Familial isolated hyperparathyroidism (FIHP) is a genetic type of primary hyperparathyroidism (PHPT). It is inherited in an autosomal dominant manner and is presumably caused by mutations of distinct genes. However, it could not yet be related to specific causes and remains an exclusion diagnosis. FIHP involves the development of benign tumors in the parathyroid glands, an increased release of parathyroid hormone, and the resulting imbalance of calcium homeostasis. The decompensation of hypercalcemia may have fatal consequences but can usually be avoided by early treatment.
Serum calcium levels are above reference ranges, and the majority of FIHP patients is diagnosed after the incidental detection of hypercalcemia and a corresponding workup. On the other hand, hypercalcemia may manifest in renal, gastrointestinal, or neuromuscular symptoms . Polyuria and polydipsia are common presenting symptoms of the PHPT-related endocrine imbalance, and they may be accompanied by nephrocalcinosis or nephrolithiasis. The latter conditions may go unnoticed until the urinary system is examined employing imaging techniques. With regard to the gastrointestinal tract, patients may claim constipation. Loss of appetite, nausea, and vomiting may also be reported. Muscle weakness and arrhythmia reflect the adverse effects of hypercalcemia on skeletal and heart muscles, respectively. Disorders of the cardiac rhythm may be recognized in an electrocardiogram or may become symptomatic.
The progressive loss of bone mass manifests during advanced stages of the disease, when the patients develop osteitis fibrosa cystica . This condition is characterized by the replacement of healthy bone by fibrous tissue, increasing tenderness or bone pain, skeletal deformities, and pathological fractures. Beyond that, the permanent increase of calcium concentrations may interfere with the function of the central nervous system. This may result in constitutional symptoms like lethargy, cognitive dysfunction, and reduced consciousness.
Besides this classical presentation of PHPT, FIHP patients may remain asymptomatic for prolonged periods of time, present with a palpable mass in the anterior neck, attend the emergency room due to a hypercalcemic crisis. The latter is a rare but potentially life-threatening manifestation of severe disturbances of calcium homeostasis. Those suffering a hypercalcemic crisis may present with nausea, vomiting, profound weakness, cognitive impairment, somnolence, acute kidney injury, and symptomatic arrhythmias .
As per definition, FIHP patients don't present associated endocrinopathies or neoplasms .
- Facial Angiofibroma
Other common features include adrenocortical and carcinoid tumors, facial angiofibromas, collagenomas, ependymomas, leiomyomas, lipomas, and meningiomas An individual with multiple primary or multi-focal endocrine tumors An individual with a personal [genedx.com]
Multiple facial angiofibromas and collagenomas in patients with multiple endocrine neoplasia type 1. Arch Dermatol 133: 853–7, 1997. 21. Dinnen JS, Greenwoood RH, Jones JH, Walker DA, Williams ED. [journals.lww.com]
- Long Arm
Fourteen DNA markers at 10 polymorphic loci closely linked to the MEN1 locus on the long arm of chromosome 11 and 5 markers close to the MEN2A gene on chromosome 10 were tested using Southern blot analysis and polymerase chain reaction-based techniques [ncbi.nlm.nih.gov]
The Metabolic Diseases Branch participated in an international collaborative effort to identify the gene responsible for HPT-JT on the long arm of chromosome 1. [grantome.com]
Most cases of FHH result from a loss-of-function mutation in the gene encoding the calcium-sensing receptor (CaSR 3) (MIM 601199) on the long arm of chromosome 3 (10,38,46,77). [journals.lww.com]
- Short Arm
Additionally, two polymorphic markers (Mir1 and Mir2) within the prepro-PTH gene on the short arm of chromosome 11 were analyzed using denaturant gradient gel electrophoresis. [ncbi.nlm.nih.gov]
The diagnosis of FIHP is based on clinical, laboratory, imaging, and histological findings, and the exclusion of other types of PHPT :
- Standard analyses of blood and urine samples reveal hypercalcemia, hypophosphatemia, and hypercalciuria. These findings directly relate to elevated concentrations of parathyroid hormone. Additional hormonal imbalances are not to be expected in FIHP patients.
- Diagnostic imaging is employed to examine the parathyroid glands and to exclude the presence of additional tumors suggestive of syndromic PHPT. FIHP patients may develop diffuse parathyroid hyperplasia, may present large adenomas or multiple tumors. Tissue degeneration may be limited to a single gland or may affect more than one. The involvement of all four parathyroid glands is not uncommon . If no anomalies can be detected in the parathyroid despite strong suspicion of PHPT, the presence of ectopic parathyroid tumors should be evaluated. Although these are rare occurrences, FIHP-related tumors have been found in the thyroid, thymus, and superior mediastinum . Beyond that, tumors in other organs rather indicate a different diagnosis.
