HPT-JT (OMIM 607393) is a rare autosomal dominantly inherited disorder characterized by fibrous-osseous tumors of mandible and/or maxilla (ossifying fibroma), Wilms' tumor, papillary renal carcinoma, polycystic kidney disease, renal cysts and PHPT. The latter exhibits an aggressive behavior within this syndrome and it is frequently sustained by parathyroid carcinoma.
In the context of PHPT-related syndromes (Table I), HPT-JT syndrome is one of the least common and relatively unknown pictures, although not less interesting or important. About 80% of patients present with PHPT, that may develop in late adolescence or older. A reduced penetrance in females has been reported, and parathyroid carcinoma may occur in approximately 10-15% of affected individuals. When compared to MEN1-related PHPT, HTP-JT syndrome may run a more aggressive course: the patients tend to have more severe hypercalcemia and hypercalcemic crisis could represent the first clinical evidence. In order to monitor the presence/absence of PHPT, HPT-JT patients should undergo annual blood tests evaluating ionized calcium and intact parathyroid hormone (iPTH) levels, beginning by 15 years of age. However, it should be taken always into account, due to their possible severity, that lesions in the maxilla, mandible, kidney, and uterus should be carefully monitorized by imaging studies (i.e. orthopantography of the face, perhaps once in every 3 years, and annual abdominal ultrasound or computed tomography scan).
Pathology
PHPT in HPT-JT syndrome generally consists of involvement of one or two parathyroid glands (adenoma or double adenoma) (Table III) that may be or may be not synchronously present, differently from the MEN1-PHPT in which all glands are frequently involved. Parathyroid carcinoma may occur in approximately 10-15% of affected individuals. The high incidence of cystic figure in resected parathyroid glands represents a classical pathological feature of parathyroid neoplasia in HPT-JT syndrome. In fact, due to frequent identification of parathyroid recurring cystic adenomas this clinical entity can be referred to also as familial cystic parathyroid adenomatosis (Table III). The jaw lesions typically associated to this syndrome have been reported to be histologically distinct from the typical ones representing the bone disease classically associated to PHPT.
Molecular aspects
Very recently, the HRPT2 gene, responsible for this syndrome, has been identified in the "tumor suppressor gene" parafi- bromin, previously mapped at 1q25-q32 (Table II). This gene appears to be involved also in the pathogenesis of sporadic forms of PHPT. Fourteen germline inactivating mutations of HPRT2 gene were identified in 26 kindreds (Table II). The gene encodes a protein of 531 amino acids, named parafi- bromin, involved in the development of parathyroid tumors and ossifying fibromas. To date, the protein does not exhibit any homology to known protein domains. The gene appears to be ubiquitously expressed in several human tissues such as kidney, heart, liver, pancreas, skeletal muscles, brain and lung. However, its role in development and tumorigenesis still remains to be elucidated.
Loss of wild-type alleles in HPT-JT syndrome was found both in renal and parathyroid tumors. These findings, together with the inactivating nature of the germline mutations strongly suggest a tumor suppressive role for parafibromin. Such LOH are not as frequent as reported in MEN1-related tumors. To date, it has been no possible to describe a genotype-phe- notype correlation and more data from other affected families and from genetic studies are necessary to possibly determine the eventual existence of such a correlation. However, the possibility to perform DNA test provides the great opportunity for an early identification of an asymptomatic gene carrier who will receive the needed stringent clinical screening procedures.
Treatment of HPT-JT-PHPT manifestations
As soon clinical evidence of PHPT as occurred, neck surgery should be promptly performed. However, a general consensus on which type of surgical approach should be adopted, if removal of the enlarged gland with long-term follow-up or complete parathyroidectomy followed by auto-transplantation to the nondominant forearm has not been reached. For parathyroid carcinoma neck surgery, specifically an en bloc resection of primary tumor, is the only curative treatment (Table III). Alternatively, affected patients could undergo repetitive palliative surgical exeresis of metastatic nodules.
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