Genetic analyses in familial isolated hyperparathyroidism: implication for clinical assessment and surgical management.
OBJECTIVE
Familial isolated primary hyperparathyroidism (FIPH) can result from either incomplete expression of a syndromic form of familial primary hyperparathyroidism [multiple endocrine neoplasia type 1 (MEN 1), hyperparathyroidism-jaw tumour syndrome (HPT-JT) or familial hypocalciuric hypercalcaemia (FHH)] or still unrecognized causes. Design Genetic analyses of MEN1, HRPT2 and CASR genes in FIHP.


METHODS
Seven well-characterized Italian kindreds with FIHP, with negative clinical features for MEN 1, HPT-JT and FHH. The mean age (+/- SD) at diagnosis was 45 +/- 17 years (range 18-70 years) in the probands and 42 +/- 18 years (range 15-69 years) in the other affected subjects.


METHODS
Direct sequencing of germline DNA of the MEN1, HRPT2 and CASR genes from probands. The region of interest was amplified in some family members.


RESULTS
Germline MEN1 mutations were detected in three kindreds. Multiglandular involvement was found in all but one affected subject belonging to the three kindreds with MEN1 mutations. In these patients persistence/relapse of the disease was observed unless an extensive parathyroidectomy (excision of 3(1)/(2) glands) had been performed, with the exception of one patient, who is currently normocalcaemic 168 months after excision of two glands. No mutations of MEN1, HRPT2 and CASR genes were identified in the remaining four families.


CONCLUSIONS
MEN1 genotyping appears worthwhile in FIHP families, as the finding of mutation(s) may predict multiglandular involvement and therefore have practical surgical implications, and prompt further investigation in the family, with the possibility of identifying new cases and beginning a programme of periodic surveillance for emergence of tumours in all carriers.
Cetani
Filomena
F
Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy. cetani@endoc.med.unipi.it
Pardi
Elena
E
Ambrogini
Elena
E
Lemmi
Monica
M
Borsari
Simona
S
Cianferotti
Luisella
L
Vignali
Edda
E
Viacava
Paolo
P
Berti
Piero
P
Mariotti
Stefano
S
Pinchera
Aldo
A
Marcocci
Claudio
C
D000236:Adenoma / Q000150:complications / Q000235:genetics / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000368:Aged; D001483:Base Sequence; D005192:Family Health; D005260:Female; D006801:Humans; D049950:Hyperparathyroidism, Primary / Q000150:complications / Q000235:genetics* / Q000473:pathology; D006965:Hyperplasia / Q000150:complications / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010280:Parathyroid Glands / Q000473:pathology; D010282:Parathyroid Neoplasms / Q000150:complications / Q000235:genetics / Q000473:pathology; D010375:Pedigree; D011518:Proto-Oncogene Proteins / Q000235:genetics; D044169:Receptors, Calcium-Sensing / Q000235:genetics; D012008:Recurrence; D025521:Tumor Suppressor Proteins / Q000235:genetics
C095550:CASR protein, human; C454900:CDC73 protein, human; C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins; D044169:Receptors, Calcium-Sensing; D025521:Tumor Suppressor Proteins