- The general condition of the patient's skeleton should also be assessed by means of diagnostic imaging.
- Histologically, parathyroid hyperplasia and adenoma are characterized by the absence of fibroadipose tissues within the lesion. They are completely circumscribed by normal parathyroid tissue and don't show signs of malignancy, such as high mitotic rates and invasive growth . Cystic degeneration may be observed .
- Although the genetic background of FIHP remains unknown, molecular biological studies should be realized to rule out syndromic PHPT and clinically similar diseases like familial benign hypocalciuric hypercalcemia. In this context, genes MEN1, RET, HRPT2, CASR, GNA11, and AP2S1 may have to be assessed. The absence of symptoms commonly observed in patients with the aforementioned disorders, e.g., fibroma of the jaw, renal and uterine lesions in individuals suffering from hyperparathyroidism-jaw tumor syndrome, should not be considered an exclusion criterion: The incomplete expression of any familial form of PHPT or hypercalcemia may result in a FIHP-like phenotype  .
Parathyroidectomy is the mainstay of treatment, but the extent of surgery remains a matter of discussion . In case of uniglandular disease, most surgeons opt for the mere removal of hyperplastic tissue and/or adenoma(s). Subtotal parathyroidectomy is the method of choice if multiple nodes are detected in distinct glands. To avoid endocrine complications, 20-30 mg of one of the glands should be preserved. Intraoperative measurements of serum levels of parathyroid hormone may help to assure the successful resection of degenerated tissues and to reduce the risk of post-surgical hypoparathyroidism . For the same purpose, the heterotopic autotransplantation of resected parathyroid tissue is recommended as a compensating measure if a total parathyroidectomy is realized .
Indeed, some experts prefer total parathyroidectomy over other procedures and base their decision on the high rate of recurrence in FIHP patients. Further surgery implicates renewed risks of morbidity and mortality, and should be avoided whenever possible - but data regarding the efficacy of alternative therapies are scarce. Medical therapy may be considered in case of persistent hyperparathyroidism, and poor surgical candidates may also benefit from the administration of calcimimetics like cinacalcet . By contrast, post-surgical hypoparathyroidism requires the administration of vitamin D and calcium.
Patients diagnosed with incomplete syndromic PHPT should be offered surveillance for the development of additional, non-parathyroid tumors and other complications commonly observed in individuals carrying mutations of the same gene as the index case.
Hypercalcemic crisis is a rare, yet possibly fatal complication of FIHP. An individual patient's risk of experiencing such a crisis depends on their serum calcium concentration and parathyroid hormone levels. Furthermore, nephrolithiasis has been identified as a risk factor for this type of decompensation . Fortunately, most patients respond well to parathyroidectomy, and their risk of suffering hypercalcemic crises can be reduced significantly.
Parathyroid carcinoma may arise from benign tumors and is most commonly observed in patients with hyperparathyroidism-jaw tumor syndrome. Accordingly, FIHP patients who carry mutations of the HRPT2 gene may be at increased risk of malignant transformation  .
The specific causes of FIHP remain elusive. Genealogical analyses suggest an autosomal dominant pattern of inheritance, but no underlying mutation has yet been identified. While syndromic forms of familial PHPT have been associated with mutations of the MEN1 and HRPT2 genes, among others, the involvement of these genes in FIHP pathogenesis remains unclear. It has been speculated that minor sequence anomalies, which do not suffice to induce the respective syndromes, may render the parathyroid susceptible to tumor development after a somatic, second-hit mutation . Those patients who test negative for mutations of any of the candidate genes presumably form a genetically heterogeneous group that may eventually require further subdivision. What's more, the occasional use of the term FIHP to refer to incomplete syndromic PHPT illustrates the need for a more precise classification system: Clinical diagnoses made today don't necessarily correlate with the results of genetic studies   . Diagnostic guidelines would help to address this issue but might need to be revised in the foreseeable future, when additional information about the genotype of FIHP patients becomes available.
