Skip to main content
Erschienen in: Journal of Medical Case Reports 1/2010

Open Access 01.12.2010 | Case report

A possible new syndrome with double endocrine tumors in association with an unprecedented type of familial heart-hand syndrome: a case report

verfasst von: Masashi Demura, Takashi Yoneda, Shigehiro Karashima, Toshinori Higashikata, Hiroshi Mabuchi, Mitsuhiro Kawano, Masakazu Yamagishi, Yoshiyu Takeda

Erschienen in: Journal of Medical Case Reports | Ausgabe 1/2010

download
DOWNLOAD
print
DRUCKEN
insite
SUCHEN

Abstract

Introduction

The combination of a pituitary prolactinoma and an aldosterone-producing adrenal adenoma is extremely rare. To the best of our knowledge, double endocrine tumors in association with heart-hand syndrome have not previously been reported.

Case presentation

A 21-year-old Japanese woman presented with galactorrhea and decreased visual acuity. A large pituitary adenoma with an increased level of serum prolactin was apparent by computed tomography. She additionally showed mild hypertension (136/90 mmHg) accompanied by hypokalemia. The plasma aldosterone concentration was increased. Computed tomography showed a mass in the right adrenal gland. No other tumors were found despite extensive imaging studies. Physical and radiographic examinations showed skeletal malformations of the hands and feet, including hypoplasia of the first digit in all four limbs. An atrial septal defect was demonstrated by echocardiography. Similar digital and cardiac abnormalities were detected in our patient's father, and a clinical diagnosis of hereditary heart-hand syndrome was made.

Conclusion

No established heart-hand syndrome was wholly compatible with the family's phenotype. Her father had no obvious endocrine tumors, implying that the parent of transmission determined variable phenotypic expression of the disease: heart-hand syndrome with multiple endocrine tumors from the paternal transmission or no endocrine tumor from the maternal transmission. This suggests that the gene or genes responsible for the disease may be under tissue-specific imprinting control.
Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1752-1947-4-347) contains supplementary material, which is available to authorized users.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

MD had primary responsibility for drafting the manuscript. TY, TH, HM, and YT contributed to patient's evaluation. MD, SK, and MK performed genetic testing for HOS, and MEN1. TY, TH, HM, MY, and YT were involved in the patient's clinical assessment and treatment. All authors read and approved the final manuscript.

Introduction

The multiple endocrine neoplasia (MEN) syndrome is characterized by the occurrence of tumors involving two or more endocrine glands within a single patient. There are two major forms of MEN, type 1 and 2. MEN1 is characterized by the combined occurrence of tumors of the parathyroids, pancreatic islet cells, and anterior pituitary. MEN2 describes the association of medullary thyroid carcinoma, pheochromocytomas, and parathyroid tumors. MEN1 is caused by mutation in the MEN1 gene, while MEN2 is caused by mutation in the RET gene [1].
Heart-hand syndromes are a broad category of diseases [2]. The most common form is Holt-Oram syndrome (HOS; MIM No. 142900) caused by a loss-of-function mutation in the TBX5 gene located on chromosome 12q24.1 (heart-hand syndrome I) [3]. Diagnosis is based on skeletal abnormalities with a pre-axial radial ray distribution as well as cardiac malformations that typically include atrial and/or ventricular septal defects and arterioventricular nodal dysfunction. Skeletal malformations are limited to the upper limbs. Other forms of heart-hand syndrome have been described [48].

