Hyperparathyroidism-Jaw Tumour Syndrome Overview

Questions and Answers

What is the primary genetic cause of Hyperparathyroidism–jaw tumour syndrome (HPT-JT)?

PATH1 gene mutation

VHL gene mutation

MEN1 gene mutation

CDC73 sequence variants or deletions (correct)

What percentage of known CDC73 mutation carriers typically exhibit jaw tumours?

2.5–20% (correct)

10–40%

30–50%

40–60%

Which clinical feature is the most common initial presentation of HPT-JT?

Renal tumours

Jaw lesions

Uterine tumours

Parathyroid adenoma or carcinoma (correct)

In patients with HPT-JT, how common is it to find a single adenoma or carcinoma at presentation?

60–80% Signup and view all the answers

What is a significant laboratory finding indicative of HPT-JT?

Severely elevated serum PTH levels Signup and view all the answers

What other type of tumours occurs at an increased incidence in patients with HPT-JT, although they are considered rare?

Uterine and renal tumours Signup and view all the answers

What is the recommended terminology for referring to CDC73-related disorder?

CDC73-related disorder Signup and view all the answers

What is the ICD-11 code for primary hyperparathyroidism related to HPT-JT?

5A51.0 Signup and view all the answers

What is the estimated lifetime risk of parathyroid carcinoma in patients with HPT-JT?

15% Signup and view all the answers

What percentage of patients with sporadic parathyroid carcinomas may have undiagnosed HPT-JT indicated by CDC73 mutations?

30% Signup and view all the answers

What is the primary role of parafibromin in parathyroid tumors?

Acts as a tumor suppressor Signup and view all the answers

Which feature is NOT considered a morphological clue of parafibromin-deficient parathyroid tumors?

Fractured cellular architecture Signup and view all the answers

What is the penetrance of primary hyperparathyroidism in non-index mutation carriers at 50 years of age?

53% Signup and view all the answers

Which type of renal pathology is predominantly associated with HPT-JT?

Simple cysts Signup and view all the answers

In which anatomical location do jaw tumors associated with HPT-JT most commonly arise?

Mandible Signup and view all the answers

What is the role of the polymerase-associated factor 1 complex (PAF1C) in relation to parafibromin?

Controls transcription Signup and view all the answers

Which of the following is the estimated occurrence of CDC73 mutations in unselected parathyroid tumors?

0.19% Signup and view all the answers

Under which condition might a tumor be classified as parafibromin-deficient?

Complete absence of nuclear staining in all neoplastic cells Signup and view all the answers

What type of uterine pathology is most commonly reported in female patients with HPT-JT?

Benign leiomyomas Signup and view all the answers

What is the clinical significance of cystic change in parafibromin-deficient parathyroid tumors?

Occasionally described Signup and view all the answers

What is the expected age range for the presentation of HPT-JT-associated tumors?

7-66 years Signup and view all the answers

What is the status of parafibromin expression in parathyroid neoplasms for individuals with a CDC73 mutation?

Positive staining does not exclude HPT-JT diagnosis. Signup and view all the answers

Which characteristic histological appearance distinguishes HPT-JT-related ossifying fibromas from brown tumors?

Avascular, fibroblast-rich stroma with bony trabeculae. Signup and view all the answers

What is the recommendation for genetic testing when a parafibromin-deficient parathyroid tumor is identified?

Genetic testing is advised at any age. Signup and view all the answers

Which mutations are predominantly found in CDC73 regarding parathyroid tumors?

Frameshift, nonsense, and splice-site mutations. Signup and view all the answers

In patients with HPT-JT, what should be the threshold for diagnosing invasive growth in tumors?

A lower threshold should be applied. Signup and view all the answers

What is the purpose of performing fine needle aspiration biopsy (FNAB) on large parathyroid tumors?

To distinguish them from thyroid lesions. Signup and view all the answers

What is an essential diagnostic criterion for HPT-JT?

Demonstration of a constitutional pathogenic variant in CDC73. Signup and view all the answers

What factors are primarily monitored in lifelong surveillance of HPT-JT patients?

