48: Inherited Palmoplantar Keratodermas Flashcards

Question

Which syndromes are associated with PPK and squamous cell carcinoma?

Answer 1

- Huriez syndrome - Unna-Thost syndrome - Dyskeratosis congenita - Rothmund-Thomson syndrome - Xeroderma pigmentosum

Answer 2

- 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

Answer 3

- Short term or intermittent therapy is sometimes recommended.

Answer 4

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.

Answer 5

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.

Answer 6

Surgical excision and grafting is an option in focal PPK and in cases associated with mutation.

Answer 7

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).

Answer 8

Autoamputation of digits can accompany PPK in loricrin keratoderma (LK).

Answer 9

Leprosy, tertiary syphilis, scleroderma, Raynaud syndrome, amniotic bands, ergotamine poisoning, spinal medulla tumors, syringomyelia, and scar formation from frostbite, burns, and trauma.

Answer 10

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.

Answer 11

EPPK is associated with heterozygous mutations in KRT9 encoding keratin 9, and a minority of cases have mutations in KRT1 encoding keratin 1.

Answer 12

Inhibition of KRT9 mutant allele expression in a mouse model using RNA interference (RNAi)–based therapy has shown promise.

Answer 13

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.

Answer 14

EPPK is an autosomal dominant genodermatosis caused by heterozygous mutations in KRT9 or, less commonly, KRT1.

Answer 15

Histopathologic findings include compact orthokeratosis, hypergranulosis, acanthosis, and epidermolytic hyperkeratosis with perinuclear vacuolization of keratinocytes.

Answer 16

NEPPK features hyperhidrosis, refractory secondary dermatophyte infections, pitted keratolysis, hyperkeratosis around the umbilicus and nipple, and dryness of knees and elbows.

Answer 17

Unna-Thost Palmoplantar Keratoderma is associated with mutations in KRT9 and KRT1.

Answer 18

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.

Answer 19

Sybert PPK is characterized by epidermal hyperplasia with hypergranulosis, parakeratosis, orthokeratosis, and sparse lymphocytic infiltrate.

Answer 20

The essential clinical features are honeycomb-like keratoderma and generalized ichthyosis.

Answer 21

Histopathological findings include hyperkeratosis, orthokeratosis, acanthosis, and hyper- or hypo-granulosis.

Answer 22

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.

Answer 23

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.

Answer 24

GOF mutations in the gene AQP5, encoding water-channel protein aquaporin 5 (AQP5).

Answer 25

Mostly found in the apical plasma membrane and involved in the excretion of water from exocrine glands (salivary gland, lacrimal gland, and sweat gland).

Answer 26

Also expressed in epithelial cells of the lung and the cornea.

Answer 27

Sjögren syndrome has been associated with decreased expression of AQP5.

Answer 28

AQP5 is localized to the plasma membrane of keratinocytes of the stratum granulosum.

Answer 29

AQP5 expression is retained, and affected keratinocytes are subject to increased water uptake through the plasma membrane.

Answer 30

Autosomal recessive disorder.

Answer 31

Onset of the disease: infancy or early childhood.

Answer 32

Diffuse transgressive yellowish waxy hyperkeratotic plaques outlined by a red scaly border over the palms and soles preceded by prominent and persistent erythema.

Answer 33

Palmoplantar hyperkeratosis progresses with age and extends onto the dorsal surface of the hands and feet in a glove and stocking distribution.

Answer 34

Knuckle pads, lichenoid or keratotic plaques over joints, perioral erythema, hyperhidrosis with superinfection, malodorous maceration and painful fissures.

Answer 35

Non-specific findings.

Answer 36

Include orthohyperkeratosis.

Answer 37

Mild lymphocytic infiltrate in the upper dermis.

Answer 38

Information not provided.

Answer 39

Loricrin Keratoderma is caused by heterozygous frameshift insertion or deletion mutations in LOR, which encodes loricrin.

Answer 40

Features include diffuse, homogeneous hyperkeratosis with a yellowish hue, hyperhidrosis, maceration, and secondary fungal infections.

Answer 41

Palmoplantar Keratoderma Bothnia Type is associated with gain-of-function mutations in the AQP5 gene, encoding aquaporin 5.

Answer 42

- 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)

Answer 43

- 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

Answer 44

Keratinocytes are cells in the stratum granulosum layer of the skin.

