A rare, inherited, cancer predisposition syndrome characterized by the early-onset of multiple primary cancers including breast cancer, soft tissue and bone sarcomas, brain tumors, adrenal cortical carcinoma (ACC), leukemias, and other cancers.

Summary:
Epidemiology
More than 400 families with Li-Fraumeni (LFS) have been reported in the literature. The estimated prevalence of pathogenic and likely pathogenic germline TP53 mutations is not well defined but has been estimated to range between 1/3,555-5,476.
Clinical description
The core cancers in Li-Fraumeni syndrome (LFS) are early-onset breast cancer, ACC, soft tissue sarcomas, osteosarcomas, and brain tumors. Also seen in LFS are leukemias, lymphomas, colorectal cancer, and many other cancers. People with LFS have about a 50% increased risk of developing a second cancer.
Etiology
LFS is caused by germline mutations in the tumor suppressor gene TP53 (17p13.1) in the majority of families with classic LFS. This gene encodes the tumor antigen p53 protein involved in many cellular processes such as DNA repair, growth arrest and apoptosis. 7-20% of TP53 mutations are estimated to be de novo. No other gene has been associated with LFS thus far.
Diagnostic methods
Diagnosis is confirmed by genetic testing and identification of a TP53 mutation. Individuals may also be clinically diagnosed with LFS if they meet classic LFS criteria which include: (1) a person with a sarcoma diagnosed before age 45 years and (2) a first-degree relative with any cancer diagnosed before age 45 years and (3) a first- or second degree relative with any cancer diagnosed before age 45 years or a sarcoma diagnosed at any age. The Chompret criteria may also be used to identify individuals for whom TP53 testing is indicated: (1) an individual with a tumor belonging to the LFS tumor spectrum before age 46 years and a first- or second-degree relative with an LFS tumor (except multiple breast cancer tumors or breast cancer before 56 years of age); (2) an individual with multiple tumors (except multiple breast tumors), two of which belong to the LFS tumor spectrum , with the first occurring before 46 years of age; (3) an individual with ACC or CPC, or anaplastic embryonal rhabdomyosarcoma regardless of family history; or (4) an individual with breast cancer before 31 years of age.
Differential diagnosis
Differential diagnoses include hereditary breast and ovarian cancer syndrome, CHEK2 cancer susceptibility syndrome, and constitutional mismatch repair deficiency syndrome.
Antenatal diagnosis
Prenatal and preimplantation genetic diagnoses are available for families with a TP53 mutation.
Genetic counseling
The pattern of inheritance is autosomal dominant; the risk of inheriting the mutation from a carrier is 50%. The lifetime risk of cancer in LFS is estimated to be about 70% for men and over 90% for women, although these may be overestimates. The age-related cancer risks are estimated at 22% between 0-15 years, 51% between 16-50 years, and 27% between 51-80 years. Genetic counseling is recommended to inform individuals of issues related to genetic testing, cancer risks, medical surveillance, and psychosocial and family impact.
Management and treatment
Management of LFS-related cancers generally follows standard treatment protocols, with minimizing radiation when possible. Mastectomies are recommended over lumpectomies for the treatment of breast cancer. Prophylactic mastectomy can also be offered to those with a known TP53 mutation for risk reduction. Regular surveillance (adapted from the ''Toronto protocol'') is recommended for individuals with TP53 mutations, and incorporate screening with biochemical and imaging modalities. Complete physical exams and ultrasound of the abdomen and pelvis is recommended every 3-4 months from birth until age 18. Children and adults are advised to have annual whole-body and brain magnetic resonance imaging (MRI). Women are recommended to have clinical breast exams every 6-12 months, an annual breast MRI from age 20 and an annual mammogram from age 30. For other cancer risks, physical exam is recommended every 6-12 months from age 18 years, with annual dermatologic exam. Colonoscopy and upper endoscopy are recommended every 2-5 years from age 25 (or 5 years before the earliest colon cancer in the family). Other screening may also be recommended.
Prognosis
Prognosis depends on the type and severity of cancers developed. Patients followed on the Toronto screening protocol were reported to have higher 5-year survival rates.