Case presentation

A 21-year-old Japanese woman presented to our clinic with galactorrhea and decreased visual acuity in the left eye. She was a full-term baby and was delivered after an uncomplicated pregnancy. A heart murmur was detected at age 17. She is 165 cm tall and weighs 52 kg. Physical and radiographic examinations showed skeletal malformations of the hands and feet, including hypoplasia of the first digit in all four limbs (Figure 1a,b). Symmetric phalangeal hypoplasia was observed. An atrial septal defect was demonstrated by echocardiography, with no electrocardiographic evidence of a conduction disturbance (Figure 1c). No additional clinical or radiologic abnormalities were present. Similar digital and cardiac abnormalities were detected in our patient's father (Figure 1d,e), and a clinical diagnosis of hereditary heart-hand syndrome was made. However, no established heart-hand syndrome was wholly compatible with our patient's phenotype.
The serum prolactin concentration was increased (1751 ng/mL; normal, 1.4 to 14.6), and a large pituitary adenoma was apparent on computed tomography (CT). Our patient underwent trans-sphenoidal surgery, which accomplished removal of about 50 percent of this prolactin-secreting tumor (prolactinoma). However, galactorrhea and hyperprolactinemia (200 ng/mL) persisted. Administration of bromocriptine ameliorated these abnormalities.
Our patient additionally showed stage 1 hypertension (JNC 7, 136/90 mmHg) accompanied by hypokalemia (serum potassium, 2.6 mEq/L). The plasma aldosterone concentration was increased (738.4 pg/mL; normal, 20.0 to 130.0), and plasma renin concentration was decreased (less than 2.0 pg/mL; normal, 2.5 to 21.4). CT disclosed a mass in the right adrenal gland. The tumor was resected and diagnosed histologically as adrenocortical adenoma. Hypertension, hypokalemia, and hyporeninemic hyperaldosteronemia all resolved upon resection, and a diagnosis of aldosterone-producing adenoma was made. No other tumors were found despite extensive imaging studies. The combination of prolactinoma and aldosterone-producing adenoma does not correspond to any known multiple-endocrine-tumor syndrome.
Except with respect to lower-limb abnormalities, the individuals here described closely resembled the HOS phenotype. Considering the possibility of contiguous gene syndrome, mutational analysis concerning the TBX5 gene was performed in our patient. By metaphase chromosomal analysis her karyotype was 46,XX (normal female) and G-banding of the prometaphase chromosome 12 in peripheral lymphocytes was also normal. We next analyzed transcripts of the TBX5 gene in lymphoblast cells (LBC). Only a novel splice-variant of the TBX5 mRNA omitting exon 2 (DDBJ Accession No. AB051068) was expressed in both our patient and normal subjects; direct sequencing of TBX5 cDNA from our patient's LBC disclosed no mutation. Complete gene deletion was unlikely because of absence of allelic loss on 12q24.1 as determined using a polymorphic marker of intron 2 (D12S1646). These various findings argued strongly against a mutation of the TBX5 gene.
Despite no report on identified MEN1 mutations in patients with a prolactinoma and an aldosterone-producing adenoma, the rare combination of tumors might occur in the MEN1 patients. Mutational analysis, however, showed no mutation in the MEN1 gene. She possessed two alleles of polymorphic markers of PYGM and D11S4946, showing no loss of heterozygosity on the MEN1 locus.

Conclusion

We report the case of a female patient with double endocrine tumors (prolactinoma and aldosterone-producing adenoma) in association with familial heart-hand syndrome. A combination of prolactinoma and aldosterone-producing adenoma was rare [9]. We found no mutation in the TBX5 and MEN1 genes. These findings suggested that another genetic factor was involved in the complex of double endocrine tumors, atrial septal defect and pre-axial brachydactyly in this family.
Recent studies have indicated that Tbx5 is important for normal development of the upper limb in the chick, while Tbx4 is important for the lower limb [10]. Upstream regulatory genes for TBX4 (on chromosome 16) and for TBX5 may be involved in the present case.
Prolactinoma and aldosterone-producing adenoma, an extremely rare combination of endocrine tumors, were present in the proband but not in the father (Figure 2). Many genes are imprinted in a tissue-specific manner, with monoallelic expression in some cell types and biallelic expression in others. Paternal inheritance of a mutation at some imprinted locus could lead to heart-hand syndrome plus endocrine tumors while maternal inheritance of the same mutation could lead to heart-hand syndrome without endocrine tumors.
Since inheritance of these tumors is not obvious in our proband, she may exhibit multiple genetic disorders. We, however, suspect that she had a germ-line mutation of an unknown gene associated with endocrine tumorigenesis under tissue-specific imprinting control. We speculate that a close association might exist in some other patients between a novel type of heart-hand syndrome and rare combinations of endocrine tumors.
Written informed consent was obtained from the patient and her father for publication of this case report and any accompanying images. A copy of the written consent is available for review by the journal's Editor-in-Chief.