Answer 45

PPKB lesions retain AQP5 expression, leading to increased water uptake through the plasma membrane.

Answer 46

Mal de Meleda is an autosomal recessive disorder with onset in infancy or early childhood.

Answer 47

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.

Answer 48

Additional features include knuckle pads, lichenoid or keratotic plaques over joints, perioral erythrema, hyperhidrosis with superinfection, malodorous maceration, and painful fissures.

Answer 49

Non-specific findings include orthohyperkeratosis and mildly lymphocytic infiltrate in the upper dermis.

Answer 50

NPPK is an autosomal recessive disorder and the most common type of PPK in Asian populations.

Answer 51

In Japan, the estimated prevalence is 1.2 in 10,000.

Answer 52

In China, the estimated prevalence is 2.3 to 3.1 in 10,000.

Answer 53

NPPK begins in the first years of life and progresses until puberty with no further progression.

Answer 54

It is diffuse, well-demarcated, erythematous palmoplantar hyperkeratosis extending to the dorsal surfaces of hands, feet, inner wrists, ankles, and Achilles tendon.

Answer 55

Yes, involvement of elbows and knees is common.

Answer 56

NPPK is frequently complicated by hyperhidrosis, superinfection by dermatophytes, distinct odor, and maceration.

Answer 57

No evidence of malignancy has been reported.

Answer 58

Distinct odor and maceration.

Answer 59

Biallelic mutations in the gene **SERPINB7**, encoding serpin family B member 7 (SERPIN7).

Answer 60

Mutations resulting from aberrant splicing or premature stop codons with nonsense or frameshift mutations.

Answer 61

Mutation c.830C>T, resulting in proline to leucine change.

Answer 62

Mutation c.796C>T, prevalent in both Chinese and Japanese NPPK patients, likely reflecting a founder effect.

Answer 63

Hyperkeratosis, orthokeratosis, foci of parakeratosis, marked acanthosis.

Answer 64

More pronounced stratum lucidum and a perivascular lymphohistiocytic infiltrate.

Answer 65

A less abrupt transition between the stratum granulosum and stratum corneum.

Answer 66

Normal intermediate filaments and corneodesmosomes.

Answer 67

SLURP-1 is a secreted epidermal neuromodulator essential for epidermal homeostasis and inhibition of tumor necrosis factor (TNF) necrosis.

Answer 68

It upregulates the expression of transglutaminase 1, cytokeratin 10, and caspases 3 and 8, influencing apoptotic activity.

Answer 69

Regulates epidermal differentiation through cholinergic pathways.

Answer 70

Increased susceptibility to viral infections and development of malignancies.

Answer 71

Increased susceptibility to viral infections and development of malignant melanoma (MM).

Answer 72

Mal de Meleda is caused by biallelic mutations in the SLURP1 gene, which encodes a secreted epidermal neuromodulator.

Answer 73

Features include diffuse, well-demarcated erythematous palmoplantar hyperkeratosis extending to dorsal surfaces, hyperhidrosis, and maceration.

Answer 74

Mal de Meleda features diffuse transgressive yellowish waxy hyperkeratotic plaques with a red scaly border, hyperhidrosis, and complications like pseudoainhum and nail abnormalities.

Answer 75

- 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.

Answer 76

- 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.

Answer 77

It results in a proline to leucine change.

Answer 78

The mutation c.796C>T is prevalent in Chinese and Japanese NPPK patients, likely reflecting a founder effect.

Answer 79

SLURP-1 deficiency affects the efficiency of triglyceride hydrolysis in keratinocytes, crucial for forming acylceramides that maintain the epidermal barrier.

Answer 80

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.

Answer 81

SLURP-1 may play a role in the pathogenesis of psoriasis, with expression upregulated in imiquimod-induced psoriasis in mice.

Answer 82

Findings include hyperkeratosis, orthokeratosis, foci of parakeratosis, marked acanthosis, and a pronounced stratum lucidum.

Answer 83

It is a pathological finding in palmoplantar keratoderma.

Answer 84

It shows a less abrupt transition between the stratum granulosum and stratum corneum, with normal intermediate filaments and corneodesmosomes.

Answer 85

They are non-specific, irregularly shaped, with a spongy appearance.

Answer 86

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.

Answer 87

It may inhibit proteases and protect keratinocytes or corneocytes from damage, contributing to the development of NPPK.

Answer 88

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.

Answer 89

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.

Answer 90

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.