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Dr Junne KAMIHARA  -  Katherine SCHNEIDER


Lichen amyloidosis is a rare chronic form of cutaneous amyloidosis (see this term), a skin disease characterized by the accumulation of amyloid deposits in the dermis, clinically characterized by the development of pruritic, often pigmented, hyperkeratotic papules on trunk and extremities, especially on the shins, and histologically by the deposition of amyloid or amyloid-like proteins in the papillary dermis.


A rare cutaneous variant of lichen planus which affects hair follicles. It may occur on its own or in association with more common forms of lichen planus, usually classical type and/or oral lichen planus.

Summary:
Epidemiology
The prevalence is unknown. LPP is more frequent in women than in men.
Clinical description
The disease manifests in adulthood (40-60 years of age), with some rare cases in childhood. Patients present with peri-follicular inflammation and hair loss. They may be asymptomatic or have itch or discomfort. The scalp is the commonest area affected but any hair bearing skin may be affected, like for example the axillae or the pubic area. Perifollicular erythema, scales, and/or keratotic plugs are seen at the edge of the affected area. Single or multiple lesions of scarring alopecia lacking follicular orifices are typical. Two other variants of LPP can be observed: frontal fibrosing alopecia (FFA), and Lassueur-Graham-Little syndrome (see these terms). In FFA, there is symmetrical, progressive anterior hairline loss of the scalp associated with eyebrow loss. The Lassueur-Graham-Little syndrome constitutes a combination of lichen planus follicularis of the scalp with follicular keratosis and noncicatricial alopecia of the axillae and pubes.
Etiology
Etiology is unknown but LPP is thought to be an autoimmune disorder in which T-lymphocytes attack and destroy keratinocytes expressing unknown target antigens. Triggering factors could be pharmacologic agents, contact sensitizers or infectious agents.
Diagnostic methods
Diagnosis is based on clinical and histopathological findings. Biopsy of an inflammatory lesion shows a band-like perifollicular lymphocytic infiltrate at the level of the isthmus and infundibulum. There may be vacuolar changes of the basal layer and follicular plugging. In more advanced lesions, perifollicular fibrosis and replacement of hair follicles by fibrosis are found. Diagnosis is difficult in the later stages when inflammation disappears.
Differential diagnosis
Differential diagnosis includes discoid lupus erythematosus (DLE), folliculitis decalvans, mucous membrane pemphigoid (see these terms), seborrheic dermatitis, alopecia areata, and central centrifugal cicatricial alopecia (CCCA).
Management and treatment
There is no long-term effective treatment for LPP. Current treatments aim at slowing down progression of hair loss and reduction of symptoms. Topical, intralesional and oral corticosteroids are the mainstay of treatment. Unfortunately, relapse is common. Other options for treatment include hydroxychloroquinine, ciclosporin and methotrexate.
Prognosis
LPP can progress slowly or rapidly. Some cases may spontaneously resolve but others are progressive.

                            Last update:
                            March 2011

                            - Expert reviewer(s):
                            Dr Susan COOPER


Lichen planus (LP) pemphigoides is a rare cross-over syndrome between lichen planus and bullous pemphigoid (see these terms).

Summary:
Epidemiology
The prevalence is unknown.
Clinical description
LP pemphigoides affects primarily adult men in middle age (40-50 years of age), but several cases have been reported in children. It is quite distinct from bullous lichen planus (see this term), both clinically and pathologically. In lichen planus pemphigoides, bullous lesions arise in both normal skin and skin affected by lichenoid lesions, whereas in bullous lichen planus, the blisters only develop on lichenoid papules. The bullae in LP pemphigoides can be hemorrhagic or clear, and have a predilection for acral sites.
Etiology
Epitope spreading seems to account for the pathogenesis of lichen planus pemphigoides, whereby damage to the basal layer in LP lesions exposes a basement membrane antigen (e.g. BP180 epitope) leading to the development of circulating antibodies. Occurrence of LP pemphigoides has been reported following the use of several medications including cinnarizine, angiotensin-converting enzyme (ACE) inhibitors (ramipril and captopril), simvastatin and anti-tuberculous drugs, and also following Psoralen and Ultraviolet A Light (PUVA) therapy.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Stephanie ARNOLD  - Dr Susan COOPER


Lichen planus (LP) pigmentosus is a rare variant of cutaneous lichen planus (see this term) characterized by the presence of hyperpigmented lichenoid lesions in sun-exposed or flexural areas of the body.

