48: Inherited Palmoplantar Keratodermas Flashcards
What are inherited palmoplantar keratodermas (PPKs) characterized by?
Inherited palmoplantar keratodermas (PPKs) are characterized by hyperkeratosis of the palms and soles, with or without associated features, and are classified according to their morphology, inheritance, and the presence or absence of extracutaneous features.
What is Epidermolytic PPK (EPPK) and its common cause?
Epidermolytic PPK (EPPK) is the most common form of diffuse keratoderma, resulting from heterozygous mutations in KRT9 (most cases) or KRT1 (the minority of cases) encoding keratin 9 and keratin 1, respectively.
What is the significance of the term ‘Diffuse NEPPK with transgrediens’?
Diffuse NEPPK with transgrediens may be observed in Greither syndrome and PPK Bothnia type, caused by missense heterozygous mutations in KRT1 and heterozygous gain-of-function mutations in AP1S, respectively, and manifests with a white, spongy appearance of the palms and soles upon exposure to water.
What is the relationship between Mal de Meleda and its genetic mutations?
Mal de Meleda is a form of autosomal recessive, progressive, diffuse, mutilating PPK caused by biallelic mutations in SLURP1.
What are the characteristics of Naxos disease (ND) and Carvajal syndrome (CS)?
Naxos disease (ND) and Carvajal syndrome (CS) are characterized by diffuse PPK and cardiocutaneous syndromes featuring mutations in the genes JUP and DSP, affecting plakoglobin and desmoplakin. ND is associated with right ventricular cardiomyopathy and mainly left ventricular involvement.
What are the features of Striate PPK?
Striate PPK results from heterozygous nonsense or frameshift mutations in the genes encoding desmoglein 1, desmoplakin, and to a lesser degree keratin 1. It is characterized by striate patterns on the palms and soles.
What are the three morphological patterns of Palmoplantar Keratoderma (PPK)?
- Diffuse PPK - uniform involvement of the entire palmoplantar surface.
-
Focal PPK - localized hyperkeratosis, predominantly on pressure points:
- Areata or nummular type: oval lesions, mainly on the plantar surface.
- Striate type: longitudinal hyperkeratotic lesions extending from the palms along the volar surface of the fingers.
- Punctate PPK - multiple, discrete 1-mm to 1-cm round keratotic papules over the palms and soles.
What is the epidemiological prevalence of Epidermolytic PPK (EPPK)?
- EPPK has a prevalence of 4.4 per 100,000 people.
- It is the most common form of diffuse keratoderma with a worldwide incidence of 2.2 to 4.4 per 100,000 live newborns.
What are the key components of the diagnosis algorithm for Palmoplantar Keratoderma (PPK)?
- Cutaneous findings - PPK morphology (e.g., diffuse, focal, punctate, mutilating), hair (e.g., woolly hair), or nail abnormalities, along with features associated with other genodermatoses (e.g., skin fragility).
- Extracutaneous findings - such as periodontitis and deafness.
- Mode of inheritance - e.g., autosomal dominant, autosomal recessive, mitochondrial inheritance.
- Histopathologic findings - such as epidermolytic hyperkeratosis, disadhesion of keratinocytes, or parakeratosis.
A patient presents with uniform thickening of the entire palmoplantar surface. What morphological pattern of PPK does this suggest?
This suggests Diffuse PPK, characterized by uniform involvement of the entire palmoplantar surface.
A patient has localized hyperkeratosis on pressure points with oval lesions on the plantar surface. What type of PPK is this?
This is Focal PPK, specifically the Areata or nummular type, characterized by oval lesions mainly on the plantar surface.
What is the prevalence of Nonepidermolytic PPK (NEPPK) in Northern Sweden?
The prevalence of Nonepidermolytic PPK (NEPPK) in Northern Sweden is 0.3% to 0.55%.
What are the four sets of data used in the diagnostic algorithm for PPK?
The four sets of data are: 1) Cutaneous findings (e.g., PPK morphology, hair, nail abnormalities), 2) Extracutaneous findings (e.g., periodontitis, deafness), 3) Mode of inheritance (e.g., autosomal dominant, autosomal recessive), and 4) Histopathologic findings (e.g., epidermolytic hyperkeratosis).
A patient has constricting bands around digits leading to autoamputation. What mutation-related condition might this indicate?
This might indicate a mutation causing pseudoainhum, which is associated with constricting bands around digits.
What is the most common form of diffuse keratoderma worldwide?
The most common form of diffuse keratoderma worldwide is Epidermolytic Palmoplantar Keratoderma (EPPK).
How does the epidemiology of Epidermolytic PPK (EPPK) compare to that of Nonepidermolytic PPK (NEPPK) and Unna-Thost syndrome?
- Epidermolytic PPK (EPPK): Prevalence of 4.4 per 100,000 people.
- Nonepidermolytic PPK (NEPPK): Prevalence of 0.3% to 0.55%.
- Unna-Thost syndrome: Prevalence rate of 5.2 in 10,000.
What are the main categories of conditions associated with palmo plantar keratoderma?
The main categories of conditions associated with palmo plantar keratoderma include:
Category | Conditions |
|———-|————|
| Inflammatory Skin Disorders | Psoriasis, Lichen planus, Hypertension, Chronic dermatitis, Reactive arthritis |
| Metabolic Disorders | Hypothyroidism, Myxedema, Chronic lymph edema |
| Drugs and Chemical Exposures | Lithium, Hydroxyurea, Chemotherapeutic agents, Chronic alcohol exposure |
| Infectious Diseases | Dermatitis, Syphilis, Tuberculosis |
| Malignancies | Pancreatic keratoderma, Cutaneous lymphoma |
| Miscellaneous | Keratoderma climactericum, Punctate keratolysis |
What are some acquired conditions that occur later in life associated with palmo plantar keratoderma?
Acquired conditions that occur later in life associated with palmo plantar keratoderma include:
Condition | Description |
|———–|————-|
| Inflammatory Skin Disorders | Conditions like psoriasis and lichen planus |
| Infectious Diseases | Conditions such as syphilis and tuberculosis |
| Malignancies | Including pancreatic keratoderma and cutaneous lymphoma |
What are some genodermatoses associated with palmo plantar keratoderma?
Genodermatoses associated with palmo plantar keratoderma include:
Genodermatosis | Description |
|—————-|————-|
| Autosomal recessive congenital ichthyosis (ARCI) | A genetic skin disorder characterized by dry, scaly skin |
| Ichthyosis Curth-Macklin | A form of ichthyosis with palmoplantar keratoderma |
| Keratitis ichthyosis congenita-keratoderma (KLICK) syndrome | A rare genetic disorder with skin and eye symptoms |
| Channarin-Dorfman syndrome | A genetic disorder with ichthyosis and other features |
What are the key criteria used in the diagnostic algorithm for inherited palmoplantar keratodermas (PPKs)?
The diagnostic algorithm for inherited palmoplantar keratodermas (PPKs) is based on four key criteria:
1. Skin disorders associated with PPK
2. Extracutaneous features present
3. Pathological findings observed
4. Family history of similar conditions
These criteria help in identifying the specific type of PPK and associated syndromes.
What are some acquired conditions associated with palmoplantar hyperkeratosis and other features resembling palmoplantar keratoderma?
Acquired conditions associated with palmoplantar hyperkeratosis include:
- Inflammatory Skin Disorders:
- Psoriasis
- Lichen planus
- Pityriasis rubra pilaris
- Metabolic Disorders:
- Hypothyroidism
- Myxedema
- Infectious Diseases:
- Dermatitis
- Syphilis
- Malignancies:
- Cutaneous lymphoma
- Bullous epidermolysis
These conditions can occur later in life and may present with similar symptoms to inherited forms of PPK.
What are some genodermatoses associated with palmoplantar keratoderma as a feature?
Genodermatoses associated with palmoplantar keratoderma include:
- Ichthyoses:
- Autosomal recessive congenital ichthyosis (ARCI)
- Epidermolytic ichthyosis
- Keratosis:
- Keratitis ichthyosis congenita-keratoderma (KLICK) syndrome
- Ectodermal Dysplasia:
- Schopf-Schulz-Passarge syndrome
- Oculodentodigital dysplasia
These syndromes highlight the genetic basis of palmoplantar keratoderma and its association with other systemic features.
What distinctive characteristics can accompany PPK in loricrin keratoderma (LK)?
Autoamputation of digits can accompany PPK in loricrin keratoderma (LK).
What are some nonhereditary diseases that may cause constricting bands with or without hyperkeratosis?
- Leprosy
- Tertiary syphilis
- Yaws
- Scleroderma
- Raynaud syndrome
- Amniotic bands
- Ergotamine poisoning
- Spinal medulla tumors
- Syringomyelia
- Scar formation from frostbite, burns, and trauma
Which syndromes are associated with PPK and squamous cell carcinoma?
- Huriez syndrome
- Unna-Thost syndrome
- Dyskeratosis congenita
- Rothmund-Thomson syndrome
- Xeroderma pigmentosum
What are common topical treatments for PPK?
- Emollients
- Topical keratolytic formulations (e.g., 10% to 20% salicylic acid or 35% to 70% propylene glycol combined with thick emollient)
- Topical calcipotriol and topical tazarotene
- Soaking in water and mechanical removal of hyperkeratotic areas
- Reducing repeated trauma to the feet with orthotics or cushioned footwear
What are the recommended oral retinoids for treating PPK?
- Short term or intermittent therapy is sometimes recommended.
What are the treatments for PPK?
Treatments for PPK include emollients, topical keratolytic formulations (e.g., 10% to 20% salicylic acid), topical calcipotriol, topical tazarotene, soaking in water, mechanical removal of hyperkeratotic areas, and reducing repeated trauma with orthotics or cushioned footwear.
What are the recommended oral retinoids for treating PPK?
Short term or intermittent therapy is sometimes recommended. Systemic retinoids are effective in conditions like EPPK, MDM, VS, LK, OS, Huriez syndrome, Punctate PPK 1, and PLS. A low starting dose of acitretin (0.5 mg/kg/day) or alitretinoin (10 mg/day) is advised.
What surgical therapy options are available for PPK?
Surgical excision and grafting is an option in focal PPK and in cases associated with mutation.
What are the common therapeutic approaches for PPK?
Common therapeutic approaches include topical treatments (e.g., emollients, keratolytic formulations), oral retinoids (e.g., acitretin, alitretinoin), and surgical therapy (e.g., excision and grafting for focal PPK).
What are some distinctive characteristics that can accompany PPK in loricrin keratoderma (LK)?
Autoamputation of digits can accompany PPK in loricrin keratoderma (LK).
Which nonhereditary diseases may cause constricting bands with or without hyperkeratosis?
Leprosy, tertiary syphilis, scleroderma, Raynaud syndrome, amniotic bands, ergotamine poisoning, spinal medulla tumors, syringomyelia, and scar formation from frostbite, burns, and trauma.
What are the clinical features of Epidermolytic Palmoplantar Keratoderma (EPPK)?
EPPK is characterized by yellowish, diffuse PPK with erythematous sharp margins at the edges of the palms and soles, presenting at birth or during the first weeks of life, with complications like painful fissures, hyperhidrosis, maceration, and secondary infections.
What are the genetic mutations associated with Epidermolytic Palmoplantar Keratoderma (EPPK)?
EPPK is associated with heterozygous mutations in KRT9 encoding keratin 9, and a minority of cases have mutations in KRT1 encoding keratin 1.
What are the specific treatments for Epidermolytic Palmoplantar Keratoderma (EPPK)?
