIR of 102 in offspring of affected parents (n = 4, 95% CI 27–270) and 3100 in multiplex families (n = 4, 95% CI 810-8100). An increase in renal cancers was noted in family members of these patients. Concordant hypothalamic dysfunction showed a high SIR of 18,000, but only one sibling pair was noted. Sibling risks were increased for the following concordant diseases: polycystic ovarian disease (n = 4, SIR 680, 95% CI 180–1800), testicular hypofunction (n = 4, SIR 460, 95% CI 120–1200), and Cushing’s syndrome (n = 2, SIR 15, 95% CI 1.4–54).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The diagnostics of nonthyroid endocrine diseases have changed over time, and the present study was dependent on hospital discharge diagnoses, usually rendered in specialist wards. The observed very high familial risks are a witness to diagnostic accuracy because any false diagnoses would dilute the findings toward null. Moreover, many known familial syndromes can be discerned through the presentation of nonthyroid endocrine diseases and the related cancers. For example, familial risks in hyperparathyroidism associated with anterior pituitary hyperfunction and parathyroid adenomas and insulinomas signal multiple endocrine neoplasia (MEN) 1 (1, 2). Similarly, association of adrenomedullary hyperfunction with renal cancers could relate to von Hippel Lindau disease and that of anterior pituitary hyperfunction with pheochromocytoma could be part of MEN2.

Primary hyperparathyroidism is one of the most common endocrine disorders and it was the most common diagnosis in the present series. The familial forms may be associated with MEN1 and MEN2 syndromes and an unrelated familial type often presenting with jaw tumors; these are autosomal dominant diseases with MEN1, receptor tyrosine kinase, and hyperparathyroidism as associated genes. MEN syndromes manifest various endocrine tumors and biochemical evidence of hyperparathyroidism, manifesting through hypercalcemia in a large majority of the affected individuals (1). Primary hyperparathyroidism is associated with a number of nonendocrine tumors, such as breast, colon, kidney, and skin cancers (7). Familial hypoparathyroidism is usually an autoimmune disorder affecting multiple endocrine organs. In the present analysis, there was a cooccurrence of hypoparathyroidism with adrenal cortical hypofunction, which could be due to an autoimmune condition.

Diseases of the pituitary gland included, combined, the largest number of patients. Pituitary diseases may involve oversecretion or undersecretion of pituitary hormones. Pituitary adenomas, most of which are benign, are diagnosed in increasing numbers in nonsymptomatic patients due to advance imaging techniques (8, 9). Oversecretion is often caused by pituitary adenomas, which are manifested in two syndromes, MEN1 and Carney complex (1). Carney complex is very rare, featuring endocrine, cutaneous, and neural tumors (1). Familial aggregation of pituitary adenomas is known beyond these syndromes (10, 11). Vierimaa et al. (12) identified germline mutations in the aryl hydrocarbon receptor interacting protein gene in patients diagnosed with pituitary adenoma. The large number of siblings (114) diagnosed with anterior pituitary hypofunction appears to suggest a novel familial aggregation, unrelated to any cancer risk; however, this finding could also be related to familial isolated pituitary adenoma with or without gonadal hypofunction (10, 12). Even though young siblings could be preferentially hospitalized, the diagnostics would be based on endocrinological examination. The median year of hospital discharge for familial patients was 1993, by which time basic endocrine diagnostics of pituitary hypofunction were available in the Swedish hospitals. The association of anterior pituitary hypofunction with testicular hypofunction could be due to hyperprolactinemia, which may result from stalk section effects in nonhormone producing tumors (1).

The very high risk of adrenal cortical hyperfunction may not signal recessive inheritance, but it may be due to selective hospitalization. The SIR of 8.94 for offspring of affected parents together with the high sibling risk provide evidence of a familial aggregation that may be due to some of the known syndromes, such as Cushing’s syndrome or primary adrenocortical nodular hyperplasia or many syndromes manifesting adrenocortical tumors (13). The familial aggregation of both hyperfunction and hypofunction may be due to tumors with various hormone-secreting characteristics or medical intervention leading to hypofunction in one sibling. Autoimmune Addison disease is the most common cause of adrenal cortical hypofunction, and it may be part of autoimmune polyendocrine syndrome 1 (APS1), which also affects parathyroid; this syndrome is caused by dysfunctioning autoimmune regulator protein encoded by the AIRE gene (14, 15, 16). APS1 shows autosomal recessive inheritance with a variable age of presentation of Addison disease, ranging from 6 months to 40 yr (15, 17). In the present series, the median diagnostic age for familial adrenal cortical hypofunction was 29 yr; an undefined proportion of the patients were APS1 patients. The sibling SIR (51.85) clearly exceeded that of offspring of affected parents (8.27), making a strong case for a recessive condition, and the association with hypoparathyroidism (sibling SIR 22.58) strengthened the likelihood of APS1 diagnosis.

Many of the above associations can be, at least in part, explained by known endocrine syndromes, but what novel aspects do our data offer? First, we have provided population-level familial risks for nonthyroid endocrine diseases and note that they were very high compared with most other diseases for which such data are available (3). Second, for many of the nonthyroid endocrine diseases, sibling risks vastly exceeded the risks for offspring and parents, which should alert clinicians to search for recessive conditions. Third, the increased familial risks for the large number of siblings diagnosed with anterior pituitary hypofunction may be associated with a novel familial aggregation, which does not appear to carry a risk of cancer. Finally, the high familial risks indicate that in the clinical setting, it will be useful to inquire about a family history even though the disease presentation does not directly propose a syndromatic case.