Summary:
Epidemiology
LP pigmentosus is a rare disease in Europe but it is common in Indian populations and in the Middle East. The overall prevalence is unknown. There is no difference in distribution between males and females.
Clinical description
The disease usually appears in the third and fourth decade of life. The lesions are asymptomatic or mildly pruritic. Skin changes are dark brown or slate grey macules or papules with, in most cases, a diffuse pigmentation pattern. They most commonly affect the face, neck and upper limbs. Predominantly a intertriginous disease, usually in the axillae and groin (described mostly in Caucasians), it has also been termed as lichen planus pigmentosus inversus. The scalp, nails or mucosa are not affected. LP pigmentosus can exist in association with typical LP lesions.
Etiology
Etiology is unknown but various factors (e.g. viral infections and certain topical agents including mustard oil, amla oil and henna hair dyes) can trigger the disease. One case has been reported in association with Bazex syndrome (see this term).
Diagnostic methods
Histological features of LP pigmentosus are similar but milder than classic LP, with a lichenoid interface reaction, vacuolar change and apoptotic keratinocytes. Melanin incontinence is prominent, and may be the only feature of older lesions; it may extend deeper into the dermis than typical post-inflammatory pigmentation.
Prognosis
Lichen planus pigmentosa seems to follow a chronic progressive course.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Stephanie ARNOLD  - Dr Susan COOPER


A rare genetic disease characterized by frequent infections associated with neutropenia and IgA deficiency, in combination with osteoporosis and skeletal anomalies, such as posterior spinal arch fusion defect, metacarpal subluxation, syndactyly, and camptodactyly. Reported dysmorphic features include synophrys, anteverted nostrils, and single palmar crease. There have been no further descriptions in the literature since 1972.


A rare genetic form of low-renin hypertension characterized by hypertension associated with decreased plasma levels of potassium and aldosterone.

Summary:
Epidemiology
Liddle syndrome prevalence is unknown. The condition is considered rare with less than 80 families reported worldwide.
Clinical description
The disease can be clinically heterogeneous, ranging from mild to severe. Most patients are diagnosed in young adulthood, although the diagnosis may be made as early as in infancy, especially when family screening of an affected patient is performed. The typical clinical features are resistance to treatment with conventional anti-hypertensives, salt-sensitive arterial hypertension, hypokalemia and metabolic alkalosis often associated with a family history of early-onset hypertension and sudden death. Associated manifestations of hypokalemia may include muscular weakness, polyuria/polydipsia. Sudden death due to stroke or myocardial infarction or associated with malignant arrhythmias elicited by severe hypokalemia has been reported. Mild forms with essential normal plasma electrolytes have also been reported.
Etiology
Liddle syndrome is due to gain-of-function mutations in the genes SCNN1A (16p13), SCNN1B (16p12.2-p12.1) and SCNN1G (16p12.2), encoding, respectively, the alpha, beta and gamma subunits of the epithelial sodium channel (ENaC), a key protein involved in sodium reabsorption in the distal renal tubules. Physiologically, ENaC channel abundance is regulated by aldosterone. The gain-of-function mutations causing Liddle syndrome impair the retrieval from the apical membrane and subsequent degradation of ENaC by the ubiquitin proteasome pathway. The prolonged tenancy of mutated ENaC in the membrane results in increased sodium reabsorption independent of aldosterone with consequent hypertension.
Diagnostic methods
Diagnosis is suspected by the detection of hypertension, associated with hypokalemic alkalosis and suppressed renin and aldosterone, especially in the presence of a relevant family history. It can be confirmed by genetic testing.
Differential diagnosis
Liddle syndrome needs to be distinguished from other forms of hypertension with hypokalemic alkalosis. The suppressed renin and aldosterone levels separate it from primary and secondary forms of hyperaldosteronism, such as Conn syndrome or renovascular hypertension. A family history consistent with dominant inheritance, a urine steroid profile and genetic testing can separate it from apparent mineralocorticoid excess and glucocorticoid remediable hypertension.
Genetic counseling
The pattern of inheritance is autosomal dominant, the risk to offspring of inheriting the mutation from an affected parent is 50%. Given the variable phenotype reported in some families, genetic screening should be performed in first-degree relatives of a mutation carrier.
Management and treatment
Treatment is based on administration of potassium-sparing diuretics, such as amiloride or triamterene, which act by blocking ENaC activity. This results in reduction of blood pressure and correction of hypokalemia and metabolic alkalosis. Conventional antihypertensive therapies are not effective. Patients must also follow a low sodium diet.
Prognosis
With adequate treatment, prognosis is good. Without treatment, cardiovascular and renal complications usually occur.