Inhibition of KRT9 mutant allele expression in a mouse model using RNA interference (RNAi)–based therapy has shown promise.
How does Unna-Thost Palmoplantar Keratoderma (NEPPK) differ from Epidermolytic Palmoplantar Keratoderma (EPPK)?
NEPPK has a later onset, well-demarcated yellowish thick hyperkeratosis with an erythematous rim, and is smoother and waxier compared to the thicker and fissured texture of EPPK.
What is the genetic basis of Epidermolytic Palmoplantar Keratoderma (EPPK)?
EPPK is an autosomal dominant genodermatosis caused by heterozygous mutations in KRT9 or, less commonly, KRT1.
What are the histopathologic findings in EPPK?
Histopathologic findings include compact orthokeratosis, hypergranulosis, acanthosis, and epidermolytic hyperkeratosis with perinuclear vacuolization of keratinocytes.
What are the clinical features associated with NEPPK?
NEPPK features hyperhidrosis, refractory secondary dermatophyte infections, pitted keratolysis, hyperkeratosis around the umbilicus and nipple, and dryness of knees and elbows.
What mutation is associated with Unna-Thost Palmoplantar Keratoderma?
Unna-Thost Palmoplantar Keratoderma is associated with mutations in KRT9 and KRT1.
What are the clinical features of Greither Syndrome?
Greither Syndrome features autosomal dominant inheritance, onset after the 2nd year of life, diffuse thickened scaly yellowish PPK with an erythematous rim, and involvement of skin over the Achilles tendon.
What is the pathology associated with Sybert PPK?
Sybert PPK is characterized by epidermal hyperplasia with hypergranulosis, parakeratosis, orthokeratosis, and sparse lymphocytic infiltrate.
What are the essential clinical features for diagnosing Loricrin Keratoderma?
The essential clinical features are honeycomb-like keratoderma and generalized ichthyosis.
What are the histopathological findings associated with Diffuse NEPPK?
Histopathological findings include hyperkeratosis, orthokeratosis, acanthosis, and hyper- or hypo-granulosis.
How does the clinical presentation of Greither Syndrome differ from Sybert PPK?
Greither Syndrome presents with diffuse, thickened, scaly PPK with an erythematous rim, while Sybert PPK is characterized by progressive diffuse PPK with transgrediens and autoamputation.
What are the clinical features of Palmoplantar Keratoderma Bothnia type?
Palmoplantar Keratoderma Bothnia type is characterized by diffuse homogeneous hyperkeratosis with a yellowish hue, high prevalence in Northern Sweden, and typical white spongy appearance upon exposure to water.
What is the etiology and pathogenesis of Palmoplantar Keratoderma Bothnia type?
GOF mutations in the gene AQP5, encoding water-channel protein aquaporin 5 (AQP5).
Where is AQP5 mostly found?
Mostly found in the apical plasma membrane and involved in the excretion of water from exocrine glands (salivary gland, lacrimal gland, and sweat gland).
In which cells is AQP5 also expressed?
Also expressed in epithelial cells of the lung and the cornea.
What condition has been associated with decreased expression of AQP5?
Sjögren syndrome has been associated with decreased expression of AQP5.
Where is AQP5 localized in normal palmoplantar skin?
AQP5 is localized to the plasma membrane of keratinocytes of the stratum granulosum.
What is the expression of AQP5 in PPKB lesions?
AQP5 expression is retained, and affected keratinocytes are subject to increased water uptake through the plasma membrane.
What are the clinical features of Mal de Meleda?
Autosomal recessive disorder.
When does the onset of Mal de Meleda occur?
Onset of the disease: infancy or early childhood.
Describe the appearance of plaques in Mal de Meleda.
Diffuse transgressive yellowish waxy hyperkeratotic plaques outlined by a red scaly border over the palms and soles preceded by prominent and persistent erythema.
How does palmoplantar hyperkeratosis progress?
Palmoplantar hyperkeratosis progresses with age and extends onto the dorsal surface of the hands and feet in a glove and stocking distribution.
What additional features are associated with Mal de Meleda?
Knuckle pads, lichenoid or keratotic plaques over joints, perioral erythema, hyperhidrosis with superinfection, malodorous maceration and painful fissures.
What are the histopathological findings in Palmoplantar Keratoderma Bothnia type?
Non-specific findings.
What does the histopathological examination include?
Include orthohyperkeratosis.
What is noted in the upper dermis during histopathological examination?
Mild lymphocytic infiltrate in the upper dermis.
What is the genetic basis of Loricrin Keratoderma?
Information not provided.
What is the genetic basis of Loricrin Keratoderma?
Loricrin Keratoderma is caused by heterozygous frameshift insertion or deletion mutations in LOR, which encodes loricrin.
What are the clinical features of Palmoplantar Keratoderma Bothnia Type?
Features include diffuse, homogeneous hyperkeratosis with a yellowish hue, hyperhidrosis, maceration, and secondary fungal infections.
What mutation is associated with Palmoplantar Keratoderma Bothnia Type?
Palmoplantar Keratoderma Bothnia Type is associated with gain-of-function mutations in the AQP5 gene, encoding aquaporin 5.
What are the clinical features of Palmoplantar Keratoderma Bothnia type?
- Autosomal dominant form of diffuse NEPPK
- High prevalence (0.3% to 0.55%) in West and Northwest Gulf of Bothnia in Northern Sweden
- Chinese Han descent
- Manifests during infancy or childhood with a diffuse, homogeneous hyperkeratosis with a yellowish hue over the palms and soles that extends to the dorsal digits
- Typical white spongy appearance of affected areas upon exposure to water
- Hyperhidrosis, maceration, and secondary fungal infections are common
- Abnormal nails (curved with ragged cuticles)
What is the pathogenesis of Palmoplantar Keratoderma Bothnia type?
- GOF mutations in the gene AQP5, encoding water-channel protein aquaporin 5
- Mostly found in the apical plasma membrane and involved in the excretion of water from exocrine glands (salivary gland, lacrimal gland, and sweat gland)
- Also expressed in epithelial cells of the lung and the cornea
- Normal palmoplantar skin: AQP5 is localized to the plasma membrane of keratinocytes of the stratum granulosum
What are keratinocytes of the stratum granulosum?
Keratinocytes are cells in the stratum granulosum layer of the skin.
What are PPKB lesions?
PPKB lesions retain AQP5 expression, leading to increased water uptake through the plasma membrane.
What are the clinical features of Mal de Meleda?
Mal de Meleda is an autosomal recessive disorder with onset in infancy or early childhood.
What do the plaques in Mal de Meleda look like?
They are diffuse, transgressive yellowish waxy hyperkeratotic plaques outlined by a red scaly border over the palms and soles, preceded by prominent and persistent erythrema.
What additional features can be seen in Mal de Meleda?
Additional features include knuckle pads, lichenoid or keratotic plaques over joints, perioral erythrema, hyperhidrosis with superinfection, malodorous maceration, and painful fissures.
What are the histopathological findings in Palmoplantar Keratoderma Bothnia type?
Non-specific findings include orthohyperkeratosis and mildly lymphocytic infiltrate in the upper dermis.
What are the clinical features of Nagashima-type palmoplantar keratoderma (NPPK)?
NPPK is an autosomal recessive disorder and the most common type of PPK in Asian populations.
What is the estimated prevalence of NPPK in Japan?
In Japan, the estimated prevalence is 1.2 in 10,000.
What is the estimated prevalence of NPPK in China?
In China, the estimated prevalence is 2.3 to 3.1 in 10,000.
When does NPPK begin and how does it progress?
NPPK begins in the first years of life and progresses until puberty with no further progression.
What does the palmoplantar hyperkeratosis in NPPK look like?
It is diffuse, well-demarcated, erythematous palmoplantar hyperkeratosis extending to the dorsal surfaces of hands, feet, inner wrists, ankles, and Achilles tendon.
Is there involvement of other joints in NPPK?
Yes, involvement of elbows and knees is common.
What complications are frequently associated with NPPK?
NPPK is frequently complicated by hyperhidrosis, superinfection by dermatophytes, distinct odor, and maceration.
Is there evidence of malignancy in NPPK?
No evidence of malignancy has been reported.
What are the distinct features of Nagashima-type palmoplantar keratoderma (NPPK)?
Distinct odor and maceration.
What genetic mutations are associated with Nagashima-type palmoplantar keratoderma (NPPK)?
Biallelic mutations in the gene SERPINB7, encoding serpin family B member 7 (SERPIN7).
What are loss-of-function (LOF) mutations?
Mutations resulting from aberrant splicing or premature stop codons with nonsense or frameshift mutations.
What is compound heterozygosity for a missense founder mutation?
Mutation c.830C>T, resulting in proline to leucine change.
What is a recurrent nonsense mutation in SERPINB7?
Mutation c.796C>T, prevalent in both Chinese and Japanese NPPK patients, likely reflecting a founder effect.
What are the pathologic features observed in patients with Malignant Melanoma (MDM)?
Hyperkeratosis, orthokeratosis, foci of parakeratosis, marked acanthosis.
What are the notable histological findings in MDM patients?
More pronounced stratum lucidum and a perivascular lymphohistiocytic infiltrate.
What does electron microscopy reveal in MDM patients?
A less abrupt transition between the stratum granulosum and stratum corneum.
What are the characteristics of normal intermediate filaments?
Normal intermediate filaments and corneodesmosomes.
What is the significance of SLURP-1 in palmoplantar keratoderma?
SLURP-1 is a secreted epidermal neuromodulator essential for epidermal homeostasis and inhibition of tumor necrosis factor (TNF) necrosis.
What does SLURP-1 regulate?
It upregulates the expression of transglutaminase 1, cytokeratin 10, and caspases 3 and 8, influencing apoptotic activity.
How does SLURP-1 affect epidermal differentiation?
Regulates epidermal differentiation through cholinergic pathways.
What can deficiency in SLURP-1 lead to?
Increased susceptibility to viral infections and development of malignancies.
What is the susceptibility to viral infections and development of malignant melanoma (MM)?
Increased susceptibility to viral infections and development of malignant melanoma (MM).
What gene mutation causes Mal de Meleda?
Mal de Meleda is caused by biallelic mutations in the SLURP1 gene, which encodes a secreted epidermal neuromodulator.
What are the clinical features of Nagashima-Type Palmoplantar Keratoderma?
Features include diffuse, well-demarcated erythematous palmoplantar hyperkeratosis extending to dorsal surfaces, hyperhidrosis, and maceration.
What are the clinical features of Mal de Meleda?
Mal de Meleda features diffuse transgressive yellowish waxy hyperkeratotic plaques with a red scaly border, hyperhidrosis, and complications like pseudoainhum and nail abnormalities.
What are the clinical features of Nagashima-type palmoplantar keratoderma (NPPK)?
- Autosomal recessive disorder
- Most common type of PPK in Asian populations
- Estimated prevalence: Japan: 1.2 in 10,000; China: 2.3 to 3.1 in 10,000
- Begins in the first years of life and progresses until puberty with no further progression
- Diffuse, well-demarcated, erythematous palmoplantar hyperkeratosis extending to dorsal surfaces of hands, feet, inner wrists, ankles, and Achilles tendon
- Involvement of elbows and knees is common
- Frequently complicated by hyperhidrosis, superinfection by dermatophytes, distinct odor, and maceration.
What genetic mutations are associated with Nagashima-type palmoplantar keratoderma?
- Biallelic mutations in the gene SERPINB7, encoding serpin family B member 7 (SERPIN7)
- Loss-of-function (LOF) mutations resulting from aberrant splicing or premature stop codons
- Compound heterozygosity for a missense founder mutation c.830C>T, resulting in prol.