FIHP accounts for <1% of cases of primary hyperparathyroidism, whose annual incidence has been estimated at 1 in 5,000 people  . To date, little more than 100 families affected by FIHP have been described. Contrary to sporadic PHPT, which is typically diagnosed in postmenopausal women, FIHP symptom onset generally occurs in the early third decade of life. The penetrance of the underlying mutations is assumed to be incomplete.
Calcium homeostasis is largely dependent on the release of parathyroid hormone. This hormone mediates a reduction of calcium excretion, an increase of intestinal calcium absorption, and the mobilization of depot calcium from the skeleton. The excess release of parathyroid hormone thus results in hypercalcemia. Under physiological conditions, it is partly counteracted by calcitonin, a thyroid hormone. Furthermore, negative feedback mechanisms should assure the decrease of parathyroid hormone secretion as soon as calcium levels exceed and phosphate levels fall below certain threshold concentrations. However, hyperplastic and neoplastic parathyroid tissues are no longer responsive to these regulatory mechanisms.
There can only be speculation about the molecular biological background of this irresponsiveness. Possibly, a dysfunction of the calcium-sensing receptors of parathyroid chief cells interferes with the detection of calcium levels in blood. These receptors are encoded by the CASR gene, and mutations of this gene have occasionally been identified in FIHP patients  . Another hypothesis is based on anomalies in downstream signal conduction, as is the case in carriers of HRPT2 mutations. Pathogenic mutations of the HRPT2 gene are generally related to hyperparathyroidism-jaw tumor syndrome, but they have also been reported in FIHP patients. HRPT2 is involved in transcriptional and post-transcriptional control pathways and has been characterized as a tumor suppressor gene.
Genetic counseling should be offered to affected families, although an early diagnosis may not be feasible if the disease cannot be related to mutations of determined genes. Any prophylactic risk assessment must then be based on genealogical data. The incomplete penetrance of disease alleles should be considered in this context. The presymptomatic identification of family members likely to develop FIHP is largely facilitated if the disease can be related to a predisposing, if not causative mutation of some gene.
Familial PHPT occurs in an isolated non-syndromic form, which is referred to as FIHP, or as part of a syndrome like multiple endocrine neoplasia or hyperparathyroidism-jaw tumor syndrome. The clinical distinction of these entities is mainly based on the presence of non-parathyroid symptoms, such as islet cell tumors of the pancreas, neoplasms of the pituitary gland, jaws, or urogenital tract, which are absent in FIHP patients. The diagnosis of syndromic PHPT is generally supported by the detection of mutations in genes like MEN1 and HRPT2, while genetic defects aren't usually identifiable in those affected by FIHP. However, there may be individuals presenting with clinical FIHP who do carry mutations of genes originally attributed to syndromic PHPT. This apparent contradiction reflects the shortcomings of current classification systems, where FIHP presumably comprises a heterogeneous group of diseases that don't fulfill the diagnostic criteria of better-described disorders . The common denominators of those diseases recognized as FIHP are autosomal dominant inheritance and isolated PHPT.
Familial isolated hyperparathyroidism (FIHP) is a rare genetic disorder. It is inherited in an autosomal dominant manner, i.e., the likelihood of a child to inherit the pathogenic allele from an affected parent is 50%. Carriers of the respective mutations, which have not yet been characterized in detail, are predisposed to the development of parathyroid hyperplasia or adenoma.
The parathyroid consists of four small glands, which are located close to the thyroid, in the anterior neck. Its main function is the synthesis and secretion of parathyroid hormone, a key player in calcium homeostasis. FIHP patients release excess amounts of parathyroid hormone, which induces an increase in calcium concentrations in blood. This is referred to as hypercalcemia. While this condition may go unnoticed, severe hypercalcemia results in a series of symptoms that are often referred to as "stones, bones, abdominal groans and psychic moans":
- Patients tend to develop urinary stones.
- Depot calcium is mobilized from the bones, resulting in a reduction of bone density and propensity to fractures. Affected individuals may experience bone pain or tenderness.
- Abdominal pain, nausea, vomiting, and constipation are characteristic symptoms of hyperparathyroidism.
- Hypercalcemia may interfere with cognitive functions and consciousness.
The diagnosis of FIHP relies on anamnestic data, clinical and laboratory findings, and the exclusion of other causes of hyperparathyroidism. In most cases, the surgical removal of degenerated parathyroid tissue results in a normalization of blood calcium levels and an alleviation of symptoms. However, some patients may develop post-surgical hypoparathyroidism, which requires medical treatment. There is also a chance of recurrence: Patients who relapse may be considered for renewed surgery or pharmacotherapy.
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