                            Last update:
                            May 2020

                            - Expert reviewer(s):
                            Pr Detlef BÖCKENHAUER | ERKNet*

                                * European Reference Network


LIG4 syndrome is a hereditary disorder associated with impaired DNA double-strand break repair mechanisms and characterized by microcephaly, unusual facial features, growth and developmental delay, skin anomalies, and pancytopenia, which is associated with combined immunodeficiency (CID).

Summary:
Epidemiology
Prevalence is unknown. To date, at least 12 patients have been reported.
Clinical description
LIG4 syndrome presents in childhood with microcephaly, unusual facial features that have been described as ''bird-like'' (beak-like nose and micrognathia), growth and developmental delay, skin anomalies including photosensitivity and psoriatic-like lesions, and pancytopenia. The disease is associated with immunodeficiency. Some patients have been reported as having telangiectasias, leukemia, lymphoma, bone marrow abnormalities, and type 2 diabetes. One patient presented with features of Omenn syndrome (see this term).
Etiology
LIG4 syndrome is caused by mutations in the LIG4 gene (13q22-q34). The resulting defect of DNA ligase IV, a component of the classical non-homologous end-joining (NHEJ) pathway, affects the major mechanism of DNA double-strand break repair.
Diagnostic methods
Diagnosis is based on evidence of the characteristic clinical signs of LIG4 syndrome, particularly the ''bird-like'' facial features, and low T and B cells. Diagnosis is confirmed on the basis of molecular genetic analysis and the evidence of radiosensitivity of cell lines. Chromosome 7/14 translocations are also common.
Differential diagnosis
Differential diagnoses include other rare DNA damage response diseases such as Seckel syndrome, Nijmegen breakage syndrome (NBS), Cernunnos-XLF deficiency and Fanconi anemia (see these terms).
Antenatal diagnosis
Prenatal diagnosis can be performed by chorionic villus sampling in families with previously affected members.
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Supportive treatment is with prophylactic antibiotics and anti-virals. Hematopoietic stem cell transplantation may be indicated in some patients using modified conditioning regimens without radiotherapy.
Prognosis
Lifespan is generally limited with an increased incidence of leukemia or lymphoma.

                            Last update:
                            July 2012

                            - Expert reviewer(s):
                            Pr Andrew GENNERY


Light and heavy chain deposition disease

A rare non-amyloid monoclonal immunoglobulin deposition disease characterized by secretion of abnormal light and heavy chains, which are deposited in tissues and cause organ dysfunction, but do not form amyloid beta-pleated sheets or contain an amyloid P component. The condition most frequently occurs in association with multiple myeloma. The kidneys are most commonly affected (clinically manifesting as nephrotic syndrome and renal failure), but liver, heart, peripheral nerves, blood vessels, and joints may also be involved.


A rare non-amyloid monoclonal immunoglobulin deposition disease characterized by deposition of abnormal immunoglobulin light chains in the kidneys, resulting in nephrotic syndrome and renal failure. Symptomatic extrarenal deposition is uncommon, although hepatic, cardiac, and neural deposits have been reported. The condition frequently occurs in association with multiple myeloma or in patients with M protein and marrow plasma cells at monoclonal gammopathy of undetermined significance levels.


Limb body wall complex (LBWC) is characterized by severe multiple congenital anomalies in the fetus with exencephaly/encephalocele, thoraco- and/or abdominoschisis (anterior body wall defects) and limb defects, with or without facial clefts.

