RSS-Feed abonnieren
DOI: 10.1055/s-0031-1286358
© Georg Thieme Verlag KG Stuttgart · New York
Hereditäre Formen des primären Hyperparathyreoidismus
MEN1, MEN2, HPT-JT, FHH, FIHPTHereditary variants of primary hyperparathyroidismMEN1, MEN2, HPT-JT, FHH, FIHPTPublikationsverlauf
eingereicht: 2.2.2011
akzeptiert: 19.5.2011
Publikationsdatum:
13. September 2011 (online)

Zusammenfassung
Hintergrund: Die Herausforderung in der Diagnostik des primären Hyperparathyreoidismus (pHPT) besteht darin, die etwa 5 % hereditären Fälle präoperativ zu diagnostizieren. Neben den multiplen endokrinen Neoplasien Typ 1 und 2 (MEN1/MEN2) sollte an das Hyperparathyreoidismus-Kiefertumor-Syndrom (HPT-JT, hyperparathyroidism jaw tumor), an die familiäre hypokalziurische Hyperkalziämie (FHH) und an den familiären isolierten Hyperparathyreoidismus (FIHPT) gedacht werden. Ziel der Arbeit ist es, die Unterschiede und Gemeinsamkeiten der hereditären Formen des pHPT zu untersuchen.
Patienten und Methoden: Retrospektive Fallserie (1980 – 2010) von 80 Patienten mit hereditärem pHPT. Angaben zum klinischen Befund und Verlauf, Familienanamnese, Therapie, Labor und zur molekulargenetischen Diagnostik wurden erhoben.
Ergebnisse: Unter 80 Patienten mit hereditärem pHPT hatten 52 eine MEN1, 15 eine MEN2, 7 ein HPT-JT und 4 eine FHH sowie 2 ein FIHPT. Die höchste Penetranz des pHPT kommt beim MEN1 vor (85 %), gefolgt von HPT-JT (64 %), FHH (28,5 %) und MEN2 (8 %). Die jüngsten Patienten finden sich in der MEN2/HPT-JT-Gruppe mit 7 bzw. 16 Jahren bei Diagnose des pHPT. Den höchsten Kalzium-Spiegel hatten Patienten mit HPT-JT-Syndrom mit im Mittel 3,6 mM, die höchste Rezidiv-Rate gab es in der MEN1-Gruppe (40,5 %). Nebenschilddrüsenkarzinome kamen ausschließlich beim HPT-JT-Syndrom vor. Auch bei der FHH entwickelt sich in Einzelfällen ein pHPT.
Folgerungen: Unter den Formen des hereditären pHPT ist die MEN1 die häufigste mit der höchsten Rezidivrate. Eine frühe Diagnose des HPT-JT-Syndroms ist wegen des Auftretens des Nebenschilddrüsenkarzinoms wichtig. Auch bei der FHH gibt es in Einzelfällen einen pHPT. Die präoperative Diagnosesicherung des hereditären pHPT hat therapeutische Konsequenzen für die Art der zu planenden OP und Implikationen für den betroffenen Patienten und seine Verwandten.
Abstract
Objective: The challenge in diagnosing primary hyperparathyroidism (HPT) is to detect hereditary cases before first surgery. About 5 % of cases are hereditary and integral component of multiple endocrine neoplasia type 1 and 2 (MEN1/MEN2), hyperparathyroidism-jaw tumor syndrome (HPT-JT), familial hypocalciuric hypercalcemia (FHH), and familial isolated hyperparathyroidism (FIHPT). Aim of this study was to evaluate similarities and differences in hereditary varieties of HPT.
Patients: 80 patients with hereditary HPT were evaluated in a retrospective analysis between 1980 and 2010 concerning clinical findings, family history, therapy, biochemical and molecular-genetic findings and follow-up.
Results: 80 patients with hereditary HPT are described, 52 belonged to MEN1, 15 to MEN2, 7 to HPT-JT, 4 to FHH and 2 to FIHPT kindreds. Penetrance of HPT was highest in MEN1 (85 %), followed by HPT-JT (64 %), FHH (28.5 %), and MEN2 (8 %). Youngest age at diagnosis of HPT was 7 and 16 years in the MEN2/HPT-JT group. Serum Calcium was highest in the HPT-JT group (3.6 mM), recurrencies of HPT were highest in the MEN1 group (40.5 %). Parathyroid cancer solely occurred in the HPT-JT group. In single cases HPT occurs in FHH.
Conclusion: Among the different varieties of hereditary HPT MEN1-HPT is most frequent and carries the utmost recurrence rate. Early diagnosis of HPT-JT syndrome is important because of the occurrence of parathyroid cancer. Single cases of HPT in FHH are described. Preoperative diagnosis of hereditary HPT has therapeutic consequences concerning extent of surgery and implications concerning patient and family care.
