Pathogenic variants in CDC73 tend to predispose patients to a number of syndromes that are associated with an increased risk of primary hyperparathyroidism, parathyroid adenomas or carcinomas.


In familial isolated primary hyperparathyroidism (FIHP) patients or families do not show further syndrome manifestations. However, carriers of a CDC73 variant may sometimes have a younger age of manifestation and/or a clinically more severe phenotype compared to families without a CDC73 variant.


About 95% of all patients with hyperparathyroidism-jaw tumor syndrome (HPT-JT) have primary hyperparathyroidism, which is usually caused by a parathyroid adenoma, but is also due to parathyroid carcinoma (in about 10-15% of cases). In addition, (usually non-malignant) fibromas of the upper or lower jaw can be observed in 30-40% of those affected. Renal cysts, renal hamartomas, Wilms tumors or uterine tumors (benign and malignant) are diagnosed in rare cases.


Pathogenic CDC73 variants are detected in 20-29% of patients with sporadic parathyroid carcinoma. These are usually functional and manifest themselves in primary hyperparathyroidism.


Diagnostic criteria have not yet been established. In addition, some genetic changes in CDC73 show a highly variable penetrance and expressivity. However, if one of the following points applies to a patient, a genetic clarification may be indicated:


  • pHPT and fibromas of the upper/lower jaw;
  • pHPT <45 years of age and cystic, atypical and/or malignant parathyroid histology, or no nuclear expression of parafibromin in an immunohistochemical examination;
  • pHPT in child/adolescent;
  • fibromas of the upper/lower jaw in children (however, the frequency of pathogenic CDC73 variants in sporadic fibroma of the jaw seems to be low);
  • pHPT or fibromas of the jaw and other HPT-JT associated manifestations (e.g., Wilms tumor) in the patient's own or family history;
  • familial pHPT and unremarkable MEN1 findings.


Depending on the patient's own and family history, a differential diagnosis may include MEN1, MEN2 or MEN4 syndromes, familial hypocalciuric hypercalcemia (FHH, OMIM 145980, 600740, 615361) or GCM2-associated familial primary hyperparathyroidism (OMIM 146200).


The CDC73 gene (also known as HRPT2) encodes the protein parafibromin, which plays a role in transcriptional gene regulation and prevents excessive cell proliferation. Outside the nucleus, parafibromin is probably involved in the organization of the cytoskeleton. Pathogenic variants in CDC73 do not lead directly to tumor development; cell proliferation and degradation of the affected cell occurs only after failure of the second, intact allele by spontaneous somatic variants.


Due to the rarity of pathogenic CDC73 variants and the variable expressivity, there are currently no precautionary recommendations for carriers or persons at risk. However, various strategies have been suggested, including annual monitoring of the calcium serum level from the age of 6 years, periodic ultrasound scans of the parathyroid glands to exclude non-functional parathyroid adenomas/carcinomas, screening for renal cysts and, in female carriers, gynecological examinations for uterine tumors.



Hyde et al. CDC73-Related Disorders. 2018. GeneReviews®: www.ncbi. / van der Tuin et al. 2017, J Clin Endocrinol Metab 102:4534 / Chen et al. 2016, Diagn Pathol 22:11




Multiple endocrine neoplasia (MEN) is a group of syndromes that favor the development of lesions in endocrine organs. A distinction is generally made between the three syndromes MEN1, MEN2 and MEN4, depending on the phenotype and the affected gene.


MEN1 is associated with the occurrence of parathyroid adenoids (>95% of patients). In addition, adenomas or malignant tumors of the endocrine pancreas, duodenum or the adenohypophysis can be found and less frequently adrenal lesions/pheochromocytomas or thyroid lesions. MEN1 syndrome is caused by loss-of-function mutations in the MEN1 gene.


Those affected by MEN2 syndrome are usually diagnosed with medullary thyroid carcinoma (familial medullary thyroid carcinoma, FMTC). In addition, parathyroid adenomas (about 50% of those affected) and/or pheochromocytomas can be observed (MEN2A). More rarely, other phenotypic manifestations such as Marfanoid habitus, intestinal ganglioneuromatosis and/or mucosal neuroma can be observed (MEN2B, also called MEN3). The various subtypes of MEN2 syndrome are due to gain-of-function mutations in the RET gene.


MEN4 is extremely rare and associated with pathogenic variants in the CDKN1B gene. The few patients identified seen so far have mainly manifested with hyperparathyroidism and/or pituitary adenomas, similar to MEN1 syndrome. In addition, adrenal gland tumors, thyroid tumors, cervical carcinomas, bronchial and gastric carcinomas have been reported in MEN4 patients.