What is the mutation c.830C>T associated with?
It results in a proline to leucine change.
What is the recurrent nonsense mutation in SERPINB7?
The mutation c.796C>T is prevalent in Chinese and Japanese NPPK patients, likely reflecting a founder effect.
How does SLURP-1 deficiency influence the pathogenesis of palmoplantar keratoderma?
SLURP-1 deficiency affects the efficiency of triglyceride hydrolysis in keratinocytes, crucial for forming acylceramides that maintain the epidermal barrier.
What are the results of SLURP-1 deficiency?
It leads to leakage of interstitial fluids into the stratum corneum and accumulation of triglyceride droplets, favoring microorganism growth responsible for malodorous skin in MDM.
What role does SLURP-1 play in psoriasis?
SLURP-1 may play a role in the pathogenesis of psoriasis, with expression upregulated in imiquimod-induced psoriasis in mice.
What are the pathological findings associated with palmoplantar keratoderma?
Findings include hyperkeratosis, orthokeratosis, foci of parakeratosis, marked acanthosis, and a pronounced stratum lucidum.
What is observed in perivascular lymphohistiocytic infiltrate?
It is a pathological finding in palmoplantar keratoderma.
What does electron microscopy show in palmoplantar keratoderma?
It shows a less abrupt transition between the stratum granulosum and stratum corneum, with normal intermediate filaments and corneodesmosomes.
What are the characteristics of keratohyalin granules in palmoplantar keratoderma?
They are non-specific, irregularly shaped, with a spongy appearance.
What is the role of SERPINB7 in the epidermis?
SERPINB7 is distributed in the epidermis, particularly in the stratum granulosum and upper part of the stratum corneum. In NPPK skin, SERPINB7 immunoreactivity is markedly diminished.
What is suggested about chronic exposure to mechanical stress regarding SERPINB7?
It may inhibit proteases and protect keratinocytes or corneocytes from damage, contributing to the development of NPPK.
What are the clinical features of Olmsted Syndrome?
Olmsted Syndrome is characterized by:
- Rare prevalence < 1 in 1,000,000; M>F
- Onset at birth or early childhood, progressively worsening over time
- Symmetric, sharply demarcated diffuse PPK with yellowish-brown hyperkeratosis and painful fissures
- Involvement of areas around the mouth, nostrils, and perigenital region, extending to other body parts
- Additional findings include severe pruritus, onychodystrophy, abnormal dentition, and hair abnormalities.
What are the extracutaneous manifestations associated with Olmsted Syndrome?
Extracutaneous manifestations of Olmsted Syndrome include:
- Hearing loss
- Ocular abnormalities (e.g., corneal dystrophy)
- Short stature and mental retardation
- Primary sclerosing cholangitis
- Joint laxity, ankyloses, osteopenia, and osteolysis
- Erythromelalgia.
What are the pathological findings associated with Olmsted Syndrome?
Pathological findings in Olmsted Syndrome include:
- Orthohyperkeratosis with acanthosis and hypergranulosis
- Mild to moderate perivascular lymphocytic infiltrate in the upper dermis
- Predominance of CD4+ T cells with barely detectable CD20+ B cells in dermal infiltrates.
What genetic mutations are associated with Olmsted Syndrome?
Genetic mutations associated with Olmsted Syndrome include:
- Mutations in the TRPV3 gene, which is highly expressed in keratinocytes and plays a role in epidermal barrier formation and pain sensation.
- X-linked recessive mutations in MBTPS2, which encodes a zinc metalloprotease essential for cholesterol homeostasis and endoplasmic reticulum function.
What is essential for cholesterol homeostasis and endoplasmic reticulum stress response?
Epidermal protease inhibitors are essential for cholesterol homeostasis and endoplasmic reticulum stress response.
What mutation is associated with Nagashima-Type Palmoplantar Keratoderma?
Nagashima-Type Palmoplantar Keratoderma is associated with biallelic mutations in the SERPINB7 gene, encoding serpin family B member 7.
What are the clinical features of Olmsted Syndrome?
Olmsted Syndrome features symmetric, sharply demarcated diffuse PPK with painful fissures, periorificial keratotic plaques, and complications like pseudoainhum and SCC.
What mutation is linked to Olmsted Syndrome?
Olmsted Syndrome is linked to mutations in the TRPV3 gene, encoding transient receptor potential vanilloid 3.
What role do epidermal protease inhibitors play in maintaining skin health?
Epidermal protease inhibitors, such as EKT1, LEKT1-2, elafin, and serpins, maintain epidermal homeostasis by inhibiting both endogenous proteases in the stratum granulosum and exogenous proteases from various sources.
Mutations affecting serpins can lead to symptoms through:
1. Loss of protease inhibitory activity, resulting in uncontrolled protease activity.
2. Aggregation of mutant serpin polymers in cells, causing cell death and tissue damage (known as ‘serpinopathies’).
How does the distribution of SERPINB7 in the epidermis relate to the clinical features of Non-Palmoplantar Keratoderma (NPPK)?
SERPINB7 is distributed in the epidermis, particularly in the stratum granulosum and upper part of the stratum corneum. In NPPK, SERPINB7 immunoreactivity is markedly diminished, suggesting that chronic mechanical stress may inhibit its protective role against protease-induced damage.
What may inhibit stress’s protective role against protease-induced damage?
Stress may inhibit its protective role against protease-induced damage, leading to the characteristic clinical features of NPPK, which is limited to areas like hands, feet, knees, and elbows.
What are the key clinical features of Olmsted Syndrome?
Olmsted Syndrome is characterized by:
- Rare prevalence: < 1 in 1,000,000; affects both males and females.
- Onset: Appears at birth or in early childhood, progressively worsening over time.
- Skin manifestations: Symmetric, sharply demarcated diffuse palmoplantar keratoderma (PPK) with yellowish-brown hyperkeratosis, painful fissures, and erythematous borders, often affecting pressure points and leading to flexion deformities.
- Additional findings: Severe pruritus, onychodystrophy, abnormal dentition, and various hair abnormalities.
What extraneous features are associated with Olmsted Syndrome?
Extraneous manifestations of Olmsted Syndrome include:
- Hearing loss and ocular abnormalities (e.g., corneal dystrophy).
- Short stature and mental retardation.
- Joint issues: Primary sclerosing cholangitis, joint laxity, ankyloses, osteopenia, and osteolysis.
- Erythromelalgia.
How do the features of Olmsted Syndrome impact patient quality of life?
These features can significantly impact the quality of life, leading to physical limitations and increased healthcare needs.
What genetic mutations are associated with Olmsted Syndrome?
Olmsted Syndrome is associated with mutations in: TRPV3 and MBTPS2.
What is TRPV3?
A gene involved in pain sensation and pruritus, highly expressed in keratinocytes and hair follicles, affecting epidermal barrier formation.
What is MBTPS2?
An X-linked recessive mutation that encodes a zinc metalloprotease essential for cholesterol homeostasis and endoplasmic reticulum stress response.
What are the implications of these mutations?
These mutations lead to increased apoptosis in keratinocytes, contributing to the clinical manifestations of the syndrome.
What are the specific treatments for palmoplantar keratosis?
- Partial excision of palmoplantar keratosis or full-thickness excision with skin grafting.
- EGFR inhibitors have been shown to improve PPK.
- TRPV3 antagonists may be an effective treatment for patients harboring GOF mutations in the TRPV3 gene.
What are the clinical features of Vohwinkel Syndrome?
- Triad of diffuse, mutilating PPK with a “honeycomb-like” appearance.
- Starfish-shaped keratotic plaques on the dorsal hands, feet, and extensor surfaces.
- Fibrous constricting bands (pseudoainhum) at the interphalangeal joints.
What are the associated findings in KID syndrome?
- Chronic cheilitis and perleche.
- Nail dystrophy and oral manifestations (leukokeratosis, deep fissures of the tongue).
What are the clinical features of palmoplantar keratoderma?
Features include leukokeratosis and deep fissures of the tongue.
What are the symptoms associated with palmoplantar keratoderma?
Hypohidrosis and heat intolerance.
What is the prevalence of sparse hair in palmoplantar keratoderma?
10% to 23% of individuals have congenital atrichia.
What characterizes progressive keratitis?
It begins in childhood and is characterized by corneal inflammation and pain.
What is a common feature of congenital severe non-progressive hearing loss?
It is bilateral and severe.
What infections are individuals with palmoplantar keratoderma prone to?
They are prone to mucocutaneous infections, mostly bacterial and candidal.
What are gap junctions?
They are intercellular junctions formed by connexons.
What do gap junctions facilitate?
They facilitate and regulate the passage of water and small molecules between adjacent cells.
What are the common findings in Bart-Pumphrey syndrome?
It is a rare, autosomal dominant disorder.
What is a notable feature of severe SNHL in Bart-Pumphrey syndrome?
It has a honeycomb-like appearance.
What are knuckle pads and leukonychia?
They are common findings in Bart-Pumphrey syndrome.
What are the most common findings in Bart-Pumphrey syndrome?
Hearing loss and knuckle pads; leukonychia and PPK are seen less frequently.
What are the features of PPK?
It features diffuse, sharply demarcated thickening of the palmoplantar skin with a punctate, grainy surface reminiscent of Vohwinkel Syndrome.
What are the clinical features of Vohwinkel Syndrome?
It features diffuse mutilating PPK with honeycomb-like appearance, starfish-shaped plaques, pseudoainhum, and high-frequency sensorineural hearing loss.
What are the clinical features of KID Syndrome?
It features erythrokeratoderma, diffuse PPK, congenital bilateral severe sensorineural hearing loss, and progressive keratitis leading to visual decline.
What are the clinical features of Bart-Pumphrey Syndrome?
It features severe sensorineural hearing loss, PPK with a honeycomb-like appearance, knuckle pads, and leukonychia.
What are the key clinical features of Vohwinkel Syndrome (VS) associated with palmoplantar keratoderma?
Key clinical features of Vohwinkel Syndrome include:
-
Triad of symptoms:
- Diffuse palmoplantar keratoderma with a “honeycomb-like” appearance.
- Starfish-shaped keratotic plaques on dorsal hands, feet, and extensor surfaces.
- Fibrous constricting bands (pseudoainhum) at interphalangeal joints.
-
Associated conditions:
- High-frequency sensorineural hearing loss (SNHL).
- Generalized ichthyosis, acanthosis nigricans, cicatricial alopecia, and nail anomalies.
- Bullous lesions on soles and craniofacial anomalies.
- Risk of skin cancers (SCC and BCC) in hyperkeratotic lesions.
How does KID syndrome manifest and what are its associated findings?
KID syndrome manifests with:
-
Cutaneous features:
- Erythrokeratoderma with symmetrical, well-circumscribed hyperkeratotic plaques.
- Thickened skin with coarse-grained appearance or follicular hyperkeratosis.
- Diffuse palmoplantar keratoderma with a rough, stippled, or grainy appearance.
-
Associated findings:
- Chronic cheilitis, nail dystrophy, and oral manifestations (leukokeratosis).
- Hypohidrosis, heat intolerance, and sparse hair (10-23% congenital atrichia).
- Progressive keratitis leading to photophobia and corneal inflammation.
- Congenital, bilateral, and severe SNHL, prone to infections and benign tumors.
What are the treatment options for palmoplantar keratoderma associated with genetic mutations?
Treatment options for palmoplantar keratoderma include:
- Surgical intervention
What are surgical interventions for palmoplantar keratoderma?
Partial excision of palmoplantar keratosis or full-thickness excision with skin grafting.