Summary:
Epidemiology
Approximately 250 cases have been reported in the literature so far.
Clinical description
Clinical manifestations vary widely and include limb defects and visceral malformations (95% of cases), spinal abnormalities, absent diaphragm, bowel atresia and renal agenesis. LBWC generally presents as a short umbilical cord, abdominal placental attachment, persistence of an extraembryonic celom, anorectal malformations, urogenital abnormalities, lumbosacral meningomyelocele and kyphoscoliosis. A spectrum of LBWC manifestations is included in the amniotic band sequence (see this term), presenting mostly with craniofacial defects, facial clefts, amniotic bands and/or adhesions. At present, it remains unclear whether these two entities represent a single disorder.
Etiology
The etiology of LBWC remains unknown. Karyotypes have been reported as normal and no correlations with gender, parental age and teratogenic agents have been found. The principal theories are an extrinsic origin by early amniotic rupture, or a vascular origin due to an early vascular accident during embryological development. Single cases of familial occurrence have been documented.
Diagnostic methods
Diagnosis is based on the presenting features.
Differential diagnosis
LBWC should be differentiated from gastroschisis (see this term), which has better prognosis.
Antenatal diagnosis
Early antenatal diagnosis is feasible by ultrasound examination and may be followed by medical termination of the pregnancy.
Prognosis
LBWC is fatal, with death occurring antenatally or early in the neonatal period.

                            Last update:
                            March 2009

                            - Expert reviewer(s):
                            Pr Didier LACOMBE


Limb-girdle muscular dystrophy due to POMK deficiency is a form of limb-girdle muscular dystrophy presenting in infancy with muscle weakness and delayed motor development (eventually learning to walk at 18 months of age) followed by progressive proximal weakness, pseudohypertrophy of calf muscles, mild facial weakness, and borderline intelligence.


Limb-girdle muscular dystrophy (LGMD) is a heterogeneous group of muscular dystrophies characterized by proximal weakness affecting the pelvic and shoulder girdles. Cardiac and respiratory impairment may be observed in certain forms of LGMD.

Summary:
Epidemiology
The estimated prevalence for all forms of LGMD ranges from 1/44,000 to 1/123,000.
Clinical description
LGMD ranges from severe forms with onset in the first decade and rapid progression (resembling Duchenne muscular dystrophy) to milder forms with late onset and slower progression (similar to Becker muscular dystrophy). LGMD is characterized by weakness and wasting predominantly of the limb musculature (proximal greater than distal). The initial presentations are usually weakness of the hip and proximal leg muscles. Affected individuals usually have normal early motor and intellectual milestones and show a positive Gowers' sign. Cardiac involvement in the form of dilated or hypertrophic cardiomyopathy and dysrhythmias are present in LGMD 2C-F, 2I, 2W, 2X, 1B, and 1E. At some stage, when upper arm muscles are involved, all subtypes may also have respiratory muscle weakness with nocturnal hypoventilation, in particular type 2I where it is noted from an earlier stage. Additional clinical features include a waddling gait, muscle pain during exercise, hypertrophy of the deltoids and quadriceps, and muscle wasting, affecting either the pelvis and/or shoulder girdle. The facial muscles are usually spared or involved only minimally.
Etiology
LGMD is caused by mutations in more than 25 genes which encode numerous components of the myofiber, contractile apparatus, nuclear lamina, sarcolemma or the cytoplasm.
Diagnostic methods
Diagnosis of LGMD involves physical examination and muscle biopsy, which reveals fiber size variation including (non specific) fiber hypertrophy, scattered degenerating and regenerating muscle fibers, and a mild increase in perimysial tissue. Serum creatine-kinase can be normal or mildly to grossly elevated. Diagnosis of a specific LGMD subtype can be achieved by biochemical protein testing performed on muscle biopsies, followed by confirmation with genetic testing. Genetic testing, using panels, is becoming more readily available and can confirm diagnosis.
Differential diagnosis
The differential diagnosis of LGMD includes facioscapulohumeral muscular dystrophy, Emery-Dreifuss muscular dystrophy, congenital muscular dystrophy, polymyositis, myotonic, myofibrillar, distal and metabolic myopathy, collagen 6-related disorders and dermatomyosistis.
Antenatal diagnosis
Prenatal diagnosis is available when a causative gene in a family is known.
Genetic counseling
There are at least 30 different genetic forms of LGMD, among which the type 1 LGMDs (LGMD1) are inherited in an autosomal dominant manner and the type 2 LGMDs (LGMD2) are inherited in an autosomal recessive manner. Genetic counseling should be offered to families according to the mode of inheritance.
Management and treatment
Treatment of LGMD remains palliative and supportive and includes weight control to avoid obesity, physical therapy and stretching exercises to promote mobility and prevent contractures, use of mechanical aids to help ambulation and mobility, surgical intervention for orthopedic complications, use of respiratory aids when indicated, monitoring for cardiomyopathy in LGMD types with cardiac involvement, and social as well as emotional support and stimulation.
Prognosis
The clinical course of LGMD is typically progressive, although it is highly variable and is dependent on the severity of the individual genetic mutation. In most childhood onset forms of LGMD (in particular the rapidly progressive forms), ambulation is achieved but is invariably lost in later years. In other forms of LGMD, ambulation can be maintained and wheelchair assistance needed only later in life.