Schlüsselwörter
hereditärer Hyperparathyreoidismus - MEN1 - MEN2 - HPT-JT - FHH - FIHPT - Nebenschilddrüsenkarzinom
Keywords
hereditary hyperparathyroidism - MEN1 - MEN2 - HPT-JT - FHH - FIHPT - parathyroid carcinoma
Literatur
- 1
Bilezikian J P, Khan A A, Potts Jr J T.
Guidelines for the
management of asymptomatic primary hyperparathyroidism: summary
statement from the third international workshop.
J Clin
Endocrinol Metab.
2009;
94
335-339
MissingFormLabel
- 2
Brandi M L, Gagel R F, Angeli A. et al .
Guidelines for diagnosis and therapy of
MEN type 1 and type 2.
J Clin Endocrinol Metab.
2001;
86
5658-5671
MissingFormLabel
- 3
Carling T, Szabo E, Bai M. et
al .
Familial hypercalcemia and hypercalciuria caused
by a novel mutation in the cytoplasmic tail of the calcium receptor.
J Clin Endocrinol Metab.
2000;
85
2042-2047
MissingFormLabel
- 4
Carpten J D, Robbins C M, Villablanca A. et al .
HRPT2, encoding parafibromin,
is mutated in hyperparathyroidism-jaw tumor syndrome.
Nat
Genet.
2002;
32
676-680
MissingFormLabel
- 5
Chandrasekharappa S C, Guru S C, Manickam P. et al .
Positional cloning of the
gene for multiple endocrine neoplasia-type 1.
Science.
1997;
276
404-407
MissingFormLabel
- 6
Frank-Raue K, Haag C, Schulze E. et al .
CDC73-related hyperparathyroidism: five
new mutations and the clinical spectrum.
Eur J Endocrinol.
2011;
165
477-483
MissingFormLabel
- 7
Frank-Raue K, Hoppner W, Frilling A. et al .
Mutations of the ret protooncogene in German
multiple endocrine neoplasia families: relation between genotype
and phenotype. German Medullary Thyroid Carcinoma Study Group.
J Clin Endocrinol Metab.
1996;
81
1780-1783
MissingFormLabel
- 8
Frank-Raue K, Leidig-Bruckner G, Haag C. et al .
Inactivating calcium-sensing receptor mutations
in patients with primary hyperparathyroidism.
Clin Endocrinol
(Oxf).
2011;
75
50-55
MissingFormLabel
- 9
Frank-Raue K, Rondot S, Hoeppner W. et al .
Coincidence of multiple endocrine neoplasia
types 1 and 2: mutations in the RET protooncogene and MEN1 tumor
suppressor gene in a family presenting with recurrent primary hyperparathyroidism.
J Clin Endocrinol Metab.
2005;
90
4063-4067
MissingFormLabel
- 10
Frank-Raue K, Rybicki L A, Erlic Z. et al .
Risk profiles and penetrance estimations
in multiple endocrine neoplasia type 2A caused by germline RET mutations
located in exon 10.
Hum Mutat.
2010;
32
51-58
MissingFormLabel
- 11
Hannan F M, Nesbit M A, Christie P T. et al .
A homozygous inactivating
calcium-sensing receptor mutation, Pro339Thr, is associated with
isolated primary hyperparathyroidism: correlation between location
of mutations and severity of hypercalcaemia.
Clin Endocrinol
(Oxf).
2010;
73
715-722
MissingFormLabel
- 12
Kloos R T, Eng C, Evans D B. et al .
Medullary thyroid cancer: management guidelines
of the American Thyroid Association.
Thyroid.
2009;
19
565-612
MissingFormLabel
- 13
Lourenco Jr D M, Coutinho F L, Toledo R A. et al .
Early-onset, progressive, frequent,
extensive, and severe bone mineral and renal complications in multiple
endocrine neoplasia type 1-associated primary hyperparathyroidism.
J Bone Miner Res.
2010;
25
2382-2391
MissingFormLabel
- 14
Machens A, Schaaf L, Karges W. et al .
Age-related penetrance of endocrine tumours
in multiple endocrine neoplasia type 1 (MEN1): a multicentre study
of 258 gene carriers.
Clin Endocrinol (Oxf).
2007;
67
613-622
MissingFormLabel
- 15
Marx S J, Attie M F, Levine M A. et al .
The hypocalciuric or benign
variant of familial hypercalcemia: clinical and biochemical features
in fifteen kindreds.
Medicine (Baltimore).