What are pharmacological treatments for palmoplantar keratoderma?
EGFR inhibitors have shown improvement in palmoplantar keratoderma.
TRPV3 antagonists may be effective for patients with gain-of-function mutations in the TRPV3 gene.
What are the clinical features of Bart-Pumphrey syndrome?
Severe sensorineural hearing loss (SNHL) and palmoplantar keratoderma with a honeycomb-like appearance.
What are common findings in Bart-Pumphrey syndrome?
Knuckle pads and leukonychia.
What is the progression of symptoms in Bart-Pumphrey syndrome?
Hearing loss and knuckle pads may develop early in life, with PPK being less frequent.
PPK features diffuse, sharply demarcated thickening of palmoplantar skin resembling Vohwinkel Syndrome.
What are connexons and how do they function in cell communication?
Connexons are formed by the oligomerization of 6 connexins, leading to the formation of a hemichannel. They interact with connexons from opposing cells through their extracellular portions to form a channel, which is the basic unit of the gap junction. Each connexon consists of 4 transmembrane domains, 3 cytoplasmic domains, and 2 extracellular loops, with main differences found in the C-terminal tails.
What is the role of GJB2 in hearing loss?
GJB2 encodes Cx26, and recessive mutations producing loss of function (LOF) are the most common cause of nonsyndromic sensorineural hearing loss (SNHL) in humans.
What is a dominant-negative GJB2 mutation?
A dominant-negative GJB2 mutation can lead to progressive degeneration of sensory hair cells, resulting in the loss of the tunnel of Corti due to disturbed cortilymph homeostasis.
What are the clinical features of Vohwinkel Syndrome (VS)?
Vohwinkel Syndrome is characterized by compact hyperkeratosis, orthokeratosis, acanthosis, significant hypergranulosis with irregularly shaped keratohyaline granules, papillomatosis of the epidermis, and dermal fibrosis with sparse perivascular lymphocytic infiltrate.
What are the common mutations associated with KID syndrome?
KID syndrome is commonly associated with a recurrent missense mutation in GJB2, specifically p.Asp50Asn, which replaces aspartic acid in codon 50 with asparagine. Other mutations include p.Gly45Glu, linked to fatal forms of KID syndrome, and a heterozygous mutation in GJB6 encoding Cx30, which alters the first transmembrane helix of Cx30.
What are the specific treatments for Vohwinkel Syndrome?
Specific treatments for Vohwinkel Syndrome include:
- Cross finger flap
- Treatment with Z-plasty
- Full-thickness excision of the constriction band with a full-thickness skin graft
- Distant abdominal skin flap for fifth digit constriction bands.
What mutation is associated with Vohwinkel Syndrome?
Vohwinkel Syndrome is associated with a recurrent heterozygous missense mutation, p.Asp66His, in the GJB2 gene encoding connexin 26.
What mutation is linked to KID Syndrome?
KID Syndrome is linked to a recurrent missense mutation, p.Asp50Asn, in the GJB2 gene.
What mutation is associated with Bart-Pumphrey Syndrome?
Bart-Pumphrey Syndrome is associated with mutations in the GJB2 gene encoding connexin 26.
What are the histopathologic findings in Vohwinkel Syndrome?
Findings include compact hyperkeratosis, orthokeratosis, acanthosis, hypergranulosis, papillomatosis, and dermal fibrosis with sparse perivascular lymphocytic infiltrate.
What are the histopathologic findings in KID Syndrome?
Findings include epidermal hyperplasia, compact orthokeratotic hyperkeratosis, focal parakeratosis, and swollen keratinocytes with vacuolated cytoplasm.
What are the histopathologic findings in Bart-Pumphrey Syndrome?
Findings include massive orthokeratotic hyperkeratosis, hypergranulosis, acanthosis, and papillomatosis.
What are the specific treatments for Vohwinkel Syndrome?
Specific treatments include cross finger flap, Z-plasty, full-thickness excision of constriction bands, and distant abdominal skin flap for digit constriction bands.
What are the specific treatments for KID Syndrome?
Specific treatments include keratolimbal allograft, keratoplasty, topical corticosteroids, cyclosporine, and bevacizumab for ocular manifestations.
What are the specific treatments for Bart-Pumphrey Syndrome?
Specific treatments are not explicitly mentioned, but management focuses on addressing PPK and hearing loss.
What is the role of connexins in PPK with deafness?
Connexins form gap junctions that facilitate intercellular communication. Mutations in connexin genes (e.g., GJB2) disrupt this function, leading to PPK with deafness.
What is the genetic basis of PPK with deafness?
PPK with deafness is associated with heterozygous mutations in the GJB2 gene, such as p.R75Q.
What are the main structural components of a connexon?
Connexons are formed by the oligomerization of 6 connexins, leading to the formation of a hemichannel. They consist of:
- 4 transmembrane domains
- 3 cytoplasmic domains (including the amino-terminus, a cytoplasmic loop, and the carboxy terminus)
- 2 extracellular loops
What is the significance of connexons in cell communication?
These components allow connexons from opposing cells to interact, forming a channel that is essential for gap junction communication.
How do mutations in connexin genes affect hearing and skin conditions?
Mutations in connexin genes can lead to various conditions:
- GJB2 (Cx26) mutations are the most common cause of non-syndromic sensorineural hearing loss (SNHL).
- Vohwinkel Syndrome (VS) is often caused by a recurrent heterozygous missense mutation in GJB2, leading to skin manifestations such as hyperkeratosis and acanthosis.
- KID syndrome is associated with mutations in GJB2 that affect skin and hearing, resulting in ichthyosis and deafness.
What are the clinical features and pathology associated with Vohwinkel Syndrome (VS)?
Vohwinkel Syndrome (VS) is characterized by:
- Compact hyperkeratosis and acanthosis.
- Significant hypergranulosis with large, irregularly shaped keratohyaline granules.
What is Papillomatosis?
Papillomatosis of the epidermis.
What is Dermal fibrosis?
Dermal fibrosis with sparse perivascular lymphocytic infiltrate.
What are the ultrastructural findings in Vohwinkel Syndrome?
Marked swollen mitochondria, increased numbers of desmosomes in the spinous and granular layers, corneocytes containing many membrane coating granules and lipid-like vacuoles.
What are the specific treatments for Vohwinkel Syndrome?
- Cross finger flap
- Treatment with Z-plasty
- Full-thickness excision of the constriction band with a full-thickness skin graft
- Distant abdominal skin flap for fifth digit constriction bands.
What is the aim of surgical interventions for Vohwinkel Syndrome?
These surgical interventions aim to alleviate symptoms and improve function.
What are the clinical implications of mutations in the GJB2 gene related to KID syndrome?
Mutations in the GJB2 gene associated with KID syndrome lead to:
- Histrix-like ichthyosis-deafness (HID) syndrome, which is allelic to KID syndrome.
- The p.Asp50Asn mutation results in altered trafficking of the connexin protein, affecting gap junction formation.
- Clinical features include follicular spiny hyperkeratosis, congenital atrichia, and nail abnormalities.
Where do mutations associated with KID syndrome cluster?
These mutations cluster in regions coding for the first extracellular domain and the cytoplasmic amino terminal domain, altering the charge and structure of the connexin protein, which is crucial for its function.
What are the clinical features of Palmoplantar Keratoderma - Congenital Alopecia Syndrome?
The clinical features include two forms: 1. An autosomal dominant form with a milder phenotype (PPKCA1, Stevanovic type; OMIM #104100). 2. A recessively inherited form associated with pseudoainhum, sclerodactyly, contractures, and sometimes cataracts (PPKCA2, Wallis type; OMIM #212360). Other features include: - Birth: Hair is normal or sparse. - Early infancy: Noncicatricial alopecia involving the scalp, body, or facial hair. - PPK develops in late infancy, well-defined, focal or linear, nonmutilating, and transgrediens in dominant cases. - In recessive cases: Progressive thickening of palms and soles with erythematous rim and skin cracks, leading to contractures, pseudoainhum, and sclerodactyly.
What are the main features of Hidrotic Ectodermal Dysplasia (Clouston Syndrome)?
The main features include: - Autosomal dominant ectodermal dysplasia. - Common among the French-Canadian population. - Nail dystrophy, hair loss, and palmoplantar hyperkeratosis with normal sweat glands and teeth. - Nail abnormalities are usually present, with nearly 30% showing only nail manifestations, including thickening, brittleness, ridging, discoloration, splitting, onycholysis, and 20-nail dystrophy. - Hair abnormalities may be progressive, involving the scalp, facial, and body hair, with conditions like atrichia or hypotrichosis.
What is the etiology and pathogenesis of Palmoplantar Keratoderma - Congenital Alopecia Syndrome?
The etiology includes: - PPKCA1: A heterozygous missense mutation in the gene GJA1, encoding Cx43, which exerts a GOF effect on the Cx43 hemichannel. Cx43 is expressed in various organs, including the epidermis and hair follicles. - PPKCA1 is allelic to oculodentodigital dysplasia (ODDD), characterized by craniofacial dysmorphism, dental, ophthalmologic, and limb abnormalities, and neurodegeneration.
What are the associated findings in Palmoplantar Keratoderma - Congenital Alopecia Syndrome?
Associated findings include: - Follicular plugging with ulerythema ophryogenes-like features. - Keratosis pilaris. - Hyperkeratotic plaques over the ankles, elbows, and popliteal fossae, with multiple spiky, horn-like lesions reminiscent of ichthyosis hystrix. - Nail abnormalities (eukonychia, nail dystrophy). - Cataracts. - Meningocele. - Unilateral deafness.
A patient presents with noncicatricial alopecia and well-defined focal PPK. What genetic mutation might be responsible for this condition?
The condition could be caused by a heterozygous missense mutation in the GJA1 gene encoding Cx43, which exerts a gain-of-function effect on the Cx43 hemichannel.
What are the clinical features of the autosomal dominant form of Palmoplantar Keratoderma associated with Congenital Alopecia Syndrome?
The autosomal dominant form presents with: - A milder phenotype - PPKCA1, Stevanovic type (OMIM #104100) - Normal or sparse hair at birth - Noncicatricial alopecia in early infancy involving the scalp, body, or facial hair - Possible presence of trichorrhexis nodosa on hair microscopy - Development of PPK in late infancy, characterized by well-defined, focal or linear, nonmutilating lesions.
What are the associated findings in the recessively inherited form of Palmoplantar Keratoderma?
The recessively inherited form is associated with: - Pseudoainhum - Sclerodactyly - Contractures - Possible cataracts - Follicular plugging with ulerythema ophryogenes-like features - Keratosis pilaris - Hyperkeratotic plaques over the ankles, elbows, and popliteal fossae - Nail abnormalities such as eukonychia and nail dystrophy - Meningocele and unilateral deafness may also be present.
What is the significance of the GJA1 gene mutation in the context of Palmoplantar Keratoderma?
The GJA1 gene mutation is significant because: - It is a heterozygous missense mutation that exerts a gain-of-function effect on the Cx43 hemichannel. - Cx43 is expressed in various organs, including the epidermis and hair follicles, and is crucial for cell communication. - Mutations in this gene are associated with Palmoplantar Keratoderma and oculodentodigital dysplasia (ODDD), which includes craniofacial dysmorphism and other abnormalities.
What are the main clinical features of Hidrotic Ectodermal Dysplasia (Clouston Syndrome)?