Risk of parathyroid adenoma and carcinoma. Signup and view all the answers

What is the implication of high-impact mutations in CDC73?

They are associated with a higher risk of parathyroid carcinoma and jaw tumors. Signup and view all the answers

What histological characteristics differentiate parafibromin-deficient parathyroid tumors from typical adenomas?

Deficiency in parafibromin expression. Signup and view all the answers

What distinguishes the prognosis of parafibromin-deficient carcinoma from non–CDC73-related carcinomas?

Increased risk of recurrence and metastasis. Signup and view all the answers

What is a common consequence of benign parafibromin-deficient parathyroid tumors?

They can metastasize despite being benign. Signup and view all the answers

Which factor is less likely to be effectively identified by parafibromin immunohistochemistry?

Jaw tumors in HPT-JT. Signup and view all the answers

What should be considered in the treatment of patients with HPT-JT-related hyperparathyroidism?

Selective parathyroidectomy may be suitable when localized. Signup and view all the answers

Which clinical feature typically appears at birth and increases in number during the first two years of life in NF1 patients?

Multiple café-au-lait macules Signup and view all the answers

What is the risk associated with a subset of plexiform neurofibromas in NF1 patients?

Increased risk of high-grade malignant peripheral nerve sheath tumour (MPNST) Signup and view all the answers

Which of the following is NOT considered a skin feature related to NF1?

Neurofibromatosis Noonan syndrome Signup and view all the answers

What characteristic feature related to bone is commonly seen in adults with NF1?

Congenital tibial bowing Signup and view all the answers

Which type of neurofibroma develops typically during puberty?

Cutaneous neurofibromas Signup and view all the answers

Which diagnostic criterion is used to identify NF1?

At least two of eight specified criteria Signup and view all the answers

What is the genetic cause of Neurofibromatosis type 1?

Pathogenic variant in NF1 gene Signup and view all the answers

Which factor primarily affects the growth of plexiform neurofibromas in NF1 patients?

Age of the patient Signup and view all the answers

What is the primary function of neurofibromin (NF1) in cellular signaling?

To act as a GAP for the RAS proto-oncogene Signup and view all the answers

Which characteristic is NOT typically associated with the diagnosis of neurofibromatosis type 1 (NF1)?

Presence of sweat gland adenomas Signup and view all the answers

What is the consequence of biallelic NF1 inactivation?

Increased RAS and RAS effector signaling Signup and view all the answers

Which feature is most often related to the prognosis of malignant peripheral nerve sheath tumours (MPNSTs) in individuals with NF1?

Presence of necrosis and brisk mitotic activity Signup and view all the answers

What percentage of individuals with NF1 are likely to have a pathogenic mutation detected?

95% Signup and view all the answers

Which of the following is characteristic of atypical neurofibromas?

Cytological atypia Signup and view all the answers

Which condition is NOT commonly associated with neurofibromatosis type 1 (NF1)?

Retinoblastoma Signup and view all the answers

What term describes the potential early malignant changes in neurofibromas?

Atypical neurofibromatous neoplasm of uncertain biological potential Signup and view all the answers

What is a common clinical feature of orbitofacial neurofibromatosis?

Development of large, disfiguring tumors Signup and view all the answers

In the context of NF1, what does 'anticipation' refer to?

Earlier onset of symptoms in successive generations Signup and view all the answers

What is a significant risk factor for malignancy in NF1 patients associated with the presence of MPNSTs?

Presence of plexiform neurofibromas Signup and view all the answers

Which of the following features is included in the essential criteria for a clinical diagnosis of NF1?

Occurrence of two or more Lisch nodules Signup and view all the answers

What is a notable feature observed in orbitofacial neurofibromas compared to neurofibromas at other sites?

Differential promoter methylation of HOX family genes Signup and view all the answers

What is the hallmark of multiple endocrine neoplasia type 2 (MEN2)?

Medullary thyroid carcinoma Signup and view all the answers

Which subtype of MEN2 is characterized by mucosal neuromas and ganglioneuromatosis?

MEN2B Signup and view all the answers

In MEN2A, what other tumor is frequently associated with medullary thyroid carcinoma?