1981;
60
397-412
MissingFormLabel
- 16
Marx S J, Simonds W F, Agarwal S K. et al .
Hyperparathyroidism in hereditary
syndromes: special expressions and special managements.
J
Bone Miner Res.
2002;
17
(S2)
N37-43
MissingFormLabel
- 17
Miedlich S, Lohmann T, Schneyer U, Lamesch P, Paschke R.
Familial isolated primary hyperparathyroidism-a multiple endocrine
neoplasia type 1 variant?.
Eur J Endocrinol.
2001;
145
155-160
MissingFormLabel
- 18
Pollak M R, Brown E M, Chou Y H. et al .
Mutations in the human Ca(2+)-sensing
receptor gene cause familial hypocalciuric hypercalcemia and neonatal
severe hyperparathyroidism.
Cell.
1993;
75
1297-1303
MissingFormLabel
- 19
Raue F, Haag C, Frank-Raue K.
Hyperparathyroidism-jaw tumor syndrome. A hereditary form of
primary hyperparathyroidism with parathyroid carcinoma.
Dtsch
Med Wochenschr.
2007;
132
1459-1462
MissingFormLabel
- 20
Raue F, Haag C, Schulze E, Frank-Raue K.
The role of the extracellular calcium-sensing
receptor in health and disease.
Exp Clin Endocrinol Diabetes.
2006;
114
397-405
MissingFormLabel
- 21
Raue F, Kraimps J L, Dralle H. et al .
Primary hyperparathyroidism in multiple
endocrine neoplasia type 2A.
J Intern Med.
1995;
238
369-373
MissingFormLabel
- 22
Schaaf L, Pickel J, Zinner K. et al .
Developing effective screening strategies in
multiple endocrine neoplasia type 1 (MEN 1) on the basis of clinical and
sequencing data of German patients with MEN 1.
Exp Clin
Endocrinol Diabetes.
2007;
115
509-517
MissingFormLabel
- 23
Schuffenecker I, Billaud M, Calender A. et al .
RET proto-oncogene mutations in French
MEN 2A and FMTC families.
Hum Mol Genet.
1994;
3
1939-1943
MissingFormLabel
- 24
Simonds W F, James-Newton L A, Agarwal S K. et al .
Familial isolated
hyperparathyroidism: clinical and genetic characteristics of 36
kindreds.
Medicine (Baltimore).
2002;
81
1-26
MissingFormLabel
- 25
Steiner A L, Goodman A D, Powers S R.
Study of a kindred with pheochromocytoma,
medullary thyroid carcinoma, hyperparathyroidism and Cushing’s
disease: multiple endocrine neoplasia, type 2.
Medicine
(Baltimore).
1968;
47
371-409
MissingFormLabel
- 26
Szabo E, Hellman P, Lundgren E, Carling T, Rastad J.
Parathyroidectomy in familial hypercalcemia with clinical characteristics
of primary hyperparathyroidism and familial hypocalciuric hypercalcemia.
Surgery.
2002;
131
257-263
MissingFormLabel
- 27
Teh B T, Farnebo F, Twigg S. et al .
Familial isolated hyperparathyroidism maps
to the hyperparathyroidism-jaw tumor locus in 1q21-q32 in a subset
of families.
J Clin Endocrinol Metab.
1998;
83
2114-2120
MissingFormLabel
- 28
Tham E, Grandell U, Lindgren E. et al .
Clinical testing for mutations in the MEN1
gene in Sweden: a report on 200 unrelated cases.
J Clin
Endocrinol Metab.
2007;
92
3389-3395
MissingFormLabel
- 29
Tonelli F, Marcucci T, Giudici F, Falchetti A, Brandi M L.
Surgical approach in hereditary hyperparathyroidism.
Endocr
J.
2009;
56
827-841
MissingFormLabel
- 30
Ventz M, Quinkler M.
Primary hyperparathyroidism.
Dtsch Med Wochenschr.
2010;
135
2024-2030
MissingFormLabel
- 31
Warner J, Epstein M, Sweet A. et al .
Genetic testing in familial isolated hyperparathyroidism:
unexpected results and their implications.
J Med Genet.
2004;
41
155-160
MissingFormLabel
- 32
Wermer P.
Genetic aspects of adenomatosis of endocrine glands.
Am
J Med.
1954;
16
363-371
MissingFormLabel
Priv. Doz. Dr. med. Karin Frank-Raue
Endokrinologische Gemeinschaftspraxis und molekulargenetisches
Labor
Brückenstraße 21
69120
Heidelberg
Telefon: 06221/4390-90
Fax: 06221/4390-99
eMail: karin.frankraue@raue-endokrinologie.de