The main clinical features include: - Autosomal dominant ectodermal dysplasia - Nail dystrophy, hair loss, and palmoplantar hyperkeratosis with normal sweat glands and teeth - Nail abnormalities present in nearly 30% of cases, including thickening, brittleness, ridging, and onycholysis - Hair abnormalities may include atrichia or hypotrichosis with brittle, fine, pale, or slow-growing hair. - PPK appears diffuse with a velvet-like or cobblestoned appearance extending onto the fingertips and knuckles with fissures.
What are the rare associations with Hidrotic Ectodermal Dysplasia?
Rare associations include: - Strabismus - Cataract and photophobia - Hearing impairment - Mental deficiency - Bone abnormalities such as thickening of the skull and abnormal phalanges.
What are the clinical features of Huriez syndrome?
Huriez syndrome is characterized by: - Diffuse palmoplantar keratoderma (PPK) - Scleroatrophy of the hands and fingers - Occurrence of squamous cell carcinoma (SCC) within atrophic skin - Sclerodactyly leading to contractures - Symptoms present at birth or in the first years of life, persisting without further progression.
What are the associated findings in Huriez syndrome?
Associated findings include: - Hypohidrosis - Nail changes: hypoplasia, curving, onychorrhexis, koilonychia, longitudinal ridging, and clubbing - Poikiloderma-like changes - Distinctive small nodules on the fingers - Facial telangiectasia.
What is the estimated risk of squamous cell carcinoma (SCC) in Huriez syndrome?
The estimated risk of squamous cell carcinoma (SCC) in Huriez syndrome is 13%, which is greater than a 100-fold higher risk compared to the general population.
What are the skin manifestations of palmoplantar keratoderma (PPK) in Huriez syndrome?
In Huriez syndrome, PPK manifests as: - Diffuse, yellowish-grey, nonerythematous, well-confined hyperkeratotic plaques - Mainly involving the palms with extension towards the fingers - Accentuation of palmar creases - The soles are less frequently involved, usually showing accentuation over pressure sites.
What are the sclerodermoid changes associated with Huriez syndrome?
Sclerodermoid changes include: - Pseudosclerodermoid appearance of the hands and digits with absence of dermatoglyphs - Erythematous, atrophic appearance of the dorsal aspect of the hands, fingers, and tips of the fingers and toes, without evidence of Raynaud phenomenon.
A patient with Huriez syndrome develops skin ulcers on atrophic skin. What is the estimated risk of squamous cell carcinoma (SCC) in such cases?
The estimated risk of SCC in Huriez syndrome is 13%, which is more than 100-fold higher than the general population.
A patient with Huriez syndrome has scleroatrophy of the hands. What is the role of p53 mutations in this condition?
p53 mutations may be responsible for the development of actinic keratoses and SCC in Huriez syndrome.
A patient with Huriez syndrome shows scleroatrophy of the hands and fingers. What are the key pathological findings in this condition?
Pathological findings include marked acanthosis, papillomatosis, hypergranulosis, orthokeratotic hyperkeratosis, and dense collagen fibers in the reticular dermis.
A patient with Huriez syndrome has nail hypoplasia and clubbing. What is the risk of internal malignancies in this condition?
Although cases of internal malignancies like gastric carcinoma have been reported, they do not seem to be more frequent in Huriez syndrome than in the general population.
What are the clinical features of Huriez syndrome and how do they manifest in patients?
Huriez syndrome is characterized by: - Diffuse palmoplantar keratoderma (PPK): Yellowish-grey, nonerythematous, well-confined hyperkeratotic plaques mainly on palms, extending towards fingers and accentuating palmar creases. - Scleroatrophy of hands and fingers: Pseudoserodermoid appearance with absence of dermatoglyphs. - Skin changes: Erythematous, atrophic appearance of dorsal aspects of hands and fingers, with no evidence of Raynaud phenomenon. - Associated findings: Hypohidrosis, nail changes (hypoplasia, curving, onychorrhexis, koilonychia, longitudinal ridging, clubbing), poikiloderma-like changes, distinctive small nodules on fingers, and facial telangiectasia. - Malignant degeneration: Increased risk of squamous cell carcinoma (SCC) in atrophic skin, with an estimated risk of 13%.
What is the estimated risk of squamous cell carcinoma (SCC) in patients with Huriez syndrome, and what factors contribute to this risk?
The estimated risk of squamous cell carcinoma (SCC) in patients with Huriez syndrome is 13%, which is greater than a 100-fold higher risk compared to the general population. Factors contributing to this risk include: - Malignant degeneration starting with skin ulcers on atrophic skin. - Poor differentiation of tumors, leading to high rates of metastasis and a calculated mortality rate of 5%. - Association with internal malignancies: Although cases of gastric and pharyngeal carcinoma have been described, they do not appear to be more frequent in Huriez syndrome than in the general population.
How do mutations in GJB6 and GJB2 relate to the clinical features of hearing impairment and skin manifestations in patients with HED?
Mutations in GJB6 and GJB2 are associated with different clinical features in patients with Hidrotic Ectodermal Dysplasia (HED): - GJB6 mutations typically result in skin manifestations without evidence of hearing impairment. For example, a p.N14S mutation in GJB6 was found in a patient with HED. - GJB2 mutations can lead to both skin symptoms and deafness. A patient with HED and hearing impairment was found to have heterozygous missense mutations in GJB6 and a polymorphism in GJB2. - The presence of Cx26 (encoded by GJB2) may compensate for the absence of Cx30 in the inner ear, but not in the skin, leading to the observed clinical features.
What are the clinical features of Papillon-Lefevre Syndrome (PLS)?
PLS is characterized by: - Palmoplantar hyperkeratosis - Severe progressive periodontitis, leading to loss of primary and permanent teeth - Periodontal disease severity peaks in the teens and declines with age - Incidence: 1 to 4 cases per 1 million people - Carrier rate: 2 to 4 per 1000 - PPK appearance: May occur at birth or during the first months of life, typically developing between the sixth month and fourth year of life - Skin manifestations: Diffuse, erythematous, sharply demarcated hyperkeratotic plaques on palms and soles, with transgrediens features extending onto the dorsal aspect of hands and feet - Associated conditions: Hyperhidrosis, foul-smelling odor, nail abnormalities, increased susceptibility to infections, and potential intellectual disability.
What is the etiology of Papillon-Lefevre Syndrome (PLS)?
PLS results from: - Loss of function (LOF) mutations in the gene CTSC, which encodes cathepsin C (also known as dipeptidyl peptidase) - More than 70 mutations have been reported: approximately half are homozygous missense mutations, 25% are nonsense mutations, and nearly 25% are frameshift mutations - PLS is allelic to Haim-Munk syndrome (HMS), characterized by pes planus, arachnodactyly, acroosteolysis, and onychogryphosis, but without evidence of cerebral calcification and bacterial infections. - CTSC plays a crucial role in the intracellular degradation of proteins and the activation of serine proteases in immune cells.
What are the pathological findings in skin biopsies from patients with Palmoplantar Keratoderma (PPK)?
Pathological findings include: - Marked acanthosis, papillomatosis, and hypergranulosis with increased keratohyaline granules - Orthokeratotic hyperkeratosis - No abnormalities observed in the dermis and sweat glands - In sclerotic regions: Hypergranulosis with orthokeratotic hyperkeratosis, dense collagen fibers in the reticular dermis, and sparse dermal mononuclear cell infiltrates - Ultrastructural findings show dense bundles of tonofilaments and abundant keratohyaline distributed in large clumps of irregular density.
What is the primary cause of the severe progressive periodontitis seen in Papillon-Lefevre Syndrome (PLS)?
PLS is caused by loss-of-function mutations in the CTSC gene, which encodes cathepsin C. This leads to a lack of active CTSC enzymatic protease activity, contributing to severe periodontitis.
What are the primary pathological findings in Papillon-Lefevre Syndrome (PLS)?
Sparse dermal mononuclear cell infiltrates and ultrastructural findings show dense bundles of tonofilaments and abundant keratohyaline distributed in large clumps of irregular density.
What is the role of cathepsin C in Papillon-Lefevre Syndrome (PLS)?
Cathepsin C plays a role in intracellular protein degradation and activation of serine proteases in immune cells. Its deficiency leads to PLS.
What are the clinical features of Papillon-Lefevre Syndrome (PLS) and how do they manifest over time?
PLS is characterized by palmoplantar hyperkeratosis and severe progressive periodontitis, loss of primary and permanent teeth with periosteal changes of the alveolar bone, and severity of periodontal disease peaking in the teens and declining with age.
What are the potential complications associated with Papillon-Lefevre Syndrome (PLS)?
Complications include increased susceptibility to infections, possible intellectual disability, calcification of the dura mater, and an association with atopic diathesis and elevated immunoglobulin E (IgE) levels.
How do mutations in the CTSC gene relate to the pathogenesis of Papillon-Lefevre Syndrome (PLS)?
Mutations in the CTSC gene lead to PLS through loss of function homozygous or compound heterozygous mutations affecting the cathepsin C enzyme, which is crucial for protein degradation and immune function.
What are the clinical features of Naxos disease?
Naxos disease is characterized by a triad of diffuse palmoplantar keratoderma (PPK), cardiomyopathy, and woolly hair.
What is the most common mutation associated with Naxos disease?
The most common reported mutation in Naxos disease is a homozygous 2-bp deletion in the JUP gene, resulting in a truncated plakoglobin (PG).
What are the associated findings in Palmoplantar Hyperkeratosis with Squamous Cell Carcinoma of Skin and Sex Reversal Syndrome?
Associated findings include hypertriglyceridemia, laryngeal cancer, nodular testicular hyperplasia, bilateral cataracts, and bilateral optic nerve coloboma.
What is the primary pathological finding in Naxos disease?
Palmoplantar skin in Naxos disease reveals findings compatible with non-epidermolytic palmoplantar keratoderma (NEPPK).
What is the role of plakoglobin in Naxos disease?
Plakoglobin is a constituent protein in desmosomal junctions, and its mutation leads to the skin and cardiac manifestations of Naxos disease.
What are the clinical features of Naxos disease and how do they relate to its genetic basis?
Naxos disease is characterized by a triad of diffuse palmoplantar keratoderma (PPK), cardiomyopathy, and woolly hair, caused by biallelic mutations in the JUP gene.
Discuss the implications of the genetic mutations associated with Naxos disease on patient prognosis and management.
The most common mutation in Naxos disease is a homozygous 2-bp deletion in the JUP gene, linked to severe manifestations including ventricular tachycardia and sudden death.
What are the key clinical features and associated findings of Palmoplantar Hyperkeratosis with Squamous Cell Carcinoma of Skin and Sex Reversal Syndrome?
This syndrome is characterized by sclerodactyly, palmoplantar keratoderma (PPK), and multiple cutaneous squamous cell carcinomas (SCCs).
What are the clinical features of Palmoplantar Keratoderma with Deafness?
Characterized by orange-yellow diffuse, well-demarcated palmoplantar hyperkeratotic plaques with minimal to no erythema, typically appearing during childhood.
What are the etiological factors associated with Diffuse Inherited Palmoplantar Keratoderma with Extracutaneous Features?
Caused by a homoplasmic point mutation (c.A7445G) in the mitochondrial transfer RNA (tRNA) encoding the MTTS1 gene.
What are the key characteristics of Striate Palmoplantar Keratoderma?
A rare autosomal dominant disorder characterized by linear, thickened, hyperkeratotic plaques over the palms extending along the volar aspect of the digits.
What mutations are associated with Focal Inherited Palmoplantar Keratoderma without Extracutaneous Features?
Nonsense and frameshift heterozygous mutations in the DSG1 or DSP genes.
What are the clinical features of Palmoplantar Keratoderma with Deafness, and how does it present in patients?