Since the manifestations of the MEN syndromes partly overlap and therefore no clear suspected diagnosis can be made, panel diagnostics of all three genes can be useful. In case of certain symptoms, for example, the appearance of a pheochromocytoma, other syndromes such as von Hippel-Lindau syndrome (VHL) or paraganglioma/peochromocytoma syndrome should also be considered for a differential diagnosis.


Differential diagnosis of primary hyperparathyroidism

Primary hyperparathyroidism (pHPT) is characterized by an increased release of the parathyroid hormone and an elevated blood calcium level. In up to 80% of pHPT patients it is caused by a parathyroid gland adenoma. Parathyroid carcinomas are rarely (<1%) detected. In 5‑10%, pHPT is diagnosed as part of MEN1, MEN2 or MEN4 syndrome, or hyperparathyroidism-jaw tumor syndrome (HKTS, CDC73 gene). Treatment for this condition is a parathyroidectomy.


Hypercalcemia in the context of familial hypocalciuric hypercalcemia (FHH) must be clearly differentiated. In these cases, the increased calcium release is caused by a disturbance (insensitivity) of the calcium-sensitive receptor (CaSR, CASR gene, FHH1), more rarely by variants in GNA11 (FHH2) or AP2S1 (FHH3). This form does not require surgery and should therefore be distinguished from primary hyperparathyroidism.



Walker and Silverberg 2018, Nat Rev Endocrinol 14(2):115 / Alrezk et al. 2017, Endocr Relat Cancer 24:T195 / Marini et al. 2017, Clin Cases Miner Bone Metab 14:60 / Wasserman et al. 2017, Clin Cancer Res 23:e123 / Cardoso et al. 2016, Hum Mutat 38:1621 / Thakker 2016, J Intern Med 280:574 / Pappa und Alevizaki 2016, Endocrine 53:7 / Pacheco 2016, J Pediatr Genet 5:89 / Eastell et al. 2014, J Clin Endocrinol Metab 99:3570




Multiple endocrine neoplasia 1 (MEN1) is characterized by the appearance of neoplasia of various endocrine organs. The disease follows an autosomal dominant inheritance. The prevalence is estimated to be about 1:30,000. Clinically, MEN1 usually manifests as hormone overproduction, which is triggered by a tumor. About 95% of patients are affected by a parathyroid adenoma. Furthermore, adenomas or malignant tumors of the endocrine pancreas and duodenum as well as the adenohypophysis are among the most frequent manifestations. More rarely, dermal tumors, thyroid and adrenal gland lesions are also diagnosed. Clinically, MEN1 is considered to be confirmed if the person affected develops neoplasia in at least two endocrine organs.


MEN1 is caused by pathogenic variants in the tumor suppressor gene MEN1, which consists of 9 coding exons. The gene encodes the 610 amino acid long protein MENIN, which is believed to be involved in mechanisms to regulate DNA synthesis and the cell cycle. Various changes (point mutations, deletions of larger gene segments) have been described in the entire coding region of the MEN1 gene; there are no genotype-phenotype correlations. Germline variants in MEN1 do not lead directly to degeneration. Only after failure of the second intact MEN1 allele by somatic variants can uncontrolled division and degeneration of the affected cells occur (Knudson's two-hit hypothesis). The penetrance is 90% for carriers until the age of 50.

In about 77% of patients with familial MEN1 (where another blood relative has MEN1‑associated symptoms in addition to the affected person) germline variants can be detected in MEN1. The mutation detection rate in MEN1 patients without a significant family history is about 68%. In about 10-20% of patients no causal variant can be detected in the coding region of the gene.


Genetic testing of the MEN1 gene is recommended for:


  • occurrence of at least two MEN1-associated neoplasias in a subject;
  • hyperparathyroidism before the age of 40;
  • gastrinoma or islet cell tumor of the pancreas;
  • recurrence of pHPT, especially multiglandular hyperplasia.


Carriers of a pathogenic variant are recommended to follow a systematic screening schedule from the age of 16 (or 10 years before the youngest age of disease onset in the family). Predictive genetic testing of persons at risk with a known familial variant is currently recommended from the age of 16 and can be carried out as part of a genetic consultation.