Phaeochromocytoma Signup and view all the answers

Where do parathyroid proliferations primarily arise in patients with MEN2?

Beside and below the thyroid in the neck Signup and view all the answers

What genetic alteration is primarily responsible for MEN2?

Activating mutations in the RET proto-oncogene Signup and view all the answers

Which coding system includes the classification for MEN2A?

ICD-O Signup and view all the answers

What condition is NOT recommended terminology for MEN2?

Sipple syndrome Signup and view all the answers

Which estimate correctly reflects the prevalence of bilateral parathyroid proliferations in MEN2 patients?

70% Signup and view all the answers

What is the most characteristic genetic mutation associated with MEN2B?

RET p.M918T Signup and view all the answers

Which clinical feature is least commonly associated with MEN2B?

Hyperparathyroidism Signup and view all the answers

Which of the following statements about the prevalence of MEN2 subtypes is correct?

MEN2B is rarer than MEN2A. Signup and view all the answers

Which pathologic feature is typically seen in MTC associated with MEN2?

Nodular C-cell hyperplasia Signup and view all the answers

What is the primary reason for recommending prophylactic thyroidectomy in MEN2 mutation carriers?

To reduce the risk of MTC Signup and view all the answers

Which element is essential for the development of the enteric nervous system in MEN2?

GDNF family ligands Signup and view all the answers

What is the gender ratio observed in MEN2 individuals?

1:1, no clear predominance Signup and view all the answers

Which of the following would NOT be a desirable diagnostic criterion for MEN2?

Presence of ganglioneuromas in the gastrointestinal tract Signup and view all the answers

What is the typical macroscopic appearance of MTC in MEN2B?

White to yellow and homogeneous Signup and view all the answers

Which RET mutation is most commonly associated with familial MTC?

p.C634R Signup and view all the answers

Which of the following conditions is NOT commonly associated with Naevoid basal cell carcinoma syndrome (NBCCS)?

Thyroid cancer Signup and view all the answers

At what age are odontogenic keratocysts (OKCs) typically first evident in individuals with NBCCS?

Around 8 years Signup and view all the answers

What is the primary genetic variant associated with Naevoid basal cell carcinoma syndrome?

PTCH1 Signup and view all the answers

Which anatomical location is typically NOT affected by Naevoid basal cell carcinoma syndrome?

Liver Signup and view all the answers

Which feature is considered a major diagnostic criterion for NBCCS?

Palmar and plantar pits Signup and view all the answers

Which of the following statements about basal cell carcinomas in NBCCS is correct?

More than 90% of affected individuals have them by age 40. Signup and view all the answers

What role does radiation exposure play in individuals with NBCCS?

It induces multiple basal cell carcinomas. Signup and view all the answers

Which of the following best describes the inheritance pattern of Naevoid basal cell carcinoma syndrome?

Autosomal dominant Signup and view all the answers

What is the estimated syndromic prevalence of odontogenic keratocyst (OKC) associated with NBCCS?

Both A and C Signup and view all the answers

Which gene is primarily associated with the inactivation leading to NBCCS?

PTCH1 Signup and view all the answers

At what mean age is the onset of OKC typically reported?

15.5 years Signup and view all the answers

What percentage of patients with germline SUFU mutations are reported to develop OKC?

0% Signup and view all the answers

How are most pathogenic variants in PTCH1 distributed throughout the gene?

Evenly across the coding region Signup and view all the answers

What is a major diagnostic criterion for confirming NBCCS diagnosis?

Two major and one minor criteria Signup and view all the answers

What function does the gene product of PTCH1 perform in relation to hedgehog signaling?

Activates GLI transcription factors Signup and view all the answers

What is a characteristic histopathological feature of NBCCS-associated OKCs?

Higher frequency of epithelial rests Signup and view all the answers

What impact does being a carrier of the SUFU pathogenic variant have regarding medical surveillance?

Increased risk of brain tumors Signup and view all the answers

In patients with NBCCS, what is the reported percentage of cases with undetected PTCH1 or SUFU pathogenic variants?