Appears during childhood characterized by orange-yellow diffuse, well-demarcated palmoplantar hyperkeratotic plaques with minimal to no erythema.
What is the etiology and pathogenesis of Diffuse Inherited Palmoplantar Keratoderma with Extracutaneous Features?
Caused by a homoplasmic point mutation (c.A7445G) in the mitochondrial transfer RNA (tRNA) encoding the MTTS1 gene.
How do mutations in the DSG1 and DSP genes contribute to the development of Striate Palmoplantar Keratoderma?
Nonsense and frameshift heterozygous mutations in the DSG1 or DSP genes result in haploinsufficiency.
What is the role of desmoglein 1 in the pathogenesis of SPPK?
Desmoglein 1 regulates epidermal proliferation and differentiation; its loss leads to hyperkeratotic phenotype seen in SPPK.
What are the clinical features of the hereditary keratosis palmoplantaris variant of Wachters?
PPK variants, Brünauer-Fohs-Siemens syndrome, characterized by yellowish, nontransgredient, symmetric, nummular, hyperkeratotic plaques localized to pressure points.
What are the two subtypes of Pachyonychia Congenita (PC) and their associated mutations?
PC is divided into PC-1 (KRT6A or KRT16 mutations) and PC-2 (KRT6B or KRT17 mutations).
What are the common clinical features observed in patients with Pachyonychia Congenita?
Common features include thickened toenails, plantar keratoderma, and plantar pain.
What are the pathological findings associated with hereditary keratosis palmoplantaris variant of Wachters?
Pathological findings include hyperkeratosis, hypergranulosis, and possible focal parakeratosis.
What are the clinical features of Hereditary Keratosis Palmoplantaris Variant of Wachters?
PPK variants, Brünauer-Fohs-Siemens syndrome, Siemens syndrome. Rare autosomal dominant disease with complete penetrance. More common in males. Appears in the first or second decade of life. Characterized by yellowish, nontransgredient, symmetric, nummular, hyperkeratotic plaques localized to pressure points on the soles. Palmar hyperkeratotic lesions can be linear, nummular, membranous, fissured, or periungual. Nummular hyperkeratotic plaques may appear over elbows, knees, and Achilles tendon. Associated with palmoplantar hyperhidrosis, painful transverse fissures, and nail changes (ridging and cuticle hyperkeratosis).
How does the loss of desmoglein 1 contribute to the pathogenesis of SPPK?
Loss of desmoglein 1 results in downregulation of proapoptotic signaling, promotion of keratinocyte proliferation, and inhibition of epidermal differentiation due to unopposed ERK signaling, leading to the hyperkeratotic phenotype seen in SPPK. This deficiency results in elevated Ras activity, contributing to the disease pathology.
What are the two subtypes of Pachyonychia Congenita (PC) and their associated mutations?
Subtype | Description | Associated Mutations |
|———|————-|———————|
| PC-1 (Jadassohn-Lewandowski) | Features oral leukokeratosis | KRT6A or KRT16 |
| PC-2 (Jackson-Lawler) | Features cysts and natal teeth | KRT6B or KRT17 |
What are the common clinical features of Pachyonychia Congenita (PC)?
Common clinical features in more than 90% of PC patients include thickened toenails, plantar keratoderma, and plantar pain. Thickened toenails may appear during early childhood or in the first weeks of life, especially with mutations in KRT6A.
What is the most common manifestation of plantar keratoderma in patients with KRT mutations?
The most common manifestation of plantar keratoderma is focal PPK (FPPK) with calluses over weight-bearing areas.
What is the average age of onset for plantar keratoderma (PPK)?
The average age of onset of PPK is 4 years, although it may appear at birth or have delayed onset up to 30 years of age.
What are some additional features associated with Pachyonychia Congenita (PC)?
Additional features of PC include mucosal involvement, cyst formation, and natal teeth.
What percentage of patients with Pachyonychia Congenita exhibit oral leukokeratosis?
Oral leukokeratosis was reported in 70% of patients with Pachyonychia Congenita.
What are the key clinical features of PC associated with mutations in KRT16?
Key clinical features include mild FPPK as a universal finding, less pronounced phenotype with FPPK restricted to weight-bearing areas, limited or absent nail involvement, and no evidence of oral leukokeratosis.
What is the significance of plantar pain in patients with Pachyonychia Congenita?
Plantar pain is considered the most important and debilitating feature that affects patients’ quality of life, often secondary to blister formation deep underneath the thick callus.
What types of cysts are commonly found in patients with KRT17 mutations?
About 40% of patients with KRT17 mutations exhibit various types of epidermal inclusion cysts, such as pilosebaceous cysts and vellus hair cysts.
What is the relationship between KRT6A mutations and laryngeal leukokeratosis in infants?
Infants and children with KRT6A mutations may experience life-threatening respiratory distress secondary to laryngeal leukokeratosis.
A patient with Pachyonychia Congenita (PC) has natal teeth. What genetic mutation is most likely responsible?
Natal teeth in PC are almost exclusively associated with KRT17 mutations.
A patient with Pachyonychia Congenita (PC) has severe plantar pain. What is the underlying cause of this pain?
The severe plantar pain in PC is secondary to blister formation deep underneath the thick callus, as demonstrated by high-frequency ultrasound.
A patient with Pachyonychia Congenita (PC) has oral leukokeratosis. What is the most common genetic mutation associated with this feature?
Oral leukokeratosis is most characteristic of mutations in KRT6A or KRT17.
What is the average age of onset for focal plantar keratoderma (FPPK) in patients, and how does it vary with different mutations?
The average age of onset for FPPK is 4 years, but it may appear at birth or have a delayed onset up to 30 years of age. Patients with mutations in KRT16 and KRT6A develop keratoderma earlier than those with KRT6B and KRT17 mutations.
What are the key clinical features associated with mutations in KRT6A and KRT17 in patients with palmoplantar keratoderma?
Mutation | Key Features |
|———-|————–|
| KRT6A | High likelihood of 10 toenails affected, severe pain, oral leukokeratosis in 70% of patients |
| KRT17 | Associated with natal teeth, epidermal inclusion cysts, and follicular keratosis on the trunk and extremities |
How does the clinical presentation of palmoplantar keratoderma differ between patients with KRT16 mutations and those with KRT6A mutations?
Patients with KRT16 mutations typically present with mild FPPK restricted to weight-bearing areas, limited or absent nail involvement, and no evidence of oral leukokeratosis. In contrast, KRT6A mutations are associated with more severe symptoms, including significant pain and oral leukokeratosis.
What are the implications of oral leukokeratosis in patients with palmoplantar keratoderma, particularly regarding its onset and potential misdiagnosis?
Oral leukokeratosis appears in 70% of patients by age 5, with some cases presenting at birth. It is most characteristic in patients with KRT6A or KRT17 mutations and may be mistaken for candidiasis, potentially affecting feeding and leading to failure to thrive in newborns.
What are the inheritance patterns observed in keratin mutations related to PPK?
Autosomal dominant inheritance is observed in more than half of the cases. Remaining cases are caused by spontaneous dominant mutations. A few reports indicate apparent recessive inheritance. Semidominant inheritance for KRT17 mutations has been reported. Paternal germ cell mosaicism for a KRT6A mutation has also been described.
What are the clinical features of Howel-Evans Syndrome?
Tylosis with esophageal cancer (OMIM #148500). Rare autosomal dominant disorder with complete penetrance. Characterized by the association of PPK and mucosal SCCs, particularly of the esophagus. Prevalence is less than 1 in 1,000,000. Onset of PPK usually occurs during childhood or adolescence (between 5 and 15 years). Features include focal, yellowish, thick plaques localized to areas of pressure or friction on palms and soles, which may be associated with painful fissures and secondary infections.
What are the specific treatments for nail dystrophy associated with PPK?
Mechanical treatments (filing, grinding, cutting, or clipping) and soaking the nails are most effective. Surgical avulsion may be ineffective due to regrowth of nails. Oral leukokeratosis can be improved by maintaining good oral hygiene, gentle brushing, and using oral antibiotics. Follicular hyperkeratosis is treated with oral and topical retinoids, keratolytic agents, and emollients. Rapamycin has shown marked improvement in painful plantar calluses and quality of life by blocking translation of KRT6 mRNA, though it may cause gastrointestinal symptoms.
What are the pathological features observed in skin biopsies from PPK lesions?
Skin biopsies reveal features of NEPPK. Reduced granular layer and cytolysis in the outer root sheath of hair follicles may be seen. Epidermolytic hyperkeratosis has been observed in cases associated with mutation in KRT16. Ultrastructurally, suprabasal keratinocytes in PPK are characterized by densely aggregated keratin filament bundles, predominantly in the perinuclear region. Additional findings include reduced desmosome number, widened intercellular spaces, and reduced keratohyaline granules.
A patient with Pachyonychia Congenita (PC) presents with thickened toenails and plantar keratoderma. What are the most common genetic mutations associated with this condition?
PC is caused by heterozygous mutations in one of five keratin genes: KRT6A, KRT6B, KRT6C, KRT16, and KRT17.
A patient with Pachyonychia Congenita (PC) has severe plantar pain. What is the role of mechanical stress in this condition?
Mechanical stress leads to upregulation of both wild-type and mutant keratins, triggering the PC phenotype and worsening the condition.
What are the implications of mechanical stress on keratin expression in patients with Pachyonychia Congenita (PC)?
Mechanical stress can lead to the upregulation of both wild-type and mutant forms of keratins, resulting in perturbed intermediate filament formation due to mutant keratin incorporation. This triggers the PC phenotype and is linked to aberrant expression of additional mutant keratin as part of the wound healing response, creating a vicious cycle of gradual worsening.
What are the clinical features associated with Howel-Evans Syndrome?
Howel-Evans Syndrome is characterized by tylosis with esophageal cancer (OMIM #148500), rare autosomal dominant disorder with complete penetrance, association of PPK and mucosal squamous cell carcinomas (SCCs), particularly of the esophagus, prevalence of less than 1 in 1,000,000, and onset of PPK usually during childhood or adolescence (between 5 and 15 years), with most cases evident by 7 to 8 years of age, presenting as focal, yellowish, thick plaques on palms and soles, often associated with painful fissures and secondary infections.
What are the specific treatments for nail dystrophy in patients with inherited palmoplantar keratoderma (PPK)?
The most effective approach to nail dystrophy in patients with inherited PPK includes mechanical treatments such as filing, grinding, cutting, or clipping, soaking the nails, surgical avulsion may be ineffective due to regrowth of nails, oral hygiene and gentle brushing for oral leukokeratosis, treatment with oral and topical retinoids, keratolytic agents, and emollients for follicular hyperkeratosis, and intralesional steroid injection and oral antibiotics for secondary infections related to steatocystoma multiplex and other pilosebaceous cysts.
What are the clinical features of Richner-Hanhart Syndrome (RHS)?
Richner-Hanhart Syndrome (RHS) is characterized by tyrosinemia type II, oculocutaneous tyrosinosis, keratosis palmoplantaris with corneal dystrophy. Symptoms typically appear in early childhood, including painful palmoplantar keratoderma (PPK), bilateral keratitis, and mental retardation due to intracellular accumulation of tyrosine crystals and a secondary inflammatory response.
What is the etiology of Richner-Hanhart Syndrome?
Richner-Hanhart Syndrome (RHS) is an autosomal recessive disorder caused by mutations in the TAT gene encoding tyrosine aminotransferase (TAT). Consequences of TAT deficiency include the accumulation of tyrosine in tissues. More than 20 mutations have been identified that alter the activity and stability of the enzyme.
What are the ocular manifestations associated with Richner-Hanhart Syndrome?