Answer 91

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.

Answer 92

Epidermal protease inhibitors are essential for cholesterol homeostasis and endoplasmic reticulum stress response.

Answer 93

Nagashima-Type Palmoplantar Keratoderma is associated with biallelic mutations in the SERPINB7 gene, encoding serpin family B member 7.

Answer 94

Olmsted Syndrome features symmetric, sharply demarcated diffuse PPK with painful fissures, periorificial keratotic plaques, and complications like pseudoainhum and SCC.

Answer 95

Olmsted Syndrome is linked to mutations in the TRPV3 gene, encoding transient receptor potential vanilloid 3.

Answer 96

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. ## Footnote 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').

Answer 97

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.

Answer 98

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.

Answer 99

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.

Answer 100

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**.

Answer 101

These features can significantly impact the quality of life, leading to physical limitations and increased healthcare needs.

Answer 102

Olmsted Syndrome is associated with mutations in: TRPV3 and MBTPS2.

Answer 103

A gene involved in pain sensation and pruritus, highly expressed in keratinocytes and hair follicles, affecting epidermal barrier formation.

Answer 104

An X-linked recessive mutation that encodes a zinc metalloprotease essential for cholesterol homeostasis and endoplasmic reticulum stress response.

Answer 105

These mutations lead to increased apoptosis in keratinocytes, contributing to the clinical manifestations of the syndrome.

Answer 106

- 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.

Answer 107

- 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.

Answer 108

- Chronic cheilitis and perleche. - Nail dystrophy and oral manifestations (leukokeratosis, deep fissures of the tongue).

Answer 109

Features include leukokeratosis and deep fissures of the tongue.

Answer 110

Hypohidrosis and heat intolerance.

Answer 111

10% to 23% of individuals have congenital atrichia.

Answer 112

It begins in childhood and is characterized by corneal inflammation and pain.

Answer 113

It is bilateral and severe.

Answer 114

They are prone to mucocutaneous infections, mostly bacterial and candidal.

Answer 115

They are intercellular junctions formed by connexons.

Answer 116

They facilitate and regulate the passage of water and small molecules between adjacent cells.

Answer 117

It is a rare, autosomal dominant disorder.

Answer 118

It has a honeycomb-like appearance.

Answer 119

They are common findings in Bart-Pumphrey syndrome.

Answer 120

Hearing loss and knuckle pads; leukonychia and PPK are seen less frequently.

Answer 121

It features diffuse, sharply demarcated thickening of the palmoplantar skin with a punctate, grainy surface reminiscent of Vohwinkel Syndrome.

Answer 122

It features diffuse mutilating PPK with honeycomb-like appearance, starfish-shaped plaques, pseudoainhum, and high-frequency sensorineural hearing loss.

Answer 123

It features erythrokeratoderma, diffuse PPK, congenital bilateral severe sensorineural hearing loss, and progressive keratitis leading to visual decline.

Answer 124

It features severe sensorineural hearing loss, PPK with a honeycomb-like appearance, knuckle pads, and leukonychia.

Answer 125

Key clinical features of Vohwinkel Syndrome include: 1. **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. 2. **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.

Answer 126

KID syndrome manifests with: 1. **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. 2. **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.

Answer 127

Treatment options for palmoplantar keratoderma include: 1. **Surgical intervention**

Answer 128

Partial excision of palmoplantar keratosis or full-thickness excision with skin grafting.

Answer 129

EGFR inhibitors have shown improvement in palmoplantar keratoderma. ## Footnote TRPV3 antagonists may be effective for patients with gain-of-function mutations in the TRPV3 gene.

Answer 130

Severe sensorineural hearing loss (SNHL) and palmoplantar keratoderma with a honeycomb-like appearance.

Answer 131

Knuckle pads and leukonychia.

Answer 132

Hearing loss and knuckle pads may develop early in life, with PPK being less frequent. ## Footnote PPK features diffuse, sharply demarcated thickening of palmoplantar skin resembling Vohwinkel Syndrome.

Answer 133

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.

Answer 134

GJB2 encodes Cx26, and recessive mutations producing loss of function (LOF) are the most common cause of nonsyndromic sensorineural hearing loss (SNHL) in humans.

Answer 135

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.

Answer 136

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.

Answer 137

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.