Concolino et al. 2016, Cancer Genet 209:36 / Pacheco 2016, J Pediatr Genet 5:89 / Schernthaner-Reiter et al. 2016, Neuroendocrinology 103:18 / Gut et al. 2015, Contemp Oncol 19:176 / Thakker 2014, Mol Cell Endocrinol 386:2 / Walls 2014, Semin Pediatr Surg 23:96 / Lemos et Thakker 2008, Hum Mutat 29:22 / Marini et al. 2006, Orphanet J Rare Dis. 1:38 / Guo et Sawicki 2001, Mol Endocrinol 15:1653 / Simon et al. 2000, Dtsch Arztebl 97:698




Multiple endocrine neoplasia 2 (MEN2) is a rare hereditary tumor disease characterized by autosomal dominant inheritance and a prevalence of approximately 1:50,000. Clinically, three subtypes are distinguished: MEN2A, MEN2B and familial medullary thyroid cancer (FMTC). Medullary thyroid carcinoma is characteristic of all types of MEN2 syndrome and occurs in almost 100% of those affected. Medullary thyroid carcinoma accounts for about 5% of all thyroid carcinomas, and about 25% show familial clustering and occur as part of multiple endocrine neoplasia syndrome.



MEN2A is the most common clinical variant with about 75-80% of cases. In addition to medullary thyroid carcinoma (MTC), which occurs in early adulthood (on average at the age of 36 years), pheochromocytomas are observed in about 50% of those affected, most of whom are diagnosed after or at the same time as MTC. In about 30% of cases parathyroid adenomas/tumors (primary hyperparathyroidism) also occur. In rare cases, patients may also develop cutaneous lichen amyloidosis. Clinically, MEN2A is considered confirmed when two or more MEN2A-associated tumors are diagnosed.


MEN2B (also called MEN3)

In addition to MTC and pheochromocytoma, MEN2B patients manifest a characteristic phenotype typically with a Marfanoid habitus, intestinal ganglioneuromatosis and mucosal neuromatosis on lips, cheeks and tongue, in the nasal and pharyngeal cavity, and on the eyelids. The medullary thyroid carcinoma is particularly aggressive in MEN2B and onset is often in infancy or adolescence. MEN2B is the rarest type with about 5% of cases.



In about 25% of MEN2 cases, affected individuals are diagnosed with only MTCs. The age of onset is higher compared to MEN2A and MEN2B, and the disease is usually less aggressive compared to MEN2A and MEN2B. Clinically, FMTC is considered confirmed if there are at least four affected family members.


All subtypes of MEN2 are caused by variants in the RET proto-oncogene, which encodes a tyrosine kinase receptor. The analysis of RET is always indicated on detection of a medullary thyroid carcinoma (independent of age). About 98% of all pathogenic variants in RET which lead to the activation of the receptor are located in exons 5, 8, 10, 11, and 13-16. If the molecular genetic examination of these exons is unsuccessful, it is recommended to examine the remaining coding exons. MEN2 patients and high-risk patients should have an annual check-up by monitoring serum hormone levels and imaging tests. Prophylactic thyroidectomy is advised with the age dependent on the MEN2 subtype.


In contrast to the activating variants in RET and the occurrence of MEN2, inactivating variants are associated with Hirschsprung disease (OMIM 142623). The analysis of RET is recommended for all children with Hirschsprung disease.



Romei et al. 2016, Nat Rev Endocrinol 12:192 / Pappa et Alevizaki 2016, Endocrine 53:7 / Wells et al. 2016, Thyroid 25:567 / Wells et al. 2013, J Clin Endocrinol Metab 98:3149 / Frank-Raue et Raue 2011, Journal für Klinische Endokrinologie und Stoffwechsel 4:8




Multiple endocrine neoplasia 4 (MEN4) is extremely rare. So far, only a few affected families with incomplete penetrance have been documented. Clinically, MEN4 is similar to MEN1 syndrome, with most patients showing hyperparathyroidism or pituitary neoplasia. In addition, patients have been diagnosed with small-cell cervical carcinomas, adrenal gland tumors, bronchial and gastric carcinomas or papillary thyroid tumors, or non-endocrine tumors (including meningiomas, prostate cancer, breast cancer, schwannomas). MEN4 is caused by loss-of-function mutations in the CDKN1B gene. The CDKN1B gene consists of two exons and encodes the cyclin-dependent kinase inhibitor 1B (also called p27), which is involved in the regulation of the cell cycle.


An estimated 3% of patients with MEN1 symptoms and normal MEN1 findings are carriers of a pathogenic CDKN1B variant. The genetic analysis of CDKN1B should be discussed in patients with a MEN1-like phenotype or a pituitary adenoma in which the analysis of the MEN1 gene was inconspicuous.


Due to the fact that only a few carriers have been documented, there are currently no recommendations for a screening program. It is advisable to refer patients (and families) to specialized centers.