Ocular manifestations include:
- Photophobia
- Pain
- Tearing
- Redness
- Pseudoherpetiform keratitis with corneal ulcerations.
What percentage of cases present ocular symptoms in Richner-Hanhart Syndrome?
These symptoms occur in 75% of cases.
When do ocular symptoms typically present in Richner-Hanhart Syndrome?
They typically present soon after birth or within the first year of life.
What skin manifestations are observed in Richner-Hanhart Syndrome?
Skin manifestations typically begin after the first year of life and include:
- Well-demarcated, focal, palmoplantar, white-yellow, hyperkeratotic plaques surrounded by erythema on weight-bearing areas of the soles.
- Associated with pain and often hyperhidrosis.
- Fingertips, hypothenar, and thenar eminences can also be affected.
What neurological manifestations are associated with untreated cases of Richner-Hanhart Syndrome?
Neurological manifestations may include:
- Mental retardation
- Nystagmus
- Tremor
- Ataxia
- Convulsions.
What is the role of iRhom2 in Howel-Evans syndrome?
iRhom2 regulates the trafficking and activation of ADAM17, which plays a pivotal role in proteolytic cleavage and release of substrates like TNF-α and EGF family members.
How does dysregulated EGF signaling contribute to esophageal carcinoma?
Dysregulated EGF signaling contributes to esophageal carcinoma.
What contributes to esophageal carcinoma?
Nalin contributes to esophageal carcinoma.
What is the genetic basis of Howel-Evans syndrome?
Howel-Evans syndrome is caused by gain-of-function missense mutations in the RHBDF2 gene encoding iRhO-2, which is associated with increased risk of esophageal carcinoma.
What is the clinical significance of Howel-Evans syndrome?
A patient with Howel-Evans syndrome has esophageal lesions.
What is the recommended screening protocol for Howel-Evans syndrome?
Annual gastroscopy is recommended for screening esophageal carcinoma in Howel-Evans syndrome.
What is the role of iRhO-2 in the pathogenesis of Howel-Evans syndrome?
iRhO-2 regulates ADAM17 activity, leading to increased EGF receptor signaling and dysregulated wound repair, contributing to the syndrome.
What are the clinical features of Richner-Hanhart Syndrome (RHS)?
Richner-Hanhart Syndrome (RHS) is characterized by:
-
Triad of Symptoms:
- Painful Palmoplantar Keratoderma (PPK)
- Bilateral Keratitis
- Mental Retardation due to intracellular accumulation of tyrosine crystals.
-
Ocular Manifestations:
- Photophobia, pain, tearing, redness, and pseudoherpetiform keratitis with corneal ulcerations.
- Symptoms typically present soon after birth or within the first year of life.
-
Skin Manifestations:
- Well-demarcated, focal, palmoplantar, white-yellow, hyperkeratotic plaques surrounded by erythema on weight-bearing areas of the soles.
- Associated with pain and often hyperhidrosis.
- Fingertips, hypothenar, and thenar eminences can also be affected.
-
Neurologic Manifestations:
- Mental retardation, nystagmus, tremor, ataxia, and convulsions in untreated cases.
What is Richner-Hanhart Syndrome (RHS)?
Richner-Hanhart Syndrome (RHS) is an autosomal recessive disorder caused by mutations.
What mutations cause Richner-Hanhart Syndrome?
- Mutations in the TAT Gene: The TAT gene encodes tyrosine aminotransferase (TAT). Deficiency in TAT leads to the accumulation of tyrosine in tissues.
What is the role of disease severity in Richner-Hanhart Syndrome?
- Disease Severity: More than 20 mutations have been identified that alter the activity and stability of the TAT enzyme. Disease severity correlates with the presence of a mutant protein; its absence is associated with more favorable features.
What is the pathophysiological mechanism of Richner-Hanhart Syndrome?
- Pathophysiological Mechanism: Intracellular L-tyrosine crystals destabilize lysosomal membranes, initiating cell injury and inflammation, leading to typical skin lesions.
How do tyrosine crystals contribute to skin lesions in RHS?
In Richner-Hanhart Syndrome (RHS), the presence of tyrosine crystals contributes to skin lesions through:
- Destabilization of Lysosomal Membranes: Intracellular L-tyrosine crystals destabilize lysosomal membranes, leading to cell injury.
What initiates the inflammatory response in RHS?
- Inflammatory Response: The destabilization initiates a cascade of inflammation, resulting in the characteristic skin lesions.
What is the mechanism of hyperkeratosis in RHS?
- Hyperkeratosis Mechanism: Excessive intracellular concentration of tyrosine leads to noncovalent cross-links among keratins, forming aggregated tonofilaments, which manifest as palmoplantar hyperkeratosis.
What laboratory findings are indicative of Richner-Hanhart Syndrome?
Richner-Hanhart Syndrome (RHS) is diagnosed by a specific set of laboratory findings.
What is Richner-Hanhart Syndrome (RHS)?
RHS is diagnosed by a high level of serum tyrosine (with normal phenylalanine) and accumulation of tyrosine metabolites in the urine, including p-hydroxyphenylpyruvate, p-phenylacetate, and p-hydroxyphenylacetate.
What distinguishes RHS from type I tyrosinemia?
A static level of urinary succinylacetone distinguishes RHS from type I tyrosinemia.
What are the key pathological features of Richner-Hanhart Syndrome (RHS)?
Key pathological features of RHS include:
- Marked acanthosis and hyperkeratosis
- Significant hypergranulosis
- Parakeratosis and a parakeratotic column in the acrosyringium
- Multinucleated keratinocytes in the spinous cell layer
- Increased mitotic activity in the suprabasal layers
- Intracytoplasmic tyrosine crystals
- Ultrastructural findings such as thickening of the granular layer and increased synthesis of tonofibrils and keratohyalin.
What is the significance of early diagnosis and dietary management in Richner-Hanhart Syndrome (RHS)?
Early diagnosis and dietary management in RHS are crucial to:
1. Reduce the risk and severity of long-term complications of hypertyrosinemia, especially in the eye and skin.
2. Initiate a diet that restricts tyrosine and phenylalanine.
3. Identify RHS through tandem mass spectrometry newborn screening for inborn errors of metabolism in the asymptomatic neonatal period.
What are the clinical features of Carvajal Syndrome (CS)?
Carvajal Syndrome (CS) is characterized by:
- Woolly hair at birth, often associated with sparse eyebrows and axillary and pubic hair.
- Striate palmoplantar keratoderma (SPPK) developing during childhood.
- Cardiomyopathy.
What is SPPK?
SPPK refers to developing during childhood.
What is cardiomyopathy?
Cardiomyopathy, particularly left ventricular dilated cardiomyopathy.
What features may patients with cardiomyopathy show?
Patients may show only skin or cardiac features or the full phenotype.
What are the common causes of death in patients with Carvajal Syndrome (CS)?
The most common causes of death in patients with Carvajal Syndrome (CS) during adolescence are congestive heart failure and ventricular arrhythmia.
What genetic mutations are associated with Carvajal Syndrome (CS)?
Carvajal Syndrome (CS) is associated with mutations in the DSP gene (encoding desmoplakin). These mutations can lead to a triad of woolly hair, SPPK, and cardiomyopathy, and may involve both dominant and recessive inheritance patterns.
What is the underlying genetic mutation in a patient with Carvajal syndrome who has woolly hair and left ventricular dilated cardiomyopathy?
Carvajal syndrome is caused by mutations in the DSP gene encoding desmoplakin.
What is the biochemical defect in Richner-Hanhart syndrome?
Richner-Hanhart syndrome is caused by mutations in the TAT gene encoding tyrosine aminotransferase, leading to intracellular accumulation of tyrosine.
What is the primary treatment strategy for Richner-Hanhart syndrome to prevent long-term complications?
The key to managing Richner-Hanhart syndrome is early diagnosis and initiation of a diet restricting tyrosine and phenylalanine.
What is the role of desmoplakin in Carvajal syndrome?
Desmoplakin is a central component of desmosomes, connecting intermediate filaments to cell membranes.
What is the primary role of desmoplakin?
Desmoplakin connects intermediate filaments to desmosomal cadherins in cardiac muscle and epithelial cells.
What are the key pathological findings in Richner-Hanhart syndrome?
Pathological findings include marked acanthosis, hyperkeratosis, significant hypergranulosis, and intracytoplasmic tyrosine crystals.
What is the role of desmoplakin in Carvajal syndrome?
Desmoplakin connects intermediate filaments to desmosomal cadherins in cardiac muscle, and its mutation impairs this function, leading to cardiomyopathy.
What are the key laboratory findings that distinguish Refsum’s disease (RHS) from type I tyrosinemia?
RHS is diagnosed by a high level of serum tyrosine (with normal phenylalanine) and accumulation of tyrosine metabolites in the urine. A static level of urinary succinylacetone distinguishes RHS from type I tyrosinemia.
What are the specific treatments recommended for managing Refsum’s disease (RHS)?
The key to managing RHS includes:
- Early diagnosis and initiation of a diet that restricts tyrosine and phenylalanine to reduce long-term complications.
- Tandem mass spectrometry newborn screening for inborn errors of metabolism.
- Retinoids to improve skin and eye lesions, though they do not prevent mental retardation.
- Monitoring for complications and considering discriminatory use of retinoids in children.
What are the clinical features of Carvajal Syndrome (CS) related to desmoplakin mutations?
Carvajal Syndrome is characterized by:
- A triad of woolly hair, SPPK (striate palmoplantar keratoderma), and cardiomyopathy.
What are the components of the triad associated with Carvajal Syndrome?
The triad consists of woolly hair, SPPK (striated palmoplantar keratoderma), and cardiomyopathy.
When does left ventricular dilated cardiomyopathy develop?
It develops during childhood.
What clinical features may patients with Carvajal Syndrome show?
Patients may show only skin or cardiac features or the full phenotype.
When does woolly hair appear in affected individuals?
Woolly hair appears at birth, often with sparse eyebrows and axillary hair.
When does SPPK develop?
SPPK develops during childhood, with some cases appearing at birth.
What are the common causes of death in patients with Carvajal Syndrome during adolescence?
The most common causes of death are congestive heart failure and ventricular arrhythmia.
How do mutations in the DSP gene affect the clinical presentation of Carvajal Syndrome?
Mutations in the DSP gene (encoding desmoplakin) lead to:
- Disruption of desmosome scaffolds, affecting cell adhesion in skin and cardiac tissues.
What are the clinical features of Punctate Palmoplantar Keratoderma Type I (PPKP1)?
PPKP1 is characterized by keratosis punctate palmaris type Buschke-Fischer-Brauer. It is a rare autosomal dominant disease.
What is the estimated incidence of Punctate Palmoplantar Keratoderma?
The estimated incidence is approximately 1 to 3 per 100,000.
When does Punctate Palmoplantar Keratoderma typically onset?
Onset occurs during the first or second decades of life.
What characterizes the lesions in Punctate Palmoplantar Keratoderma?
Lesions are characterized by multiple hyperkeratotic, centrally indented, yellow to brown papules distributed irregularly over the palmoplantar skin.
Are the lesions in Punctate Palmoplantar Keratoderma painful?
Lesions may be painful, increasing in size and number with age.
What are the characteristics of Punctate Palmoplantar Keratoderma Type 2 (PPKP2)?
PPKP2; porokeratotic type; OMIM #175860.
What are the dermoscopic findings of Punctate Palmoplantar Keratoderma Type 2?
Well-demarcated, structureless, yellow-orange areas surrounded by a whitish halo.