                            Last update:
                            April 2017

                            - Expert reviewer(s):
                            Dr A.J. [Anneke] VAN DER KOOI


A rare, genetic, ectodermal dysplasia syndrome characterized by severe hand/foot anomalies, breast and/or nipple hypoplasia, and ectodermal dysplasia (principally teeth and nail anomalies). Cleft lip/palate may be variably present.


A rare corneal disorder characterized by dysfunction and/or insufficient quantity of corneal limbal stem cells, leading to impaired self-renewal of the corneal epithelium and resulting in epithelial breakdown, corneal conjunctivalization and neovascularization, chronic inflammation, persistent epithelial defects, and scarring. Patients usually present with ocular redness, decreased vision, photophobia, foreign body sensation, tearing, and pain. The condition may be genetic, idiopathic, or acquired (in the context of inflammation, infection, trauma, or ocular surface tumors).


Limited cutaneous systemic sclerosis (lcSSc) is a subtype of systemic sclerosis (SSc; see this term) characterized by the association of Raynaud's phenomenon with skin fibrosis limited to the hands, face, feet and forearms.

Summary:
Epidemiology
The prevalence is estimated at about 1/12,500 adults. Women are predominantly affected (F/M sex ratio around 4:1).
Clinical description
Women are predominantly affected (F/M sex ratio around 4:1). The disease usually manifests at between 40 and 50 years of age. Raynaud's phenomenon is the most common and often the first sign of the disease. The other signs usually appear some years later. Skin involvement is limited to the hands, face, feet and forearms. Skin tautness is absent in the chest, abdomen, back, or thighs. Telangiectasias and sclerodactyly with a risk of digital ulcers are observed. Esophageal dysmotility is common, and provokes gastroesophageal reflux and sometimes dysphagia. About 30-40% of the patients have lung fibrosis on computed tomography (CT) scan and about 10% have pulmonary arterial hypertension. In some early stages of the disease, cutaneous involvement is not yet present; as a consequence the disease is called limited SSc. In rare situations, cutaneous involvement never occurs; as a consequence, the disease is called SSc sine scleroderma. CREST syndrome (see this term) is usually considered a synonym of limited cutaneous SSc but it is rather a subtype with more frequent and more extended telangiectasias.
Etiology
The exact cause of limited cutaneous SSc is unknown. The disease originates from an autoimmune reaction which leads to overproduction of collagen. In some cases, the condition is associated with exposure to chemicals (including silica, solvents and hydrocarbons).
Diagnostic methods
Diagnosis is based on typical clinical manifestations and on evidence of specific microangiopathy with giant loops on nailfold capillaroscopy. Blood tests show a high incidence of anticentromere antibodies (ACA). The extent of the disease should be evaluated by CT, electrocardiogram, echocardiography, radiography of the hands and esophageal and gastric fibroscopy if needed.
Differential diagnosis
Differential diagnoses include Sharp syndrome, systemic lupus erythematosus, antiphospholipid syndrome, and polyarteritis nodosa (see these terms).
Management and treatment
Management is mostly symptomatic. Raynaud's phenomenon can be treated with calcium channel blockers. Proton pomp inhibitors are given for gastric reflux. Patients require regular clinical follow-up with early pulmonary function tests and echocardiography. Low doses of corticosteroids with immunosuppressive agents are needed in cases with progressive lung fibrosis. Pulmonary vasodilators are given in case of pulmonary arterial hypertension.
Prognosis
The prognosis of limited cutaneous SSc is relatively good with a long-lasting disease duration (10-year survival rate is about 80 to 90%). However, pulmonary arterial hypertension may be a complication of the disease (in about 10% of cases) and may lead to a more severe prognosis. Severe lung fibrosis may occur in some patients.

                            Last update:
                            July 2010

                            - Expert reviewer(s):
                            Pr Eric HACHULLA


Limited systemic sclerosis (lSSc) (or SSc sine scleroderma) is a subset of systemic sclerosis (SSc; see this term) characterized by organ involvement in the absence of fibrosis of the skin.

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
Patients do not have skin fibrosis but only Raynaud's phenomenon, and are at risk of organ involvement (fibrosis and vascular obliteration of lungs, heart, digestive tract). They can later present with esophageal dysmotility which provokes gastroesophageal reflux and sometimes dysphagia, and can also suffer from lung fibrosis and pulmonary arterial hypertension.
Etiology
The exact cause of lSSc is unknown. The disease originates from an autoimmune reaction which leads to overproduction of collagen. In some cases, SSc is associated with exposure to chemicals (silica, solvents, hydrocarbons, etc.).
Diagnostic methods
Diagnosis can be difficult due to the absence of skin involvement. Nailfold capillaroscopy shows a SSc pattern and blood tests show a high incidence of anti-centromere antibodies.

                            Last update:
                            July 2010

                            - Expert reviewer(s):
                            Pr Eric HACHULLA


Linear and whorled nevoid hypermelanosis

A rare hyperpigmentation of the skin disease characterized by the congenital to infantile-onset of bilateral, diffuse (occasionally localized), reticulate (swirls and streaks), macular hyperpigmentation following the lines of Blaschko, typically involving the trunk, limbs, head and neck (but sparing palms, soles and mucosa), without preceding inflammation, blistering or atrophy. Occasionally, extracutaneous abnormalities, including autism, seizures, cardiac defects, skeletal abnormalities and developmental delay, may be associated. Histologically, basal and/or suprabasal melanosis, without pigment incontinence, is observed.


Linear atrophoderma of Moulin (LAM) is characterized by mildly atrophic and hyperpigmented band-like lesions that follow the lines of Blaschko on the trunk or limbs. Since its initial description in 1992, less than 30 cases have been reported in the literature. Onset occurs during childhood or adolescence and the disease is non-progressive. There is no prior inflammation or subsequent scleroderma. The aetiology is unknown but as LAM follows the lines of Blaschko it has been suggested that the disease is caused by mosaicism of a predisposing gene.


Linear focal elastosis is a rare, acquired, dermis elastic tissue disorder characterized by asymptomatic, palpable, hypertrophic or atrophic, yellowish or red, indurated, horizontal, striae-like linear plaques distributed symmetrically across the mid and lower back. No systemic involvement has been described. Skin biopsy reveals a focal increase in abnormal elastic tissue with abundant, wavy, fragmented and aggregated, basophilic elastic fibers in the reticular dermis.


Linear hypopigmentation and craniofacial asymmetry with acral, ocular and brain anomalies

A rare ectodermal dysplasia syndrome characterized by linear hypopigmentation and hypotrichosis following the lines of Blaschko, symmetric or asymmetric facial dysmorphism, and body asymmetry, in association with ocular, dental, and acral anomalies. Reported manifestations include microphthalmia, strabismus, myopia, oligodontia, microdontia, conical teeth, abnormal enamel, brachydactyly, syndactyly, and broad first toe, as well as dysmorphic facial features such as downslanting palpebral fissures, broad nasal bridge, malar hypoplasia, and microstomia. Brain imaging may show cystic leukoencephalopathy and ventricular dilation.


A rare, acquired autoimmune bullous skin disease characterized by annular, grouped blisters on the skin and, frequently, mucous membranes with linear deposition of immunoglobulin A along the basement membrane zone (BMZ).