15–27% Signup and view all the answers

What is the life expectancy of patients with NBCCS compared to unaffected populations?

Slightly reduced Signup and view all the answers

What type of protein does SUFU act as in the hedgehog signaling pathway?

Negative regulator Signup and view all the answers

What is the purpose of conducting a comprehensive mutation analysis for NBCCS?

To identify constitutional pathogenic variants Signup and view all the answers

What percentage of OKCs have an age-dependent onset by the age of 40 years?

91% Signup and view all the answers

Study Notes

Overview of Hyperparathyroidism–Jaw Tumour Syndrome (HPT-JT)

HPT-JT is an autosomal dominant disorder linked to pathogenic variants or deletions in the CDC73 gene.
Characterized mainly by parathyroid adenoma and carcinoma, with lower occurrence of fibro-osseous jaw lesions.
ICD-O and MIM codes: 145001 Hyperparathyroidism 2 with jaw tumours; HRPT2; ICD-11 code: 5A51.0 Primary hyperparathyroidism.

Clinical Features

Primary hyperparathyroidism is the most common presentation, with 60-80% of cases showing single adenoma or carcinoma.
Metachronous tumours are likely to develop over decades in many patients.
Key diagnostic clues include young age at onset (<40 years), very large tumours, cystic change, significantly elevated serum PTH levels, and severe hypercalcaemia.
Parathyroid carcinoma is rare, but the lifetime risk in HPT-JT can be as high as 15%.

Tumour Localization and Incidence

Parathyroid tumours are usually the sole feature in most families; jaw tumours occur in 2.5-20% of CDC73 mutation carriers.
Significant renal and uterine tumours are rare but occur more frequently than in the general population.
Jaw tumours often arise in the mandible, presenting as well-demarcated radiolucent lesions.

Epidemiology and Genetics

HPT-JT is a rare cause of hyperparathyroidism, with only 0.19% of unselected parathyroid tumours linked to CDC73 mutation.
Equal sex distribution for parathyroid and jaw tumours; median age at presentation is in the 30s to 40s.
Estimated penetrance of primary hyperparathyroidism increases with age (8% by 25 years, 75% by 70 years).

Pathogenesis and Genetic Mutations

HPT-JT stems from heterozygous constitutional pathogenic variants in CDC73, a gene encoding the parafibromin protein.
Parafibromin functions as a tumor suppressor and is often absent in parafibromin-deficient parathyroid tumours.
Common mutations involve frameshift, nonsense, and splice-site alterations, with some cases showing large-scale deletions.

Diagnosis and Histopathology

Diagnosis relies on identifying a constitutional pathogenic variant in CDC73 or multiple histological parafibromin-deficient neoplasms.
Histopathological clues include a sheet-like growth pattern, eosinophilic cytoplasm, and distinctive staghorn vessels.
Immunohistochemical loss of parafibromin expression is specific for diagnosing parafibromin-deficient tumours.

Management and Prognosis

Lifelong surveillance for risks associated with parathyroid adenoma and carcinoma, as well as jaw and other possible lesions.
Surgical options for hyperparathyroidism management remain debated, though non-infiltrative tumours are often curable.
Parafibromin-deficient carcinomas may have a higher risk of recurrence and metastasis; however, metastasis from benign tumours is rare (<4%).

Important Considerations

Familial history is notable but 30% of patients with sporadic parathyroid carcinomas may have undiagnosed HPT-JT.
Uterine and renal pathologies noted in women, but often show common benign lesions prevalent in the wider population.
Differential diagnosis is essential to distinguish jaw lesions associated with HPT-JT from other benign conditions.

Overview of Neurofibromatosis Type 1 (NF1)

NF1 is an autosomal dominant disorder due to pathogenic variants in the NF1 gene, which encodes neurofibromin.
Diagnostic criteria for NF1 require at least two of eight specific features.

Coding Information

ICD-O coding: Specific code for neurofibromatosis type 1.
MIM number: 162200.
ICD-11 code: LD2D.10.