What is a common clinical feature of Punctate Palmoplantar Keratoderma Type 2?
White fluorescence with Wood light examination.
What are the clinical features of Punctate Palmoplantar Keratoderma Type 3 (PPKP3)?
PPKP3, AKE [of Costa]; OMIM #101850.
What is a rare disorder associated with Punctate Palmoplantar Keratoderma Type 3?
Rare autosomal dominant disorder.
When does Punctate Palmoplantar Keratoderma usually appear?
Usually appears during childhood or adolescence, although onset in infancy or adulthood has also been reported.
Is there any racial or ethnic predilection for Punctate Palmoplantar Keratoderma?
No racial or ethnic predilection.
What are the characteristics of lesions in Punctate Palmoplantar Keratoderma?
Asymptomatic, round to oval, whitish to yellow and translucent papules, and more rarely nodules and plaques, with a hyperkeratotic surface or umbilication.
Where are changes located in Punctate Palmoplantar Keratoderma?
Changes are located on the palms and soles with predilection for the thenar and hypothenar areas of the hands and pressure sites on the palms and soles.
What is a common finding in a patient with punctate PPK type 1?
A patient with punctate PPK type 1 has hyperkeratotic papules on the palms and soles.
What is the nature of lesions in Punctate Palmoplantar Keratoderma?
Lesions may increase in number over the years with possible extension onto the dorsal and lateral surfaces of the fingers.
What do lesions in Punctate Palmoplantar Keratoderma resemble under Wood light examination?
White fluorescence resembling ‘stars under the moonlight’ with Wood light examination.
What is a common finding in male patients with Punctate Palmoplantar Keratoderma?
Facial sebaceous hypoplasia reported in male patients.
What are hyperkeratotic papules?
Hyperkeratotic papules are lesions found on the palms and soles.
What gene mutation is associated with punctate PPK type 1?
Punctate PPK type 1 is associated with heterozygous mutations in the AAGAB gene encoding the adaptin-binding protein p34.
What is the dermoscopic finding associated with punctate PPK type 1?
Dermoscopy reveals well-demarcated, structureless, yellow-orange areas surrounded by a whitish halo.
What is the pathological hallmark of punctate PPK type 2?
Punctate PPK type 2 is characterized by compact vertical parakeratotic columns in the stratum corneum overlying hypogranular epidermis.
What is the primary pathological finding in punctate PPK type 3?
Punctate PPK type 3 is characterized by asymptomatic, round to oval, whitish to yellow papules with a hyperkeratotic surface.
What are the clinical features of Punctate Palmoplantar Keratoderma Type I (PPKP1)?
- PPKP1: keratosis punctate palmoplanataris type Buschke-Fischer-Brauer; OMI#148600.
A rare autosomal dominant disease with an estimated incidence of approximately 1 to 3 per 100,000, onset during the first or second decades of life.
What characterizes the lesions in Punctate Palmoplantar Keratoderma Type I?
- Characterized by multiple hyperkeratotic, centrally indented, yellow to brown papules distributed irregularly over the palmoplantar skin.
- Lesions may be painful, increasing in size and number with age, particularly on pressure-bearing areas of the plantar skin.
What are the dermoscopic findings of Punctate Palmoplantar Keratoderma Type II (PPKP2)?
Well-demarcated, structureless, yellow-orange areas surrounded by a whitish halo.
What do lesions reveal under Wood light examination in Punctate Palmoplantar Keratoderma Type II (PPKP2)?
White fluorescence.
What distinguishes Punctate Palmoplantar Keratoderma Type II (PPKP2) from Type I?
PPKP2; porokeratotic type; OMIM #175860.
What type of disease is Punctate Palmoplantar Keratoderma Type II (PPKP2)?
An autosomal dominant disease.
What characterizes the lesions in Punctate Palmoplantar Keratoderma Type II (PPKP2)?
Multiple, firmly attached, tiny, skin-colored to yellow, asymptomatic, keratotic spines arising on the palms and soles around puberty or in the early 20s.
How do lesions change over time in Punctate Palmoplantar Keratoderma Type II (PPKP2)?
Lesions may increase in number over the years, possibly extending onto the dorsal and lateral surfaces of the fingers.
What do lesions resemble under Wood light examination in Punctate Palmoplantar Keratoderma Type II (PPKP2)?
White fluorescence resembling ‘stars under the moonlight’.
What is facial sebaceous hypoplasia associated with?
Reported in male patients.
What are the key clinical features of Punctate Palmoplantar Keratoderma Type III (PPKP3)?
PPKP3, AKE [of Costa]; OMIM #101850.
What type of disorder is Punctate Palmoplantar Keratoderma Type III (PPKP3)?
A rare autosomal dominant disorder.
When does Punctate Palmoplantar Keratoderma Type III (PPKP3) usually appear?
Usually appears during childhood or adolescence, but onset in infancy or adulthood is also reported.
What characterizes the papules in Punctate Palmoplantar Keratoderma Type III (PPKP3)?
Asymptomatic, round to oval, whitish to yellow and translucent papules, and more rarely nodules and plaques with a hyperkeratotic surface or umbilication.
Where are changes located in Punctate Palmoplantar Keratoderma Type III (PPKP3)?
Changes are located on the palms and soles, with predilection for the thenar and hypothenar areas and pressure sites on the palms and soles.
What is the characteristic skin pattern associated with inherited palmoplantar keratoderma (PPK)?
A linear pattern or ‘paving stones’ arrangement over the radial and ulnar margins.
What is the arrangement of stones in relation to the hands?
Stones’ arrangement over the radial and ulnar margins of the hands may be seen.
What are the clinical features of Cole disease?
Cole disease is characterized by punctate PPK and irregularly shaped, hypopigmented macules distributed over the proximal extremities or less typically over the trunk, along with calcifications in several organs.
What genetic mutation is associated with Cole disease?
Cole disease is associated with heterozygous mutations in the gene ENPP1, which encodes ectonucleotide pyrophosphatase/phosphodiesterase 1.
What are the pathological findings in Cole disease?
Pathological findings include palmo-plantar lesions showing hyperkeratosis, orthokeratosis, hypergranulosis, and acanthosis, along with calcified deposits in the dermis and hypopigmented macules.
What is the significance of the ENPP1 gene in the context of Cole disease?
The ENPP1 gene is significant as it encodes a protein that generates extracellular inorganic pyrophosphate, and mutations in this gene are associated with abnormal calcium homeostasis and ectopic calcifications in Cole disease.
What is the primary pathological finding in Cole disease?
Cole disease shows hyperkeratosis, orthokeratosis, hypergranulosis, and acanthosis in palmo-plantar lesions. Hypopigmented macules demonstrate reduced melanin content in keratinocytes.
What is the role of ENPP1 in Cole disease?
ENPP1 generates extracellular inorganic pyrophosphate, and its mutation leads to abnormal calcium homeostasis and ectopic calcifications in Cole disease.
What is the role of ENPP1 mutations in Cole disease?
ENPP1 mutations affect the phosphodiesterase activity.
What are the mutations in the ENPP1 gene associated with?
Mutations in the ENPP1 gene affect the phosphodiesterase domain, leading to abnormal calcium homeostasis and ectopic calcifications, which are features of Cole disease.
What are the clinical features of Cole disease?
Cole disease is characterized by:
- Punctate palmoplantar keratoderma (PPK)
- Irregularly shaped hypopigmented macules distributed over the proximal extremities or less typically over the trunk.
- Calcifications in several organs, including tendons, breast, and spleen.
- It is a rare autosomal dominant disorder that presents at birth or during early infancy.
What is the role of the ENPP1 gene in the pathogenesis of Cole disease?
The ENPP1 gene encodes ectonucleotide pyrophosphatase/phosphodiesterase 1, which is involved in generating extracellular inorganic pyrophosphate. Its mutations lead to:
- Abnormal calcium homeostasis and ectopic calcifications.
- Inhibition of insulin signaling through interaction with the insulin receptor, suggesting a role in the pathogenesis of Cole disease.
What is the pathology associated with Cole disease and its skin manifestations?
The pathology of Cole disease includes:
- Palmo-plantar lesions showing:
- Hyperkeratosis
- Orthokeratosis
- Acanthosis
- Hypergranulosis
- Calcified deposits may be present in the dermis.
- Hypopigmented macules demonstrate:
- Hyperkeratosis
- Reduced melanin content in keratinocytes
- Normal or reduced number of melanocytes.
- Ultrastructural findings show large numbers of melanosomes in melanocytes, indicating abnormal melanosome transfer as a primary mechanism for hypopigmentation.
What is the primary mechanism for hypopigmentation?
Abnormal melanosome transfer.
What are the key features of Diffuse PPK?
Diffuse PPK is characterized by:
- Most common form of diffuse keratoderma.
- Erythematous sharp edges at the palms and soles, with thickening and fissuring.
What is the inheritance pattern of Diffuse PPK?
Autosomal Dominant (AD).
What are the clinical features associated with Naxos Disease?
Naxos Disease is characterized by:
- Diffuse, well-demarcated, nontransgressing PPK.
- Woolly hair with ectodermal dysplasia.
What is the inheritance pattern of Naxos Disease?
Autosomal Recessive (AR).
What distinguishes the features of Papillon-Lefevre Syndrome?
Papillon-Lefevre Syndrome features:
- Diffuse, erythematous, sharply demarcated hyperkeratotic PPK.
- Severe progressive periodontitis and loss of primary and permanent teeth.
What is the inheritance pattern of Papillon-Lefevre Syndrome?
Autosomal Recessive (AR).
What are the inheritance patterns and features of Focal PPK?
Focal PPK is characterized by:
- Linear, thickened hyperkeratotic plaques over palms and soles.
- Aspects of digits, circumscribed thickening of soles.
What is the inheritance pattern of Focal PPK?
Autosomal Dominant (AD).
What are the features of Hydrotic Ectodermal Dysplasia (Clouston Syndrome)?
Hydrotic Ectodermal Dysplasia features:
- Well-defined, focal nonmutilating transgressing PPK.
- Nonclassic alopecia; recessive forms may have pseudohypoparathyroidism and sclerodactyly.
What is the inheritance pattern of Hydrotic Ectodermal Dysplasia?
Autosomal Recessive (AR).
What is the form of diffuse keratoderma?
Erythematous sharp edges at the palms and soles, with thickening and fissuring.
What is the inheritance pattern of diffuse keratoderma?
Autosomal Dominant (AD).
How does the inheritance pattern differ between Focal PPK and Punctate PPK?
Focal PPK is inherited in an Autosomal Recessive (AR) manner, while Punctate PPK is inherited in an Autosomal Dominant (AD) manner.
What are the key features of Focal PPK?
Linear, thickened hyperkeratotic plaques on palms and soles.
What are the key features of Punctate PPK?
Painful, hyperkeratotic papules with central indentation on palms and soles.
What are the clinical implications of having Naxos Disease in relation to cardiac health?
Naxos Disease is associated with:
- Diffuse, well-demarcated, nontransgressive PPK
- Woolly hair and right ventricular dysplasia.
What are the clinical implications of Naxos Disease?
Patients may experience cardiac complications due to the right ventricular dysplasia, which can lead to arrhythmias and other cardiac issues.
What are the distinguishing features of Papillon-Lefevre Syndrome and its associated risks?
Papillon-Lefevre Syndrome is characterized by:
- Diffuse, erythematous, sharply demarcated PPK
- Severe progressive periodontitis and loss of primary and permanent teeth.
What are the associated risks of Papillon-Lefevre Syndrome?
Patients are at increased risk for severe periodontal disease, which can lead to tooth loss and other oral health complications.
