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Inherited disorders of connective tissue, Update of palmoplantar kerathoderma PPK, Netherton syndrome
The 18th ESPD conference got off to a sunny start in London, but the experts had forecasted that it would soon go downhill... There’s no doubt about it, we’re definitely in London! With a view of Big Ben, the participants at the Queen Elizabeth II Conference Centre were free to concentrate on this first day of the conference.
Prof. Ivelina Yordanova once again assumed the role of special correspondent for Laboratoire BIODERMA to report on the event. Here are her reports for the first three themes she chose from Thursday’s schedule.
Prof. Ivelina Yordanova
Dermatologist, Pleven University Hospital, in Bulgaria
Inherited disorders of connective tissue
In the session 2 — Connective tissues disease — a lecture “Inherited disorders of connective tissue” was presented by Dr. Nigel Burrows, Consultant Dermatologist in Addenbrooke's NHS Trust Hospital Cambridge and a valued member of the Ehler-Danlos Syndrom (EDS) UK Medical Advisory Panel.
Ehlers-Danlos syndromes (EDS) are a heterogenous group of rare inherited conditions that affect extracellular matrix in connective tissue. Connective tissue provides support in the skin, tendons, ligaments, blood vessels, internal organs and bones. There are 13 types of EDS (2017 classification) with different method of inheritance, clinical features and prognosis. They may share some symptoms, including:
- Stretchy skin (poor scars formation, hyperextensibility — up to 3 cm in the elbow)
- An increased range of joint movement (joint hypermobility)
- Fragile skin that breaks or bruises easily
The different types of EDS are caused by mutations in certain genes that make connective tissue weaker. Depending on the type of EDS, the mutation may have been inherited from one parent or both parents. Sometimes the faulty gene isn't inherited, but occurs to the person for the first time. EDS can affect some patients relatively mild, while for others their symptoms can be disabling. Some of the rare severe types can be life-threatening. The Main types of EDS are:
• Classical EDS affects Type 5 Collagen. It is less common than hypermobile EDS and tends to affect the skin more. People with cEDS may have: joint hypermobility, loose, unstable joints that dislocate easily, stretchy and fragile skin that can split easily – especially over the forehead, knees, shins and elbows, wounds that are slow to heal and leave wide scars umbilical hernias, molluscoid skin tumors.
• Hypermobile EDS is the most common type of EDS. Hypermobile is often thought to be the same as or very similar to another condition called joint hypermobility syndrome. This type are characterized by joint hypermobility, loose, unstable joints that dislocate easily, joint pain, extreme fatigue, skin bruising, pelvic and bladder dysfunctions (stress incontinence) problems with internal organs, such as mitral valve prolapse or organ prolapse.
• Vascular EDS is a rare type of EDS and is often considered to be the most serious. It affects the blood vessels and internal organs, which can cause them to split open and lead to life-threatening bleeding. The patients may have very thin skin that bruises very easily with visible small blood vessels, particularly on the upper chest and legs; fragile blood vessels that can bulge or tear, resulting in serious internal bleeding, a risk of organ problems, such as the bowel tearing, and partial collapse of the lung, hypermobile fingers and toes, specific facial features, (such as a thin nose and lips, large eyes and small earlobes, prominent cheekbones), and delayed wound healing. 80 % of children with vascular EDS die because of arterial rupture.
Pseudoxanthoma elasticum (PXE) is the name given to a group of connective tissue disorders that affects the elastic tissue of the skin, blood vessels and the eyes. It is also known as Grönblad-Strandberg syndrome. The basic fault in PXE appears to relate to genetic abnormalities on chromosome 16p13.1. It is characterized by elastorrhexia, or progressive calcification and fragmentation. The patients with PXE may have yellowish skin papules on the neck, axilles and popliteal folds, angioid eyes streaks, peau d’orange, cardiovascular complications.
Buschke–Ollendorff syndrome is an autosomal dominant connective tissue disorder manifested by multiple subcutaneous nevi or nodules, associated with Mutations in the LEMD3 gene. They may be either elastin-rich (elastoma) or collagen-rich (dermatofibrosis lenticularis disseminata) on histologic examination. The patients may have short stature, spinal stenosis, osteopoikilosis, bone pain.
Cutis laxa or elastolysis, is a rare, heterogenous group of AD, AR and X-linked inherited connective-tissue disorders, which affect elastic fibres. Depending on which organs and tissues are affected, the signs and symptoms of cutis laxa can range from mild to life-threatening. The skin becomes inelastic and hangs loosely in folds. The patient may have ingunal and umbilical hernia, childhood emphysema and arterial aneurismas.
Update of palmoplantar kerathoderma PPK
In the afternoon session, in Whittle Auditorium of Queen Elizabeth II Center in London, Edel O’Tool — Professor of Molecular Dermatology and Centre Lead, Centre for Cell Biology and Cutaneous Research, Royal London Hospital, presented the lecture "Update of Palmoplantar Keratodermas (PPK)".
This lecture was focused on the hereditary palmoplantar keratodermas (PPK) — a heterogeneous group of disorders characterized by hyperkeratosis of palmoplantar skin. The PPKs can be divided into three groups according to the clinical pattern of the hyperkeratosis including diffuse, focal (which includes striate) and punctate PPK. Affected individuals may have a simple PPK without associated features, or a syndromic PPK with associated features, such as hearing loss, cardiomyopathy, hair, dentition or nail changes. In the past few years, many causative genes of PPK have been identified, which has confirmed and/or altered the traditional clinical classification. The role of histology of a palmar biopsy and genetic testing is discussed. Prof. O’Toole directed her attention to five types Palmoplantar Keratodermas:
- Pachyonychia congenita (PC) characterized by hypertrophic nail dystrophy, painful palmoplantar keratoderma and blistering, oral leukokeratosis, palmoplantar hyperhydrosis, and follicular keratoses on the trunk and extremities, accelerated dental decay. PC is diagnosed by clinical findings and/or by the identification of a heterozygous pathogenic variant in one of the five keratin genes known to cause PC: KRT6A, KRT6B, KRT6C, KRT16, and KRT17.
