Hannan Fadil M, Nesbit M Andrew, Christie Paul T, Fratter Carl, Dudley Nicholas E, Sadler Greg P, Thakker Rajesh V
Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Churchill Hospital, Oxford, UK.
Nat Clin Pract Endocrinol Metab. 2008 Jan;4(1):53-8. doi: 10.1038/ncpendmet0718.
Familial isolated primary hyperparathyroidism (FIHP) is an autosomal dominant disorder that can represent an early stage of either the multiple endocrine neoplasia type 1 (MEN1) or hyperparathyroidism-jaw tumor (HPT-JT) syndromes; alternatively, the condition can be caused by an allelic variant of MEN1 or HRPT2 (hyperparathyroidism 2 gene), or caused by a distinct entity involving another locus. We have explored these possibilities in a patient with primary hyperparathyroidism, whose mother had a history of renal calculi and primary hyperparathyroidism.
Serum biochemistry and radiological investigations for primary hyperparathyroidism, MEN1 and HPT-JT, and genetic testing for MEN1 and HRPT2 mutations were undertaken.
FIHP with primary hyperparathyroidism as the sole endocrinopathy due to a previously unreported heterozygous missense germline MEN1 mutation, Tyr351Asn. In addition, another unreported heterozygous missense germline MEN1 mutation, Trp220Leu, was identified in an unrelated male patient with FIHP, whose mother and sister also had primary hyperparathyroidism. DNA from a parathyroid tumor from the sister revealed a loss of heterozygosity in which the mutant allele was retained. This is consistent with Knudson's 'two-hit' model of hereditary cancer and a tumor suppressor role for MEN1 in FIHP.
The patient underwent parathyroidectomy and has remained normocalcemic over a follow-up period of 6 years. The other four patients have remained normocalcemic for a follow-up period of 4-15 years following parathyroidectomy. None has developed abnormalities of the MEN1 syndrome, providing further support that FIHP is a distinct genetic variant of the MEN1 syndrome.
家族性孤立性原发性甲状旁腺功能亢进症（FIHP）是一种常染色体显性疾病，可能是1型多发性内分泌腺瘤病（MEN1）或甲状旁腺功能亢进-颌骨肿瘤（HPT-JT）综合征的早期阶段；另外，该病症可能由MEN1或HRPT2（甲状旁腺功能亢进2基因）的等位基因变异引起，或者由涉及另一位点的独特实体引起。我们在一名原发性甲状旁腺功能亢进症患者中探究了这些可能性，该患者的母亲有肾结石和原发性甲状旁腺功能亢进症病史。
对原发性甲状旁腺功能亢进症、MEN1和HPT-JT进行了血清生化和放射学检查，并对MEN1和HRPT2突变进行了基因检测。
FIHP伴原发性甲状旁腺功能亢进症作为唯一的内分泌病，原因是之前未报道的杂合错义种系MEN1突变，即Tyr351Asn。此外，在一名患有FIHP的无关男性患者中鉴定出另一种之前未报道的杂合错义种系MEN1突变，即Trp220Leu，该患者的母亲和姐姐也患有原发性甲状旁腺功能亢进症。来自姐姐甲状旁腺肿瘤的DNA显示杂合性缺失且保留了突变等位基因。这与Knudson的遗传性癌症“两次打击”模型以及MEN1在FIHP中的肿瘤抑制作用一致。
该患者接受了甲状旁腺切除术，在为期6年的随访期内血钙一直保持正常。其他四名患者在甲状旁腺切除术后4至15年的随访期内血钙一直保持正常。没有人出现MEN1综合征异常，这进一步支持了FIHP是MEN1综合征的一种独特基因变异。