Answer 138

Specific treatments for Vohwinkel Syndrome include: 1. Cross finger flap 2. Treatment with Z-plasty 3. Full-thickness excision of the constriction band with a full-thickness skin graft 4. Distant abdominal skin flap for fifth digit constriction bands.

Answer 139

Vohwinkel Syndrome is associated with a recurrent heterozygous missense mutation, p.Asp66His, in the GJB2 gene encoding connexin 26.

Answer 140

KID Syndrome is linked to a recurrent missense mutation, p.Asp50Asn, in the GJB2 gene.

Answer 141

Bart-Pumphrey Syndrome is associated with mutations in the GJB2 gene encoding connexin 26.

Answer 142

Findings include compact hyperkeratosis, orthokeratosis, acanthosis, hypergranulosis, papillomatosis, and dermal fibrosis with sparse perivascular lymphocytic infiltrate.

Answer 143

Findings include epidermal hyperplasia, compact orthokeratotic hyperkeratosis, focal parakeratosis, and swollen keratinocytes with vacuolated cytoplasm.

Answer 144

Findings include massive orthokeratotic hyperkeratosis, hypergranulosis, acanthosis, and papillomatosis.

Answer 145

Specific treatments include cross finger flap, Z-plasty, full-thickness excision of constriction bands, and distant abdominal skin flap for digit constriction bands.

Answer 146

Specific treatments include keratolimbal allograft, keratoplasty, topical corticosteroids, cyclosporine, and bevacizumab for ocular manifestations.

Answer 147

Specific treatments are not explicitly mentioned, but management focuses on addressing PPK and hearing loss.

Answer 148

Connexins form gap junctions that facilitate intercellular communication. Mutations in connexin genes (e.g., GJB2) disrupt this function, leading to PPK with deafness.

Answer 149

PPK with deafness is associated with heterozygous mutations in the GJB2 gene, such as p.R75Q.

Answer 150

Connexons are formed by the oligomerization of 6 connexins, leading to the formation of a hemichannel. They consist of: 1. **4 transmembrane domains** 2. **3 cytoplasmic domains** (including the amino-terminus, a cytoplasmic loop, and the carboxy terminus) 3. **2 extracellular loops**

Answer 151

These components allow connexons from opposing cells to interact, forming a channel that is essential for **gap junction communication**.

Answer 152

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.**

Answer 153

Vohwinkel Syndrome (VS) is characterized by: - **Compact hyperkeratosis and acanthosis.** - **Significant hypergranulosis with large, irregularly shaped keratohyaline granules.**

Answer 154

Papillomatosis of the epidermis.

Answer 155

Dermal fibrosis with sparse perivascular lymphocytic infiltrate.

Answer 156

Marked swollen mitochondria, increased numbers of desmosomes in the spinous and granular layers, corneocytes containing many membrane coating granules and lipid-like vacuoles.

Answer 157

1. Cross finger flap 2. Treatment with Z-plasty 3. Full-thickness excision of the constriction band with a full-thickness skin graft 4. Distant abdominal skin flap for fifth digit constriction bands.

Answer 158

These surgical interventions aim to alleviate symptoms and improve function.

Answer 159

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.

Answer 160

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.

Answer 161

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.

Answer 162

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.

Answer 163

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.

Answer 164

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.

Answer 165

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.

Answer 166

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.

Answer 167

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.

Answer 168

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.

Answer 169

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.

Answer 170

Rare associations include: - Strabismus - Cataract and photophobia - Hearing impairment - Mental deficiency - Bone abnormalities such as thickening of the skull and abnormal phalanges.

Answer 171

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.

Answer 172

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.

Answer 173

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.

Answer 174

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.

Answer 175

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.

Answer 176

The estimated risk of SCC in Huriez syndrome is 13%, which is more than 100-fold higher than the general population.

Answer 177

p53 mutations may be responsible for the development of actinic keratoses and SCC in Huriez syndrome.

Answer 178

Pathological findings include marked acanthosis, papillomatosis, hypergranulosis, orthokeratotic hyperkeratosis, and dense collagen fibers in the reticular dermis.

Answer 179

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.

Answer 180

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%.

Answer 181

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.

Answer 182

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.

Answer 183

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.

Answer 184

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.

Answer 185

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.

Answer 186

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.

Answer 187

Sparse dermal mononuclear cell infiltrates and ultrastructural findings show dense bundles of tonofilaments and abundant keratohyaline distributed in large clumps of irregular density.