   Acknowledgments
 
We thank professor Jan Zedenius for comments. The used database was created by linking registers maintained at Statistics Sweden and the Swedish Cancer Registry.


   Footnotes
 
This work was supported by Deutsche Krebshilfe, the Swedish Cancer Society, The Swedish Council for Working Life and Social Research, and European Union Grant LSHC-CT-2004-503465.

Disclosure Statement: The authors have nothing to disclose.

First Published Online September 30, 2008

Abbreviations: APS1, Autoimmune polyendocrine syndrome 1; CI, confidence interval; MEN, multiple endocrine neoplasia; SIR, standardized incidence ratio.

Received June 4, 2008.

Accepted September 18, 2008.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. DeLellis R, Lloyd R, Heitz P, Eng C 2004 Pathology, genetics of tumours of endocrine origin. Lyon, France: IARC Press
  2. Marx SJ, Simonds WF 2005 Hereditary hormone excess: genes, molecular pathways, and syndromes. Endocr Rev 26:615–661[Abstract/Free Full Text]
  3. Hemminki K, Li X, Sundquist K, Sundquist J 2008 Familial risks for common diseases: etiologic clues and guidance to gene identification. Mutat Res 658:247–258[CrossRef][Medline]
  4. Hemminki K, Granström C, Sundquist J, Lorenzo Bermejo J 2006 The updated Swedish family-cancer database used to assess familial risks of prostate cancer during rapidly increasing incidence. Heredit Cancer Clin Pract 4:186–192
  5. Hemminki K, Vaittinen P, Dong C, Easton D 2001 Sibling risks in cancer: clues to recessive or X-linked genes? Br J Cancer 84:388–391[CrossRef][Medline]
  6. Hemminki K, Li X, Sundquist K, Sundquist J 2007 Familial risks for asthma among twins and other siblings based on hospitalizations in Sweden. Clin Exp Allergy 37:1320–1325[CrossRef][Medline]
  7. Nilsson IL, Zedenius J, Yin L, Ekbom A 2007 The association between primary hyperparathyroidism and malignancy: nationwide cohort analysis on cancer incidence after parathyroidectomy. Endocr Relat Cancer 14:135–140[Abstract/Free Full Text]
  8. Asa SL, Ezzat S 2002 The pathogenesis of pituitary tumours. Nat Rev Cancer 2:836–849[CrossRef][Medline]
  9. Ezzat S, Asa SL, Couldwell WT, Barr CE, Dodge WE, Vance ML, McCutcheon IE 2004 The prevalence of pituitary adenomas: a systematic review. Cancer 101:613–619[CrossRef][Medline]
  10. Daly AF, Jaffrain-Rea ML, Ciccarelli A, Valdes-Socin H, Rohmer V, Tamburrano G, Borson-Chazot C, Estour B, Ciccarelli E, Brue T, Ferolla P, Emy P, Colao A, De Menis E, Lecomte P, Penfornis F, Delemer B, Bertherat J, Wemeau JL, De Herder W, Archambeaud F, Stevenaert A, Calender A, Murat A, Cavagnini F, Beckers A 2006 Clinical characterization of familial isolated pituitary adenomas. J Clin Endocrinol Metab 91:3316–3323[Abstract/Free Full Text]
  11. Hemminki K, Forsti A, Ji J 2007 Incidence and familial risks in pituitary adenoma and associated tumors. Endocr Relat Cancer 14:103–109[Abstract/Free Full Text]
  12. Vierimaa O, Georgitsi M, Lehtonen R, Vahteristo P, Kokko A, Raitila A, Tuppurainen K, Ebeling TM, Salmela PI, Paschke R, Gundogdu S, De Menis E, Makinen MJ, Launonen V, Karhu A, Aaltonen LA 2006 Pituitary adenoma predisposition caused by germline mutations in the AIP gene. Science 312:1228–1230[Abstract/Free Full Text]
  13. Libe R, Fratticci A, Bertherat J 2007 Adrenocortical cancer: pathophysiology and clinical management. Endocr Relat Cancer 14:13–28[Abstract/Free Full Text]
  14. Davidson A, Diamond B 2001 Autoimmune diseases. N Engl J Med 345:340–350[Free Full Text]
  15. Betterle C, Zanchetta R 2003 Update on autoimmune polyendocrine syndromes (APS). Acta Biomed 74:9–33[Medline]
  16. Betterle C, Coco G, Zanchetta R 2005 Adrenal cortex autoantibodies in subjects with normal adrenal function. Best Pract Res Clin Endocrinol Metab 19:85–99[CrossRef][Medline]
  17. Rizzi M, Ferrera F, Filaci G, Indiveri F 2006 Disruption of immunological tolerance: role of AIRE gene in autoimmunity. Autoimmun Rev 5:145–147[CrossRef][Medline]



This article has been cited by other articles:


Home page
 Eur J EndocrinolHome page
K. Hemminki, X. Shu, X. Li, J. Ji, K. Sundquist, and J. Sundquist
Familial risks for hospitalized Graves' disease and goiter
Eur. J. Endocrinol., October 1, 2009; 161(4): 623 - 629.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints, Permissions and Rights
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hemminki, K.
Right arrow Articles by Sundquist, K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hemminki, K.
Right arrow Articles by Sundquist, K.
Related Collections
Right arrow Adrenal and Hypertension
Right arrow Neuroendocrinology and Pituitary
Right arrow Autoimmunity
Right arrow Calcium and Bone Metabolism

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals