Skin and Nail Disease Features Quiz

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Questions and Answers

What is the most commonly observed clinical feature in patients with dyskeratosis congenita?

Lack of fingerprints

Reticular hyperpigmentation

Nail dystrophy

Oral leukoplakia (correct)

Which age group typically exhibits signs of nail dystrophy in dyskeratosis congenita?

21–30 years

1–4 years

5–13 years (correct)

14–20 years

What inheritance pattern is most commonly associated with dyskeratosis congenita?

Autosomal recessive

X-linked recessive (correct)

Autosomal dominant

Mitochondrial

Which of the following is NOT a typical mucocutaneous finding in dyskeratosis congenita?

Freckles Signup and view all the answers

Which of these cancers is associated with an increased risk in patients with dyskeratosis congenita?

Esophageal carcinoma Signup and view all the answers

Which gene is most commonly implicated in telomere maintenance associated with dyskeratosis congenita?

DKC1 Signup and view all the answers

What is the typical prevalence rate of dyskeratosis congenita?

1 in 1 million Signup and view all the answers

Which of the following symptoms is caused by bone marrow failure in dyskeratosis congenita?

Anemia Signup and view all the answers

What is the primary consequence of telomere shortening due to the lack of dyskerin?

Cellular apoptosis Signup and view all the answers

Which gene is most commonly associated with telomere elongation?

DKC1 Signup and view all the answers

Which protein complex is coded by TINF2 and ACD for telomere protection?

Shelterin complex Signup and view all the answers

What essential criterion must be demonstrated to confirm a clinical diagnosis related to telomere shortening?

Telomere shortening in peripheral blood Signup and view all the answers

Which gene is involved in the control of mRNA stability at the telomeres?

PARN Signup and view all the answers

What percentage of patients may experience bone marrow failure by the age of 40 years?

40% Signup and view all the answers

Which component is primarily involved in recruiting telomerase to the telomere?

CTC1 Signup and view all the answers

Which of the following describes a cutaneous finding associated with telomere-related conditions?

Epidermal atrophy Signup and view all the answers

What is the primary genetic cause of Bloom syndrome?

Loss-of-function variants in the BLM gene Signup and view all the answers

Which of the following clinical features is most commonly associated with Bloom syndrome?

High-pitched voice and distinctive facial features Signup and view all the answers

What type of cancer are individuals with Bloom syndrome at the greatest risk of developing?

Colorectal cancer Signup and view all the answers

Which immunological condition is most likely to be present in individuals with Bloom syndrome?

Low levels of IgM and IgA Signup and view all the answers

How significantly are individuals with Bloom syndrome at risk of developing cancers compared to the general population?

150-300 times more likely Signup and view all the answers

Which characteristic feature is least likely to be associated with Bloom syndrome?

High blood pressure Signup and view all the answers

Which epidemiological fact is true about Bloom syndrome?

It is extremely rare with about 283 cases reported Signup and view all the answers

What is a common reproductive issue faced by men with Bloom syndrome?

Oligospermia and azoospermia Signup and view all the answers

What is the primary result of loss of BLM function in Bloom syndrome?

Accumulation of errors during DNA replication Signup and view all the answers

Which population has the highest estimated prevalence of Bloom syndrome?

Ashkenazi Jewish population Signup and view all the answers

What is an essential diagnostic criterion for confirming a diagnosis of Bloom syndrome?

Biallelic pathogenic variants in the BLM gene Signup and view all the answers

What is the main cause of death in individuals with Bloom syndrome?

Cancer and related complications Signup and view all the answers

What is the recommended measure to minimize health risks for children with Bloom syndrome?

Avoidance of sunlight exposure Signup and view all the answers

Which feature is NOT typically observed in Bloom syndrome?

Increased hair growth Signup and view all the answers

What location on the chromosome is the BLM gene found?

15q26.1 Signup and view all the answers

Which of the following is a method for diagnosing Bloom syndrome?

Identification of increased sister-chromatid exchanges Signup and view all the answers

What role does ATM protein primarily play in the cell?

DNA repair Signup and view all the answers

Which of the following is NOT a characteristic feature of ataxia telangiectasia (AT)?

Enhanced ability to repair oxidative damage Signup and view all the answers

What percentage of head and neck squamous cell carcinoma (HNSCC) cases have been associated with hypermethylation of the ATM promoter?

25% Signup and view all the answers

Which protein complex is important for the optimal activation of ATM at DNA double-stranded breaks?

MRN complex Signup and view all the answers

Which statement accurately describes the pathogenesis of ATM mutations?

They can result in both truncating and missense mutations. Signup and view all the answers

What is the estimated lifetime risk of malignancy in patients with ataxia telangiectasia?

25% Signup and view all the answers

Which of the following is considered an essential diagnostic criterion for ataxia telangiectasia?

Lymphopenia Signup and view all the answers

What additional roles does ATM protein serve in cellular functions aside from DNA repair?

Includes regulation of apoptosis and oxidative stress response Signup and view all the answers

What is the inheritance pattern of Ataxia–telangiectasia?

Autosomal recessive Signup and view all the answers

Which symptoms are commonly associated with Ataxia–telangiectasia?

Cerebellar degeneration and recurrent sinopulmonary infections Signup and view all the answers

Where is the ATM gene located in the human genome?

Chromosome 11q22.3 Signup and view all the answers

Which of the following tumors is least likely to develop in patients with Ataxia–telangiectasia?

Myeloid neoplasms Signup and view all the answers

What is the typical incidence rate of Ataxia–telangiectasia?

1 in 40,000–100,000 births Signup and view all the answers

Which feature is often absent in patients with variant Ataxia–telangiectasia?

Telangiectases Signup and view all the answers

What type of immune deficiency is commonly seen in individuals with Ataxia–telangiectasia?

Deficiency of cellular immunity Signup and view all the answers

Which anatomical region commonly experiences lymphoid neoplasms in patients with Ataxia–telangiectasia?

Waldeyer ring Signup and view all the answers

Which imaging method is used for cluster 2 tumours?

FDOPA PET-CT Signup and view all the answers

What genetic alteration is primarily linked to familial paragangliomas?

Constitutional pathogenic sequence variants Signup and view all the answers

What morphological feature can suggest a genetic predisposition in paragangliomas?

Vacuolated eosinophilic cytoplasm Signup and view all the answers

Which immunohistochemical marker is commonly identified in paraganglioma cells?

Neuroendocrine markers Signup and view all the answers

What is typically characterized by a loss of expression of fumarate hydratase in familial paragangliomas?

SDH-related tumours Signup and view all the answers

What is a criterion that has a high predictive value for identifying SDHB, SDHC, or SDHD mutations?

Loss of SDHB immunoreactivity Signup and view all the answers

What is the estimated five-year overall survival rate for patients with metastatic paraganglioma?

50% to 70% Signup and view all the answers

Which main characteristic feature differentiates SDH-associated paragangliomas from sporadic ones?

Presence of clear cytoplasm Signup and view all the answers

What is a desirable diagnostic criterion for familial paragangliomas?

Loss of SDHB immunoreactivity Signup and view all the answers

What is a characteristic localization for sympathetic-derived paragangliomas?

Adrenal glands Signup and view all the answers

Which clinical feature is primarily associated with catecholamine excess from sympathetic paragangliomas?

Hypertension Signup and view all the answers

Which cluster of tumours tends to be clinically silent and is often non-secretory?

Cluster 1 tumours Signup and view all the answers

What type of imaging is useful for visualizing cluster 1 tumours due to SSTR expression?

68Ga-DOTATATE PET-CT Signup and view all the answers

Which of the following best describes the secretion profile of parasympathetic paragangliomas?

Mainly dopamine with minimal manifestations Signup and view all the answers

What is the consequence of the catecholamine profile in familial paragangliomas?

Strong genotype–phenotype correlation Signup and view all the answers

Which region are parasympathetic-derived paragangliomas most likely to arise from?

Head and neck region Signup and view all the answers

What type of paraganglioma typically leads to the symptoms of sweating and anxiety?

Sympathetic paraganglioma Signup and view all the answers

What is a clinical characteristic of spiradenomas and cylindromas in Brooke–Spiegler syndrome?

They usually appear as multiple nodules that may coalesce. Signup and view all the answers

In Brooke–Spiegler syndrome, where are salivary gland tumors primarily located?

In the parotid gland, specifically as membranous-type basal cell adenomas. Signup and view all the answers

Which of the following terms is NOT considered acceptable terminology related to Brooke–Spiegler syndrome?

Skin-salivary gland tumour diathesis Signup and view all the answers

What is the primary genetic inheritance pattern of Brooke–Spiegler syndrome?

Autosomal dominant Signup and view all the answers

What defines the phenotypic variant of Brooke–Spiegler syndrome known as multiple familial trichoepithelioma?

The exclusive development of trichoepitheliomas. Signup and view all the answers

How does the number of cutaneous tumors associated with Brooke–Spiegler syndrome typically change over time?

They increase in number and grow throughout life. Signup and view all the answers

What is the usual size range for nodules formed by spiradenomas, cylindromas, and spiradenocylindromas?

5–30 mm Signup and view all the answers

Which feature is a potential indicator of malignant transformation in Brooke–Spiegler syndrome tumors?

Rapid growth, ulceration, and bleeding. Signup and view all the answers

What is the common feature of benign cutaneous and salivary gland tumors observed macroscopically?

They appear as well-demarcated nodules. Signup and view all the answers

Which type of mutation is most commonly reported in the CYLD gene?

Frameshift mutations Signup and view all the answers

In which age group is salivary gland involvement typically observed in at-risk patients?

Over 40 years old Signup and view all the answers

What histopathological feature differentiates membranous-type basal cell adenomas (BCAs) from pleomorphic adenomas?

Basaloid appearance and palisading Signup and view all the answers

Which of the following statements is true regarding the facial nerve and parotid neoplasms?

Both facial nerve paralysis and visual alterations are rare. Signup and view all the answers

What type of inheritance is observed for the pathogenic variant in the CYLD gene associated with BSS?

Autosomal dominant inheritance Signup and view all the answers

Which characteristic appearance is associated with cylindroma on histopathology?

Mosaic-like arrangement of islands Signup and view all the answers

What is true regarding the clone of tumor cells in membranous-type BCA?

They consist of monomorphic small basaloid cells. Signup and view all the answers

Which combination of tumors indicates a higher suspicion for BSS?

Single cylindroma with multicentric salivary gland BCA Signup and view all the answers

Which factor is NOT a consideration in the inheritance pattern of the CYLD gene mutations?

Age at onset of skin lesions Signup and view all the answers

Which of the following is a significant consideration for the prognosis of salivary gland membranous-type BCA?

Local aggressive growth or distant metastases Signup and view all the answers

What type of tumorous growth pattern is primarily associated with cylindrical neoplasms?

Membranous type Signup and view all the answers

What symptom is prevalent in patients with multiple familial trichoepitheliomas (MFT)?

Skin lesions predominantly occurring during childhood Signup and view all the answers

Which immunohistochemical markers are present in the cell nests of membranous-type BCAs?

Both epithelial and myoepithelial markers Signup and view all the answers

Study Notes

Clinical Features

Characterized by a triad: oral leukoplakia (80%), nail dystrophy (90%), and reticulate hyperpigmentation/poikiloderma (80-90%).
Oral leukoplakia most often appears on the tongue.
Nail dystrophy presents as longitudinal ridging, typically observed between ages 5-13.
Reticular hyperpigmentation shows a fine, lace-like pattern, commonly on the face, upper trunk, and upper arms.
Additional mucocutaneous findings include adermatoglyphia (absence of fingerprints), palmoplantar hyperkeratosis, early greying, hair loss (scalp or eyelashes), and epiphora (watering eyes).
Bone marrow failure occurs in 90% of cases by the second decade of life.
Increased risk of squamous cell carcinoma of head and neck, upper aerodigestive tract cancers (esophageal carcinoma, gastric adenocarcinoma), and hematological malignancies like myelodysplasia and Hodgkin lymphoma.

Epidemiology

Prevalence is approximately 1 in 1 million.

Etiology

Caused by pathogenic sequence variants in genes involved in telomere biology.
Most common inheritance pattern is X-linked recessive (DKC1).
Other inheritance patterns include autosomal dominant (TERC, TINF2), autosomal recessive (NOP10, NHP2, WRAP53, CTC1), and both autosomal dominant or recessive (TERT).
De novo mutations can occur with TINF2.

Pathogenesis

Telomeres, non-coding sequences at chromosome ends, are maintained by telomerase, which prevents telomere shortening during cell division.
Primary gene affected is DKC1, encoding dyskerin essential for telomere maintenance.
Without dyskerin, telomeres shorten, leading to cellular apoptosis, senescence, and DNA replication issues.
Telomere-related genes include DKC1, TERC, TERT, NOP10, NHP2 (telomerase complex), TINF2, ACD (shelterin complex), and CTC1 (CST complex).

Histopathology

Nonspecific cutaneous findings: epidermal atrophy, dermal telangiectasia, and pigment incontinence.

Diagnostic Molecular Pathology

Diagnosis confirmed by telomere length testing, showing lengths below the first percentile in peripheral blood leukocytes.
Gene sequencing can help confirm diagnosis.

Essential and Desirable Diagnostic Criteria

Essential criteria: telomere shortening in peripheral blood; clinical findings in skin, nails, or mouth.
Desirable criteria: mutations in affected genes, including DKC1, TERC, TERT, among others.

Prognosis and Prediction

Prognosis depends on genetic and environmental factors.
Mild cases may have few clinical features; severe cases may lead to bone marrow failure by age 20.
By age 40, 40% of patients may experience bone marrow failure.

Bloom Syndrome Overview

Rare autosomal recessive chromosomal breakage syndrome caused by mutations in the BLM gene.
Characterized by a significantly increased risk of tumors, including oropharyngeal carcinoma.

Genetic Information

MIM Number: 210900
ICD-O Coding: Specific coding not defined.
ICD-11 Coding: 4A01.31, classified under DNA repair defects other than combined T-cell or B-cell immunodeficiencies.

Clinical Features

Prominent physical characteristics include small stature, reduced weight, and head size, along with a lack of subcutaneous fat.
Skin rash commonly appears on the cheeks and nose after sun exposure during infancy.
Distinctive facial features: long and narrow face, prominent nose and ears, and small lower jaw.
Affected individuals generally maintain normal intellectual abilities.
Fertility issues: men often face infertility (azoospermia and oligospermia), while women may be fertile but commonly experience early menopause.
Immune system abnormalities lead to recurrent infections in infants and increase risks of chronic obstructive lung disease and type 2 diabetes.
Cancer risk is significantly elevated (150–300 times higher than normal), with 66% of cases involving solid tumors and 33% leukemia/lymphoma.

Cancer Incidence

Colorectal cancer is the most prevalent tumor (29 cases), followed by skin, breast, and oropharyngeal cancers (24 cases each).

Epidemiology

First described in 1954 by David Bloom in New York City.
Approximately 283 cases reported in the Bloom Syndrome Registry.
Estimated prevalence in the Ashkenazi Jewish population is 1 in 48,000 births.
A specific founder mutation (BLM(Ash)) is prevalent among 1 in 100 individuals of Ashkenazi Jewish descent, with additional mutations observed in Slavic and Hispanic populations.

Etiology

Caused by mutations in the BLM gene located on chromosome 15q26.1, encoding a member of the RECQ family of DNA helicases.

Pathogenesis

Loss of BLM function leads to errors during DNA replication, resulting in chromosomal rearrangements and increased genetic instability, contributing to cancer predisposition.

Diagnosis

Confirmatory tests may include detecting biallelic pathogenic variants in the BLM gene and increased frequency of sister-chromatid exchanges in cytogenetic studies.
Essential diagnostic criteria: presence of clinical features such as small size and distinctive facial traits, along with identification of BLM mutation.

Prognosis

Main cause of mortality is cancer and related complications, typically occurring in the third decade of life.
Prevention strategies include avoidance of sun exposure to the face and limiting ionizing radiation, alongside regular cancer screening and surveillance.

Ataxia–telangiectasia (AT)

Autosomal recessive disorder caused by pathogenic variants in the ATM gene.
Different diseases can affect multiple systems due to the condition.

Coding and Identification

ICD-O code: MIM 208900 for Ataxia–telangiectasia (AT).
ICD-11 code: 4A01.31 denotes DNA repair defects not linked to combined T-cell or B-cell immunodeficiencies.

Terminology and Subtypes

Louis–Bar syndrome is not recommended terminology for AT.
Variant ataxia–telangiectasia exists, characterized by milder symptoms.

Clinical Manifestations

Symptoms include progressive cerebellar ataxia, cerebellar degeneration, and telangiectases in sun-exposed areas.
Other symptoms: recurrent sinopulmonary infections, hypogonadism, insulin resistance, and malignancies.
Malignancies often present as lymphoid neoplasms of B- and T-cell lineages with distinctions in head and neck involvement.

Epidemiology

Incidence: Approximately 1 case per 40,000–100,000 births, with global prevalence.

Etiology

Caused by homozygous pathogenic sequence variants in the ATM gene at chromosome region 11q22.3.
Some cases involve mutations in MRE11 resulting in a variant AT-like disorder.

Pathogenesis

ATM gene has 66 exons, mutations are scattered with no distinct hotspots.
Most pathogenic variants lead to classic phenotypes, while some missense mutations cause milder forms (variant AT).
ATM is a protein kinase involved in DNA repair, especially double-stranded breaks, and related to other cellular functions including cell cycle regulation and apoptosis.

Tumor Characteristics

No observable differences between AT-associated tumors and sporadic tumor presentations in macroscopic, histopathological, and cytological analyses.

Diagnostic Molecular Pathology

ATM-related deletions noted in head and neck squamous cell carcinoma (HNSCC).
Hypermethylation of the ATM promoter found in 25% of HNSCCs, correlating with decreased ATM expression.

Diagnostic Criteria

Essential criteria include characteristic neurological symptoms, telangiectases, elevated serum AFP levels in over 95% of patients, decreased immunoglobulins, lymphopenia, increased chromosome breakage post-X-ray exposure, and the presence of ATM pathogenic variants.

Prognosis

Patients with AT have a lifetime cancer risk of 25%.
Leading causes of death are cancer and respiratory insufficiency.

Familial Paraganglioma Syndromes

Inherited cancer syndromes characterized by the presence of paragangliomas.
ICD-O coding: MIM #27513; ICD-11 coding: None available.
Related terminology includes familial paraganglioma-phaeochromocytoma syndromes and hereditary paraganglioma-phaeochromocytoma syndromes.

Localization and Types

Parasympathetic-derived paragangliomas commonly found in the head and neck, especially at the carotid body and along glossopharyngeal and vagus nerves.
Sympathetic-derived paragangliomas typically are intra-adrenal (phaeochromocytoma) or retroperitoneal.

Clinical Features

Symptoms often result from catecholamine excess, including sweating, palpitations, anxiety, hypertension, and tachycardia.
Parasympathetic paragangliomas may secrete dopamine but often present with minimal clinical manifestations.
Genotype-phenotype correlation observed in catecholamine profiles.

Tumor Classifications

Cluster 1 Tumors: Pseudohypoxic pathogenesis, usually non-secretory or dopamine-secreting, express somatostatin receptors (SSTR) and are best visualized by 68Ga-DOTATATE PET-CT.
Cluster 2 Tumors: Exhibit kinase signaling, potentially functional, can be imaged with FDOPA PET-CT or 123I-MIBG.

Epidemiology

Approximately 40% of paragangliomas are hereditary.
Constitutional pathogenic sequence variants connected to younger age at presentation and presence of multiple or extra-adrenal tumors.

Etiology and Pathogenesis

Genetic alterations are the main cause of familial paraganglioma syndromes.
Tumors may present as multifocal and can resemble conditions seen in multiple endocrine neoplasia type 2.

Histopathology

Familial paragangliomas have overlapping morphology with sporadic forms, with potential genetic predisposition features.
SDH-associated tumors may show distinct patterns, while von Hippel–Lindau syndrome-associated tumors often present clear cells with vacuolation.

Immunohistochemistry

Tumors express neuroendocrine markers and various indicators can assist in diagnosing familial disease.
Loss of SDHB immunoreactivity indicates the presence of SDH-related diseases, with specific markers identifying mutations.

Cytological Diagnosis

Diagnosis can be challenging but enhanced by immunohistochemistry.

Genetic Testing and Diagnostic Criteria

Genetic testing is essential to confirm responsible mutations.
Essential diagnostic criteria: at least one paraganglioma or confirmed pathogenic sequence variant in a susceptibility gene.
Desirable criteria include loss of SDHB immunoreactivity indicating potential mutations.

Staging

TNM staging applicable for phaeochromocytomas and sympathetic paragangliomas; no published system for extra-adrenal paragangliomas in the head and neck.

Prognosis and Survival

Most paragangliomas are amenable to surgical resection.
Challenges include large tumors and multifocality, mimicking metastasis.
Five-year overall survival rates for metastatic paraganglioma range from 50% to 70%.

Overview of Brooke–Spiegler Syndrome (BSS)

Inherited autosomal dominant disorder.
Characterized by multiple skin tumors: spiradenomas, cylindromas, spiradenocylindromas, and trichoepitheliomas.
Associated with salivary gland tumors, particularly basal cell adenoma (BCA), membranous type.

Genetic and Coding Information

ICD-O coding: relevant for neoplasm classification.
MIM number for BSS: 605041.
Other related conditions include cylindromatosis (132700) and multiple familial trichoepithelioma (601606).

Localization of Tumors

Skin tumors primarily located on head and neck.
Trichoepitheliomas commonly found in nasolabial folds.
Salivary gland tumors typically occur in the parotid gland; rarely affect submandibular glands.

Clinical Features

Tumors present as multiple nodules (5–30 mm), often skin-colored, reddish, or blue.
Trichoepitheliomas are small (2–10 mm), bilateral, and frequently confluent.
Tumor growth continues throughout life and increases with age.
Signs of malignancy include rapid growth, ulceration, and bleeding, particularly in older patients.

Epidemiology

BSS and related conditions are rare; precise incidence rates are unknown.
1-2% of BSS patients develop salivary gland tumors; MFT typically presents only with skin lesions.
Skin tumors generally emerge around puberty; salivary gland involvement often seen post-40 years.

Etiology and Pathogenesis

Caused by heterozygous pathogenic variants in the CYLD gene linked to tumor suppression.
Mutations predominantly in exons 9–20; over 100 variations reported.
Somatic mutations observed in cutaneous neoplasms.

Macroscopic and Histopathological Features

Tumors appear as unencapsulated, ovoid to round nodules.
Membranous-type BCA displays homogeneous tan cut surfaces and multicentric growth.
Histologically, classic features include peripheral palisading of dark cells and a dense hyaline stroma.

Diagnostic Criteria

Essential for diagnosis: presence of multiple inherited and histologically confirmed skin tumors or identification of pathogenic variants in the CYLD gene.
Salivary gland tumors can raise suspicion for BSS if they accompany skin lesions.

Prognosis and Malignancy Potential

Salivary gland membranous-type BCA and skin lesions (spiradenoma, cylindroma) are generally benign.
Development of malignant tumors can occur, usually presenting aggressive growth or metastasis.
Prognostic data remains sparse due to rarity and variability of lesions.

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Description

Test your knowledge on the clinical features of a disease characterized by hyperpigmentation, nail dystrophy, and oral leukoplakia. This quiz focuses on the signs and prevalence of these conditions, particularly in specific age groups. Assess your understanding of this triad and its implications.