Classification and Subtypes

Known subtypes include mosaic neurofibromatosis type 1, segmental neurofibromatosis type 1, spinal neurofibromatosis, and neurofibromatosis–Noonan syndrome.
Other related syndromes include 17q11.2 microdeletion syndrome.

Localization and Clinical Features

NF1 primarily affects the central and peripheral nervous systems.
Common skin manifestations include multiple café-au-lait macules and skinfold freckling, notably in > 80% of adults with NF1.
Lisch nodules typically develop before puberty, while cutaneous neurofibromas become prevalent during puberty.
Plexiform neurofibromas emerge in 30–50% of children and are often congenital.

Tumor Progression and Risks

Plexiform neurofibromas can transform into atypical neurofibromas or malignant peripheral nerve sheath tumors (MPNST) with higher growth potential in early life.
Various neoplasms are linked to NF1, including optic pathway gliomas, juvenile myelomonocytic leukaemia, and phaeochromocytoma.

Orbital and Facial Manifestations

Orbitofacial NF1 subtypes feature large, progressive tumors that can disfigure the orbit and periorbital areas; recurrence rates after excision are high.

Epidemiology and Incidence

Birth incidence of NF1 is estimated at 1 in 3,000 live births.
Many cases arise from de novo mutations, with unaffected parents.

Pathogenesis

Neurofibromin acts as a GTPase-activating protein (GAP) for the RAS proto-oncogene, with its loss leading to increased RAS signaling.
Genetic alterations in atypical neurofibromas often involve CDKN2A/B and SMARCA2 regions, while MPNSTs may show aberrations in PRC2 complex genes and TP53.

Histopathology and Cytology

Predominant tumor type is neurofibromas resembling sporadic versions, enriched with cells from the haematopoietic lineage.
Atypical neurofibromatous neoplasms may exhibit criteria for malignant potential, including hypercellularity and increased mitotic activity.

Diagnostic Criteria

Clinical diagnosis of NF1 includes at least two features such as café-au-lait macules, neurofibromas, or a first-degree relative with NF1.
Genetic testing as part of the diagnostic process is increasingly emphasized, especially considering overlaps with other genetic syndromes.

Prognosis and Management

Lifespan may be reduced due to complications like malignant diseases and strokes; higher mortality rates are noted in women under 50.
Genetic counselling is important for affected individuals and may include options for prenatal testing.

Overview of MEN2

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant tumor syndrome linked to mutations in the RET proto-oncogene.
Typically associated with medullary thyroid carcinoma (MTC), phaeochromocytomas, parathyroid proliferations, and mucosal neuromas.

Classification and Coding

MEN2A and MEN2B are the two primary subtypes of MEN2.
ICD-O and MIM numbers:
- MEN2A: 171400
- MEN2B: 162300
ICD-11 coding: 2F7A.0 for Multiple polyglandular tumors.

Localization of Tumors

MTC most often arises at the junction of the upper third and lower two-thirds of the thyroid lateral lobes; begins as bilateral microscopic proliferations known as nodular C-cell hyperplasia.
Parathyroid proliferations typically bilateral in about 70% of patients and located adjacent to the thyroid gland.
Mucosal neuromas in MEN2B can affect oropharynx, lips, eyelids, and involve various gastrointestinal tract conditions.

Clinical Features

MEN2A features MTC usually with phaeochromocytoma and parathyroid proliferations.
MEN2B, also known as MEN3, is characterized by aggressive early-onset MTC, high-risk phaeochromocytomas, and oral/intestine ganglioneuromas.
Common symptoms include neck masses from MTC, diarrhea, flushing from calcitonin excess, and complications from ganglioneuromas.

Epidemiology

MEN2 prevalence is approximately 1 in 30,000.
MEN2A incidence is about 1 in 1,973,500, while MEN2B is rarer at 1 in 38,750,000.
The M:F ratio for MEN2 is close to 1:1 with some evidence suggesting slight female predominance.

Etiology and Pathogenesis

Caused by activating germline mutations in the RET gene, with negative family history not excluding germline disease.
MEN2B often arises from de novo mutations.
RET proto-oncogene mutations impact the tyrosine kinase receptor, crucial for the development of the enteric nervous system and other tissues.