Alrezk et al. 2017, Endocr Relat Cancer 24:T195 / Wasserman et al. 2017, Clin Cancer Res 23:e123 / Pacheco 2016, J Pediatr Genet 5:89 / Thakker 2014, Mol Cell Endocrinol 386:2 / Pellegata et al. 2006, PNAS 103:15558




Paragangliomas and pheochromocytomas are rare neuroendocrine tumors that arise from paraganglia or the adrenal medulla. The prevalence of paragangliomas (PGL) is estimated at about 1:500,000, that of pheochromocytomas (PCC) at 1:1,000,000. Some paragangliomas secrete catecholamine, which is associated with sudden or persistent high blood pressure and can occur together with headaches, dizziness and/or sweating. These paragangliomas are often located in the thorax, abdomen or pelvis. Non-secreting paragangliomas occur more frequently in the head and neck region. They can be asymptomatic or cause impairments in the ear, nose and throat area (e.g., hearing disorders, speech disorders due to tongue paralysis, difficulty swallowing, coughing).


About 30% of all paragangliomas/pheochromocytomas are hereditary and due to a causal germline variant, even in apparently sporadic cases the mutation detection rate is 11-25%. In about one third of the hereditary cases, pathogenic variants can be detected in the SDHAF2, SDHB, SDHC, SDHD or MAX genes.


Causal variants in SDHx and MAX are loss-of-function mutations that lead to the loss of function of the affected allele or its protein product. Only the failure of the second intact allele by somatic variants can lead to the degeneration of the affected cells. The most frequent variants are found in the genes SDHB, SDHC or SDHD. Pathogenic variants in SDHAF2 and MAX, on the other hand, are detected in only about 6% of patients who have previously tested negative for SDHB, SDHC and SDHD. PGL/PCC are also associated with other hereditary tumor syndromes and can occur in the context of neurofibromatosis type 1 (NF1), von Hippel-Lindau syndrome (VHL), or multiple endocrine neoplasia type 2 (RET). Pathogenic variants in the genes SDHB, SDHC and SDHD can also be detected in Carney-Stratakis syndrome (CSS). CSS is a very rare hereditary syndrome characterized by the detection of paragangliomas in association with gastrointestinal stromal tumors (GIST).


Currently, there are no standardized guidelines for the treatment and care of patients with familial paraganglioma/pheochromocytoma. Preventive medical check-ups are advised for carriers or persons at risk from the age of 10, or at the latest 10 years before the youngest age of disease onset in the family. These are carried out by means of biochemical examinations or imaging procedures and should be carried out at specialized centers if possible. If a familial pathogenic variant is confirmed, blood relatives and persons at risk can be undergo predicative testing from the age of 10 years and following a genetic consultation.



Bausch et al. 2017, JAMA Oncol 3:1204 / Lefebvre et Foulkes 2014, Curr Oncol 21:e8 / Lenders et al. 2014, J Clin Endocrinol Metab pp:1915 / Fishbein et al. 2013, Ann Surg Oncol 20:1444 / Pasini et al. 2008, Eur J Hum Genet. 16(1):79 / Neumann et al. 2002, N Engl J Med 346:1459 / Bravo 1991, Kidney Int 40:544


How to order


Exciting news in genetic research! The Human Pangenome Reference Consortium has unveiled an improved version of the human pangenome reference. This c...

Read more

Duchenne muscular dystrophy, a rare inherited muscle disorder characterized by progressive muscle weakness and degeneration that leads to difficultie...

Read more

May 12 is International Nurses Day. It is celebrated on Florence Nightingale’s birthday. She pioneered the field of modern nursing through her dedi...

Read more

Hair loss is a common problem that affects millions of men and women around the world. While genetics is believed to be the most significant factor c...

Read more

Depression is a serious mental health issue affecting over 280 million people worldwide. Recent research has revealed a potential link between gut he...

Read more

If you are unlucky enough to suffer from migraines, you will know that a migraine is not just a bad headache. The headache and accompanying symptoms ...

Read more

Autism spectrum disorder (ASD) is a neurological developmental disorder that affects brain development and function. This affects how people learn, b...

Read more

Researchers have developed a method called "Mendelian Phenotype Search Engine" (MPSE) to identify which sick infants in the neonatal intensive care u...

Read more

Did you know that wisdom teeth are actually an evolutionary leftover from our ancient ancestors that no longer serve their original purpose? These mo...

Read more

Azoospermia is a medical condition characterized by the absence of sperm in the ejaculate and is a major cause of male infertility. It affects 1 in 1...

Read more