- Water sensitive PPK, or aquagenic palmoplantar keratoderma caused by mutation of Aquaporin 5 (AQP5 gene) in 95 % of the patients. It is characterized by the rapid development of transient whitish, usually symmetric, hypopigmented flat-topped papules and plaques on palmar or plantar skin after exposure to water or sweating. Because of the high humidity patients may suffer from superinfection with Corinebacteria and dermatophytes.
- Striate palmoplantar keratoderma is a very rare form characterized by linear hyperkeratotic streaks along the volar surface of the fingers and focal keratoderma over the soles. It is a form of circumscribed keratoderma. Three types have been identified:
- Type I — due to mutations in the desmoglein 1 gene (DSG1) on 18q12.1–q12.2.
- Type II — due to mutations in the desmoplakin gene (DSP) at 6p24.
- Type III — due to mutations in the keratin 1 gene (KRT1) at 12q13.
Both desmoglein 1 and desmoplakin are critical components of the desmosomal plaque and associated keratin intermediate filaments in the upper epidermis. Mutations of the tail domain of keratin 1 have been shown to affect the function of the plaque during cornification. Partial acantholysis of keratinocytes in the spinous and granular cell layers have been reported in patients with DSG1 mutations. Some patients may develop oesophageal cancer.
- Olmsted’s syndrome : Periorificial keratoderma and oral leukokeratosis accompany the transgredient palmoplantar keratoderma, which is often mutilating. Alopecia and perianal keratotic plaques are sometimes present. Most cases are sporadic. A closely related entity with corneal epithelial dysplasia has been reported. Abnormal expression of keratins 5 and 14 appears to be the underlying disorder for developing plantar squamous cell carcinomas sometimes. The histopathological findings on palmar skin include psoriasiform hyperplasia, hypogranulosis, and alternating parakeratosis and orthohyperkeratosis. Emollients and keratolytics have been used to treat the disease. Retinoids provide temporary relief. Excision and grafting has also been used.
- Clouston syndrome is a form of ectodermal dysplasia, a group of about 150 conditions characterized by abnormal development of some or all of the ectodermal structures, which include the skin, hair, nails, teeth, and sweat glands. Clouston syndrome is specifically characterized by abnormalities of the hair, nails, and skin, with the teeth and sweat glands being unaffected. In infants with Clouston syndrome, scalp hair is sparse, patchy, and lighter in color than the hair of other family members, it is also fragile and easily broken. By puberty, the hair problems may worsen until all the hair on the scalp is lost (total alopecia). The eyelashes, eyebrows, underarm (axillary) hair, and pubic hair are also sparse or absent. Abnormal growth of fingernails and toenails (nail dystrophy) is also characteristic of Clouston syndrome. The nails may appear white in the first years of life. They grow slowly and gradually become thick and misshapen. In some people with Clouston syndrome, nail dystrophy is the most noticeable feature of the disorder. They may have thick skin on the palms of the hands and soles of the feet (palmoplantar hyperkeratosis).
Finally, new approaches to treatment of PPK with Alitretinoine, N-acethylcystein, Botulinum toxin and topical Rapamycin (Sirulimus)!
Prof. O’Toole summarized.
In the afternoon session “Disorders of keratinisation”, Cassie McDonald from Great Ormond Street Hospital for Children NHS Trust London, UK, presented a review of 15 pediatric patients with Netherton syndrome.
Netherton syndrome is a rare multisystemic genodermatosis, characterized by congenital erythroderma, trichorrhexis invaginata and atopic diathesis with high IgE. It is a severe, autosomal recessive disorder associated with mutations in the SPINK5 gene, encoding serine protease inhibitor LEKTI. Premature delivery was seen in all 15 patients with Netherton syndrome. Some affected infants were born with a collodion membrane. This membrane is shed during the first few weeks of life. Because newborns are missing the protection provided by normal skin, they are at risk of becoming dehydrated and developing infections in the skin or throughout the body (sepsis), which can be life-threatening. At the age of 3 months all affected babies fail to grow and gain weight at the expected rate(failure to thrive). By childhood 13/15 babies showed normal development. IgE analysis was initially elevated in 11/15 patients. There were not strong correlations between elevated IgE level and allergy status of the child.
After infancy, the severity of the skin abnormalities varies among patients with Netherton syndrome and can fluctuate over time. The skin continues to be red and scaly, especially during the first few years of life. Some affected individuals have intermittent redness — ichthyosis linearis circumflexa, presented with multiple ring-like patches. The stress or infections may be the triggers for the outbreaks. Itchiness is a common problem for affected individuals, and scratching can lead to frequent infections. Dead skin cells are shed at an abnormal rate and often accumulate in the ear canals, which can affect hearing if not removed regularly. The skin is abnormally absorbent of substances such as lotions and ointments, which can result in excessive blood levels of some topical medications. Because the ability of the skin to protect against heat and cold is impaired, affected individuals may have difficulty regulating their body temperature.
Patients with Netherton syndrome have hair that is fragile and breaks easily. Some strands of hair vary in diameter, with thicker and thinner spots. This feature is known as bamboo hair, trichorrhexis nodosa, or trichorrhexis invaginata. In addition to the hair on the scalp, the eyelashes and eyebrows may be affected. The hair abnormality in Netherton syndrome may not be noticed in infancy because babies often have sparse hair.
Prof. Ivelina Yordanova, MD, PhD