Acknowledgements

The authors express their deepest appreciation to the patient and her family.
Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution License ( https://​creativecommons.​org/​licenses/​by/​2.​0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

MD had primary responsibility for drafting the manuscript. TY, TH, HM, and YT contributed to patient's evaluation. MD, SK, and MK performed genetic testing for HOS, and MEN1. TY, TH, HM, MY, and YT were involved in the patient's clinical assessment and treatment. All authors read and approved the final manuscript.

Unsere Produktempfehlungen

e.Med Interdisziplinär

Kombi-Abonnement

Für Ihren Erfolg in Klinik und Praxis - Die beste Hilfe in Ihrem Arbeitsalltag

Mit e.Med Interdisziplinär erhalten Sie Zugang zu allen CME-Fortbildungen und Fachzeitschriften auf SpringerMedizin.de.

© Springer Medizin

Bis 11. April 2024 bestellen und im ersten Jahr 50 % sparen!

e.Med Allgemeinmedizin

Kombi-Abonnement

Mit e.Med Allgemeinmedizin erhalten Sie Zugang zu allen CME-Fortbildungen und Premium-Inhalten der allgemeinmedizinischen Zeitschriften, inklusive einer gedruckten Allgemeinmedizin-Zeitschrift Ihrer Wahl.

© Springer Medizin

Bis 11. April 2024 bestellen und im ersten Jahr 50 % sparen!