Answer 188

Cathepsin C plays a role in intracellular protein degradation and activation of serine proteases in immune cells. Its deficiency leads to PLS.

Answer 189

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.

Answer 190

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.

Answer 191

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.

Answer 192

Naxos disease is characterized by a triad of diffuse palmoplantar keratoderma (PPK), cardiomyopathy, and woolly hair.

Answer 193

The most common reported mutation in Naxos disease is a homozygous 2-bp deletion in the JUP gene, resulting in a truncated plakoglobin (PG).

Answer 194

Associated findings include hypertriglyceridemia, laryngeal cancer, nodular testicular hyperplasia, bilateral cataracts, and bilateral optic nerve coloboma.

Answer 195

Palmoplantar skin in Naxos disease reveals findings compatible with non-epidermolytic palmoplantar keratoderma (NEPPK).

Answer 196

Plakoglobin is a constituent protein in desmosomal junctions, and its mutation leads to the skin and cardiac manifestations of Naxos disease.

Answer 197

Naxos disease is characterized by a triad of diffuse palmoplantar keratoderma (PPK), cardiomyopathy, and woolly hair, caused by biallelic mutations in the JUP gene.

Answer 198

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.

Answer 199

This syndrome is characterized by sclerodactyly, palmoplantar keratoderma (PPK), and multiple cutaneous squamous cell carcinomas (SCCs).

Answer 200

Characterized by orange-yellow diffuse, well-demarcated palmoplantar hyperkeratotic plaques with minimal to no erythema, typically appearing during childhood.

Answer 201

Caused by a homoplasmic point mutation (c.A7445G) in the mitochondrial transfer RNA (tRNA) encoding the MTTS1 gene.

Answer 202

A rare autosomal dominant disorder characterized by linear, thickened, hyperkeratotic plaques over the palms extending along the volar aspect of the digits.

Answer 203

Nonsense and frameshift heterozygous mutations in the DSG1 or DSP genes.

Answer 204

Appears during childhood characterized by orange-yellow diffuse, well-demarcated palmoplantar hyperkeratotic plaques with minimal to no erythema.

Answer 205

Caused by a homoplasmic point mutation (c.A7445G) in the mitochondrial transfer RNA (tRNA) encoding the MTTS1 gene.

Answer 206

Nonsense and frameshift heterozygous mutations in the DSG1 or DSP genes result in haploinsufficiency.

Answer 207

Desmoglein 1 regulates epidermal proliferation and differentiation; its loss leads to hyperkeratotic phenotype seen in SPPK.

Answer 208

PPK variants, Brünauer-Fohs-Siemens syndrome, characterized by yellowish, nontransgredient, symmetric, nummular, hyperkeratotic plaques localized to pressure points.

Answer 209

PC is divided into PC-1 (KRT6A or KRT16 mutations) and PC-2 (KRT6B or KRT17 mutations).

Answer 210

Common features include thickened toenails, plantar keratoderma, and plantar pain.

Answer 211

Pathological findings include hyperkeratosis, hypergranulosis, and possible focal parakeratosis.

Answer 212

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).

Answer 213

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.

Answer 214

| 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 |

Answer 215

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.

Answer 216

The most common manifestation of plantar keratoderma is focal PPK (FPPK) with calluses over weight-bearing areas.

Answer 217

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.

Answer 218

Additional features of PC include mucosal involvement, cyst formation, and natal teeth.

Answer 219

Oral leukokeratosis was reported in 70% of patients with Pachyonychia Congenita.

Answer 220

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.

Answer 221

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.

Answer 222

About 40% of patients with KRT17 mutations exhibit various types of epidermal inclusion cysts, such as pilosebaceous cysts and vellus hair cysts.

Answer 223

Infants and children with KRT6A mutations may experience life-threatening respiratory distress secondary to laryngeal leukokeratosis.

Answer 224

Natal teeth in PC are almost exclusively associated with KRT17 mutations.

Answer 225

The severe plantar pain in PC is secondary to blister formation deep underneath the thick callus, as demonstrated by high-frequency ultrasound.

Answer 226

Oral leukokeratosis is most characteristic of mutations in KRT6A or KRT17.

Answer 227

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.

Answer 228

| 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 |

Answer 229

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.

Answer 230

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.

Answer 231

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.

Answer 232

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.

Answer 233

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.

Answer 234

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.