Macroscopic and Histopathology

MTC tumors are usually bilateral and multicentric, appearing white to yellow on cross sections.
MTC histologically resembles sporadic forms but familial cases are more often multifocal.
Parathyroid proliferations are seen in 15–30% of MEN2A patients but absent in MEN2B.

Diagnosis and Genetic Testing

A confirmed diagnosis necessitates identifying pathogenic RET variants.
Essential criterion includes the presence of RET mutations or MTC with additional MEN2 features.

Staging and Prognosis

MEN2 lacks a specific staging system; malignancies are staged using the UICC/AJCC TNM system.
Prognosis for MEN2 is generally more favorable than sporadic MTC, with 10-year survival rates varying by disease stage.

Recommendations for Surgery

Prophylactic thyroidectomy is advised for mutation carriers, ideally before age (1) for the highest-risk individuals, age (5) for high-risk groups with specific mutations, and after age (10) for moderate-risk groups.

Naevoid Basal Cell Carcinoma Syndrome (NBCCS)

An autosomal dominant condition caused by variants in genes of the hedgehog signalling pathway, predominantly PTCH1.
Commonly referred to as Gorlin syndrome or Gorlin–Goltz syndrome.
Identification number for basal cell naevus syndrome: MIM 109400.
ICD-11 classification: LD2D.4.

Localization and Clinical Features

Manifests in multiple organs: skin (basal cell carcinoma, sebaceous cysts), jaws (odontogenic keratocysts), bones (congenital anomalies), and brain (macrocephaly, falx calcification, medulloblastoma).
Other affected areas include eyelids, mouth (cleft lip/palate), and ovaries (ovarian fibromas).
Frequent clinical manifestations include multiple basal cell carcinomas and OKCs, with over 90% of cases presenting both by age 40.
Other diagnostic indicators: calcification of the falx cerebri, palmar and plantar pits, and bifid/fused ribs.

Epidemiology

Syndromic prevalence is estimated between 1:31,000 and 1:256,000.
OKC prevalence in NBCCS ranges from 66% to 86%, increasing to 91% by age 40.
Mean onset age for OKCs is around 15.5 years, but they can appear later in life.
In a study of children with OKCs, 36% were found to have NBCCS, and over half had no prior family history, highlighting the importance of genetic testing.

Etiology and Pathogenesis

Caused by inactivating variants in PTCH1 located on chromosome 9q22, with rare cases linked to PTCH2 on 1p34 or SUFU on 10q24.
Majority of OKCs are associated with PTCH1 inactivation; SUFU mutations lead to different clinical associations.
High detection rates of PTCH1 variants have increased due to improved testing methods.

Molecular and Genetic Aspects

PTCH1 encodes a receptor for hedgehog proteins necessary for regulating cell signalling that affects cell survival, differentiation, and proliferation.
Mutations typically occur throughout the PTCH1 coding region, affecting the sterol-sensing domain and transmembrane region.
Comprehensive mutation analysis and techniques like multiplex ligation-dependent probe amplification are essential for diagnosis.

Diagnostic Criteria

Diagnosis requires two major and one minor diagnostic criteria, or one major and three minor criteria.
In cases of unclear presentations, identification of a pathogenic variant in PTCH1 or SUFU is crucial.

Prognosis and Surveillance

Life expectancy for NBCCS patients is approximately 73.4 years, with minimal reduction compared to the general population, though quality of life may be compromised.
Regular surveillance is vital, with specific guidelines for monitoring patients, especially those carrying SUFU variants for potential medulloblastoma development.

Management Considerations

Genetic counseling is pivotal for affected families to aid in treatment planning and inform care strategies to mitigate radiation exposure risks.
Routine screenings and awareness of associated conditions can improve patient outcomes significantly.

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Description

This quiz explores Hyperparathyroidism-Jaw Tumour syndrome (HPT-JT), an autosomal dominant disorder linked to mutations in CDC73. It highlights the characteristics, coding classifications, and related terminologies of the syndrome, including its link to parathyroid adenoma and carcinoma.