Anhänge

Authors’ original submitted files for images

Below are the links to the authors’ original submitted files for images.
Literatur
1.
Zurück zum Zitat Thakker RV: Multiple endocrine neoplasia-syndromes of the twentieth century. J Clin Endocrinol Metab. 1998, 83 (8): 2617-2620. 10.1210/jc.83.8.2617.PubMed Thakker RV: Multiple endocrine neoplasia-syndromes of the twentieth century. J Clin Endocrinol Metab. 1998, 83 (8): 2617-2620. 10.1210/jc.83.8.2617.PubMed
2.
Zurück zum Zitat Basson CT, Solomon SD, Weissman B, MacRae CA, Poznanski AK, Prieto F, Ruiz de la Fuente S, Pease WE, Levin SE, Holmes LB, Seidman JG, Seidman CE: Genetic heterogeneity of heart-hand syndromes. Circulation. 1995, 91 (5): 1326-1329.CrossRefPubMed Basson CT, Solomon SD, Weissman B, MacRae CA, Poznanski AK, Prieto F, Ruiz de la Fuente S, Pease WE, Levin SE, Holmes LB, Seidman JG, Seidman CE: Genetic heterogeneity of heart-hand syndromes. Circulation. 1995, 91 (5): 1326-1329.CrossRefPubMed
3.
Zurück zum Zitat Li QY, Newbury-Ecob RA, Terrett JA, Wilson DI, Curtis AR, Yi CH, Gebuhr T, Bullen PJ, Robson SC, Strachan T, Bonnet D, Lyonnet S, Young ID, Raeburn JA, Buckler AJ, Law DJ, Brook JD: Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family. Nat Genet. 1997, 15 (1): 21-29. 10.1038/ng0197-21.CrossRefPubMed Li QY, Newbury-Ecob RA, Terrett JA, Wilson DI, Curtis AR, Yi CH, Gebuhr T, Bullen PJ, Robson SC, Strachan T, Bonnet D, Lyonnet S, Young ID, Raeburn JA, Buckler AJ, Law DJ, Brook JD: Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family. Nat Genet. 1997, 15 (1): 21-29. 10.1038/ng0197-21.CrossRefPubMed
4.
Zurück zum Zitat Temtamy SA, McKusick VA: The genetics of hand malformations. Birth Defects Orig Artic Ser. 1978, 14 (3): 1-619. Temtamy SA, McKusick VA: The genetics of hand malformations. Birth Defects Orig Artic Ser. 1978, 14 (3): 1-619.
5.
Zurück zum Zitat Silengo MC, Biagioli M, Guala A, Lopez-Bell G, Lala R: Heart-hand syndrome II. A report of Tabatznik syndrome with new findings. Clin Genet. 1990, 38 (2): 105-113. 10.1111/j.1399-0004.1990.tb03556.x.CrossRefPubMed Silengo MC, Biagioli M, Guala A, Lopez-Bell G, Lala R: Heart-hand syndrome II. A report of Tabatznik syndrome with new findings. Clin Genet. 1990, 38 (2): 105-113. 10.1111/j.1399-0004.1990.tb03556.x.CrossRefPubMed
6.
Zurück zum Zitat Ruiz de la Fuente S, Prieto F: Heart-hand syndrome. III. A new syndrome in three generations. Hum Genet. 1980, 55 (1): 43-47. 10.1007/BF00329125.CrossRefPubMed Ruiz de la Fuente S, Prieto F: Heart-hand syndrome. III. A new syndrome in three generations. Hum Genet. 1980, 55 (1): 43-47. 10.1007/BF00329125.CrossRefPubMed
7.
Zurück zum Zitat Sinkovec M, Petrovic D, Volk M, Peterlin B: Familial progressive sinoatrial and atrioventricular conduction disease of adult onset with sudden death, dilated cardiomyopathy, and brachydactyly. A new type of heart-hand syndrome?. Clin Genet. 2005, 68 (2): 155-160. 10.1111/j.1399-0004.2005.00476.x.CrossRefPubMed Sinkovec M, Petrovic D, Volk M, Peterlin B: Familial progressive sinoatrial and atrioventricular conduction disease of adult onset with sudden death, dilated cardiomyopathy, and brachydactyly. A new type of heart-hand syndrome?. Clin Genet. 2005, 68 (2): 155-160. 10.1111/j.1399-0004.2005.00476.x.CrossRefPubMed
8.
Zurück zum Zitat Nemec J, Heifetz S: Persistence of left supracardinal vein in an adult patient with heart-hand syndrome and cardiac pacemaker. Congenit Heart Dis. 2008, 3 (3): 219-222. 10.1111/j.1747-0803.2008.00147.x.CrossRefPubMed Nemec J, Heifetz S: Persistence of left supracardinal vein in an adult patient with heart-hand syndrome and cardiac pacemaker. Congenit Heart Dis. 2008, 3 (3): 219-222. 10.1111/j.1747-0803.2008.00147.x.CrossRefPubMed
9.
Zurück zum Zitat Demura R, Naruse M, Isawa M, Onoda N, Naruse K, Yamakado M, Demura H: A patient with a prolactinoma associated with an aldosterone producing adrenal adenoma: differences in dopaminergic regulation of PRL and aldosterone secretion. Endocrinol Jpn. 1992, 39 (2): 169-176.CrossRefPubMed Demura R, Naruse M, Isawa M, Onoda N, Naruse K, Yamakado M, Demura H: A patient with a prolactinoma associated with an aldosterone producing adrenal adenoma: differences in dopaminergic regulation of PRL and aldosterone secretion. Endocrinol Jpn. 1992, 39 (2): 169-176.CrossRefPubMed
10.
Zurück zum Zitat Takeuchi JK, Koshiba-Takeuchi K, Matsumoto K, Vogel-Hopker A, Naitoh-Matsuo M, Ogura K, Takahashi N, Yasuda K, Ogura T: Tbx5 and Tbx4 genes determine the wing/leg identity of limb buds. Nature. 1999, 398 (6730): 810-814. 10.1038/19762.CrossRefPubMed Takeuchi JK, Koshiba-Takeuchi K, Matsumoto K, Vogel-Hopker A, Naitoh-Matsuo M, Ogura K, Takahashi N, Yasuda K, Ogura T: Tbx5 and Tbx4 genes determine the wing/leg identity of limb buds. Nature. 1999, 398 (6730): 810-814. 10.1038/19762.CrossRefPubMed
Metadaten
Titel
A possible new syndrome with double endocrine tumors in association with an unprecedented type of familial heart-hand syndrome: a case report
verfasst von
Masashi Demura
Takashi Yoneda
Shigehiro Karashima
Toshinori Higashikata
Hiroshi Mabuchi
Mitsuhiro Kawano
Masakazu Yamagishi
Yoshiyu Takeda
Publikationsdatum
01.12.2010
Verlag
BioMed Central
Erschienen in
Journal of Medical Case Reports / Ausgabe 1/2010
Elektronische ISSN: 1752-1947
DOI
https://doi.org/10.1186/1752-1947-4-347

Weitere Artikel der Ausgabe 1/2010

Journal of Medical Case Reports 1/2010 Zur Ausgabe