Answer 235

PC is caused by heterozygous mutations in one of five keratin genes: KRT6A, KRT6B, KRT6C, KRT16, and KRT17.

Answer 236

Mechanical stress leads to upregulation of both wild-type and mutant keratins, triggering the PC phenotype and worsening the condition.

Answer 237

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.

Answer 238

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.

Answer 239

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.

Answer 240

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.

Answer 241

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.

Answer 242

Ocular manifestations include: - **Photophobia** - **Pain** - **Tearing** - **Redness** - **Pseudoherpetiform keratitis** with corneal ulcerations.

Answer 243

These symptoms occur in 75% of cases.

Answer 244

They typically present soon after birth or within the first year of life.

Answer 245

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.

Answer 246

Neurological manifestations may include: - **Mental retardation** - **Nystagmus** - **Tremor** - **Ataxia** - **Convulsions**.

Answer 247

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.

Answer 248

Dysregulated EGF signaling contributes to esophageal carcinoma.

Answer 249

Nalin contributes to esophageal carcinoma.

Answer 250

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.

Answer 251

A patient with Howel-Evans syndrome has esophageal lesions.

Answer 252

Annual gastroscopy is recommended for screening esophageal carcinoma in Howel-Evans syndrome.

Answer 253

iRhO-2 regulates ADAM17 activity, leading to increased EGF receptor signaling and dysregulated wound repair, contributing to the syndrome.

Answer 254

Richner-Hanhart Syndrome (RHS) is characterized by: 1. **Triad of Symptoms**: - **Painful Palmoplantar Keratoderma (PPK)** - **Bilateral Keratitis** - **Mental Retardation** due to intracellular accumulation of tyrosine crystals. 2. **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. 3. **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. 4. **Neurologic Manifestations**: - Mental retardation, nystagmus, tremor, ataxia, and convulsions in untreated cases.

Answer 255

Richner-Hanhart Syndrome (RHS) is an autosomal recessive disorder caused by mutations.

Answer 256

1. **Mutations in the TAT Gene**: The TAT gene encodes **tyrosine aminotransferase (TAT)**. Deficiency in TAT leads to the accumulation of tyrosine in tissues.

Answer 257

2. **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.

Answer 258

3. **Pathophysiological Mechanism**: Intracellular L-tyrosine crystals destabilize lysosomal membranes, initiating cell injury and inflammation, leading to typical skin lesions.

Answer 259

In Richner-Hanhart Syndrome (RHS), the presence of **tyrosine crystals** contributes to skin lesions through: 1. **Destabilization of Lysosomal Membranes**: Intracellular L-tyrosine crystals destabilize lysosomal membranes, leading to cell injury.

Answer 260

2. **Inflammatory Response**: The destabilization initiates a cascade of inflammation, resulting in the characteristic skin lesions.

Answer 261

3. **Hyperkeratosis Mechanism**: Excessive intracellular concentration of tyrosine leads to noncovalent cross-links among keratins, forming aggregated tonofilaments, which manifest as palmoplantar hyperkeratosis.

Answer 262

Richner-Hanhart Syndrome (RHS) is diagnosed by a *specific set of laboratory findings*.

Answer 263

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.

Answer 264

A static level of urinary succinylacetone distinguishes RHS from type I tyrosinemia.

Answer 265

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.

Answer 266

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.

Answer 267

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**.

Answer 268

SPPK refers to developing during childhood.

Answer 269

Cardiomyopathy, particularly left ventricular dilated cardiomyopathy.

Answer 270

Patients may show only skin or cardiac features or the full phenotype.

Answer 271

The most common causes of death in patients with Carvajal Syndrome (CS) during adolescence are congestive heart failure and ventricular arrhythmia.

Answer 272

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.

Answer 273

Carvajal syndrome is caused by mutations in the DSP gene encoding desmoplakin.

Answer 274

Richner-Hanhart syndrome is caused by mutations in the TAT gene encoding tyrosine aminotransferase, leading to intracellular accumulation of tyrosine.

Answer 275

The key to managing Richner-Hanhart syndrome is early diagnosis and initiation of a diet restricting tyrosine and phenylalanine.

Answer 276

Desmoplakin is a central component of desmosomes, connecting intermediate filaments to cell membranes.

Answer 277

Desmoplakin connects intermediate filaments to desmosomal cadherins in cardiac muscle and epithelial cells.

Answer 278

Pathological findings include marked acanthosis, hyperkeratosis, significant hypergranulosis, and intracytoplasmic tyrosine crystals.

Answer 279

Desmoplakin connects intermediate filaments to desmosomal cadherins in cardiac muscle, and its mutation impairs this function, leading to cardiomyopathy.

Answer 280

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.

Answer 281

The key to managing RHS includes: 1. **Early diagnosis** and initiation of a diet that restricts **tyrosine and phenylalanine** to reduce long-term complications. 2. **Tandem mass spectrometry** newborn screening for inborn errors of metabolism. 3. **Retinoids** to improve skin and eye lesions, though they do not prevent mental retardation. 4. Monitoring for complications and considering **discriminatory use** of retinoids in children.

Answer 282

Carvajal Syndrome is characterized by: - A triad of **woolly hair**, **SPPK** (striate palmoplantar keratoderma), and **cardiomyopathy**.

Answer 283

The triad consists of **woolly hair**, **SPPK** (striated palmoplantar keratoderma), and **cardiomyopathy**.

Answer 284

It develops during childhood.

Answer 285

Patients may show only skin or cardiac features or the full phenotype.

Answer 286

Woolly hair appears at birth, often with sparse eyebrows and axillary hair.

Answer 287

SPPK develops during childhood, with some cases appearing at birth.

Answer 288

The most common causes of death are **congestive heart failure** and **ventricular arrhythmia**.

Answer 289

Mutations in the **DSP gene** (encoding desmoplakin) lead to: - Disruption of desmosome scaffolds, affecting cell adhesion in skin and cardiac tissues.

Answer 290

**PPKP1** is characterized by keratosis punctate palmaris type Buschke-Fischer-Brauer. It is a rare **autosomal dominant disease**.

Answer 291

The estimated incidence is approximately 1 to 3 per 100,000.

Answer 292

Onset occurs during the **first or second decades of life**.

Answer 293

Lesions are characterized by **multiple hyperkeratotic, centrally indented, yellow to brown papules** distributed irregularly over the palmoplantar skin.

Answer 294

Lesions may be **painful**, increasing in size and number with age.

Answer 295

**PPKP2**; porokeratotic type; OMIM #175860.

Answer 296

Well-demarcated, structureless, yellow-orange areas surrounded by a whitish halo.

Answer 297

**White fluorescence** with Wood light examination.

Answer 298

**PPKP3**, AKE [of Costa]; OMIM #101850.

Answer 299

Rare **autosomal dominant disorder**.

Answer 300

Usually appears during **childhood or adolescence**, although onset in infancy or adulthood has also been reported.

Answer 301

No racial or ethnic predilection.

Answer 302

**Asymptomatic, round to oval, whitish to yellow and translucent papules**, and more rarely nodules and plaques, with a hyperkeratotic surface or umbilication.

Answer 303

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.

Answer 304

A patient with punctate PPK type 1 has hyperkeratotic papules on the palms and soles.

Answer 305

Lesions may increase in number over the years with possible extension onto the dorsal and lateral surfaces of the fingers.

Answer 306

**White fluorescence** resembling 'stars under the moonlight' with Wood light examination.

Answer 307

Facial sebaceous hypoplasia reported in male patients.

Answer 308

Hyperkeratotic papules are lesions found on the palms and soles.

Answer 309

Punctate PPK type 1 is associated with heterozygous mutations in the AAGAB gene encoding the adaptin-binding protein p34.

Answer 310

Dermoscopy reveals well-demarcated, structureless, yellow-orange areas surrounded by a whitish halo.

Answer 311

Punctate PPK type 2 is characterized by compact vertical parakeratotic columns in the stratum corneum overlying hypogranular epidermis.

Answer 312

Punctate PPK type 3 is characterized by asymptomatic, round to oval, whitish to yellow papules with a hyperkeratotic surface.

Answer 313

- **PPKP1**: keratosis punctate palmoplanataris type Buschke-Fischer-Brauer; OMI#148600. ## Footnote 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**.

Answer 314

- 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.

Answer 315

**Well-demarcated, structureless, yellow-orange areas** surrounded by a whitish halo.

Answer 316

**White fluorescence**.

Answer 317

**PPKP2**; porokeratotic type; OMIM #175860.

Answer 318

An **autosomal dominant disease**.

Answer 319

**Multiple, firmly attached, tiny, skin-colored to yellow, asymptomatic, keratotic spines** arising on the palms and soles around puberty or in the early 20s.

Answer 320

Lesions may increase in number over the years, possibly extending onto the dorsal and lateral surfaces of the fingers.

Answer 321

**White fluorescence resembling 'stars under the moonlight'**.

Answer 322

Reported in male patients.

Answer 323

**PPKP3**, AKE [of Costa]; OMIM #101850.

Answer 324

A rare **autosomal dominant disorder**.

Answer 325

Usually appears during **childhood or adolescence**, but onset in infancy or adulthood is also reported.

Answer 326

**Asymptomatic, round to oval, whitish to yellow and translucent papules**, and more rarely nodules and plaques with a hyperkeratotic surface or umbilication.

Answer 327

Changes are located on the palms and soles, with predilection for the thenar and hypothenar areas and pressure sites on the palms and soles.

Answer 328

A **linear pattern or 'paving stones' arrangement** over the radial and ulnar margins.

Answer 329

Stones' arrangement over the radial and ulnar margins of the hands may be seen.

Answer 330

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.

Answer 331

Cole disease is associated with heterozygous mutations in the gene ENPP1, which encodes ectonucleotide pyrophosphatase/phosphodiesterase 1.

Answer 332

Pathological findings include palmo-plantar lesions showing hyperkeratosis, orthokeratosis, hypergranulosis, and acanthosis, along with calcified deposits in the dermis and hypopigmented macules.

Answer 333

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.

Answer 334

Cole disease shows hyperkeratosis, orthokeratosis, hypergranulosis, and acanthosis in palmo-plantar lesions. Hypopigmented macules demonstrate reduced melanin content in keratinocytes.

Answer 335

ENPP1 generates extracellular inorganic pyrophosphate, and its mutation leads to abnormal calcium homeostasis and ectopic calcifications in Cole disease.

Answer 336

ENPP1 mutations affect the phosphodiesterase activity.

Answer 337

Mutations in the ENPP1 gene affect the phosphodiesterase domain, leading to abnormal calcium homeostasis and ectopic calcifications, which are features of Cole disease.

Answer 338

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.

Answer 339

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.

Answer 340

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.

Answer 341

Abnormal melanosome transfer.

Answer 342

Diffuse PPK is characterized by: - Most common form of diffuse keratoderma. - Erythematous sharp edges at the palms and soles, with thickening and fissuring.

Answer 343

Autosomal Dominant (AD).

Answer 344

Naxos Disease is characterized by: - Diffuse, well-demarcated, nontransgressing PPK. - Woolly hair with ectodermal dysplasia.

Answer 345

Autosomal Recessive (AR).

Answer 346

Papillon-Lefevre Syndrome features: - Diffuse, erythematous, sharply demarcated hyperkeratotic PPK. - Severe progressive periodontitis and loss of primary and permanent teeth.

Answer 347

Autosomal Recessive (AR).

Answer 348

Focal PPK is characterized by: - Linear, thickened hyperkeratotic plaques over palms and soles. - Aspects of digits, circumscribed thickening of soles.

Answer 349

Autosomal Dominant (AD).

Answer 350

Hydrotic Ectodermal Dysplasia features: - Well-defined, focal nonmutilating transgressing PPK. - Nonclassic alopecia; recessive forms may have pseudohypoparathyroidism and sclerodactyly.

Answer 351

Autosomal Recessive (AR).

Answer 352

Erythematous sharp edges at the palms and soles, with thickening and fissuring.

Answer 353

Autosomal Dominant (AD).

Answer 354

Focal PPK is inherited in an Autosomal Recessive (AR) manner, while Punctate PPK is inherited in an Autosomal Dominant (AD) manner.

Answer 355

Linear, thickened hyperkeratotic plaques on palms and soles.

Answer 356

Painful, hyperkeratotic papules with central indentation on palms and soles.

Answer 357

Naxos Disease is associated with: - Diffuse, well-demarcated, nontransgressive PPK - Woolly hair and right ventricular dysplasia.

Answer 358

Patients may experience cardiac complications due to the right ventricular dysplasia, which can lead to arrhythmias and other cardiac issues.

Answer 359

Papillon-Lefevre Syndrome is characterized by: - Diffuse, erythematous, sharply demarcated PPK - Severe progressive periodontitis and loss of primary and permanent teeth.

Answer 360

Patients are at increased risk for severe periodontal disease, which can lead to tooth loss and other oral health complications.