Summary:
Epidemiology
The estimated incidence varies worldwide, ranging between 0.2-1/1000,000.
Clinical description
Linear IgA dermatosis (LAD) has two forms: the infantile/childhood form and the adult form. In children, presentation is characterized by annular, tense blisters with new lesions appearing at the periphery of older lesions, giving the ''string of pearls'' appearance. Sites of predilection include the face, lower trunk, perineum, and perioral region. Childhood onset is typically before 5 years of age, rarely affects neonates, and tends to resolve spontaneously before puberty. The adult form typically involves severe pruritus with variable lesions, which may consist of annular papules, vesicles, tense bullae, erythema, urticarial plaques, and/or erosions. Scarring is possible. Sites of predilection include the face, extension faces of the limbs, large body folds, buttocks and trunk. LAD can occur at any age, however there is an increased risk of chronic disease in those less than 70 years of age. Mucous membrane involvement occurs in up to 80% of affected children and 70% of affected adults and can affect oral, nasal, pharyngeal, or esophageal mucosa. Drug induced LAD tends to be more severe than the spontaneous form. Lesions occur between 1 and 30 days after treatment and can result in toxic epidermal necrolysis that can be fatal. The disease is associated with ulcerative colitis prior to LAD onset, and with an increased risk of developing lymphoproliferative diseases.
Etiology
Spontaneous LAD is mediated by IgA autoimmunity which targets heterogeneous antigens of either the lamina lucida or sublamina densa of the BMZ. LAD can also be triggered by various drugs including vancomycin, beta lactam antibiotics, captopril, or non-steroidal anti-inflammatory drugs. Infections and malignancies have also been suspected as possible factors triggers in LAD.
Diagnostic methods
Histology analysis on skin biopsy typically demonstrates features of subepidermal blisters with a prominent neutrophilic infiltrate and linear and positive direct immunofluorescence microscopy demonstrates continuous deposition of IgA in the BMZ and/or IgG and C3. Indirect immunofluorescence microscopy on patients's sera demonstrates that circulating IgA anti-basement membrane binds the epidermal side of 1 M NACL split human skin.
Differential diagnosis
Differential diagnosis includes bullous pemphigoid, dermatitis herpetiformis, mucous membrane pemphigoid, lichen planus, lichenoid drug reaction, contact allergy, and other causes of toxic epidermal necrolysis.
Management and treatment
Dapsone and sulfapyridine (or sulfasalazine) as are the preferred therapeutics in combination with topical corticosteroids and general supportive care for skin lesions. Systemic corticosteroids may be used in severe cases. Erythromycin, colchicine, flucloxacillin, intravenous immunoglobulin, azathioprine, mycophenolic acid, and immunoadsorption have been also used in unresponsive patients. Some severe cases have been treated with rituximab. In case of drug induced LAD, the culprit drug is withdrawn and a short course of corticosteroids may be considered.
Prognosis
Prognosis is generally better for children, who frequently have spontaneous resolution and long-term remission. The prognosis is variable in adults who may have complete remission or suffer chronic disease either with permanent lesions or relapse.

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Dr Marion CASTEL | ERN-Skin* - Pr Pascal JOLY | ERN-Skin*

                                * European Reference Network


Linear lichen planus (LLP), also referred to as Blaschkoid LP, is a rare type of lichen planus characterized by a linear distribution of lichenoid lesions along the lines of Blaschko, which are embryonic pathways of skin development.

Summary:
Epidemiology
The prevalence is unknown. Less than 0.5% of patients with LP present with Blaschkoid LP. Cases have been more commonly reported in children, however LLP does occur in adults.
Clinical description
Lesions appear as pruritic, violaceous papules in a linear distribution, usually on the limbs, but also anywhere on the body. It follows a Blaschkoid, not dermatomal, pattern of distribution. It can be superimposed on the more typical non-segmental and randomly-distributed lesions of classic LP. Histology is that of classical papulosquamous lichen planus. A very rare LLP variant, called zosteriform LP, has also been observed and is characterized by a segmental zosteriform distribution of lichenoid lesions. Zosteriform LP may appear as a Koebner phenomenon following herpes zoster infection.
Etiology
Etiology of LLP is unknown, however it has been associated with metastatic carcinoma, HIV infection and hepatitis C infection. It is thought that LLP arises due to an abnormal keratinocyte clone that is only unmasked after the initiating event for lichen planus.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Stephanie ARNOLD  - Dr Susan COOPER


A rare nevus syndrome characterized by the association of an nevus sebaceous with a broad spectrum of abnormalities that affect many organ systems, most commonly the eye, skeletal and central nervous system.

Summary:
Epidemiology
The incidence of epidermal nevus (EN) (isolated finding or as a syndrome) is estimated at 1-3/1,000 live births, with nevus sebaceous (NS) estimated at half of the total. Nevus sebaceous syndrome (NSS) is rare; the exact prevalence and incidence in the general population is unknown.
Clinical description
NSS is the association of NS with extracutaneous manifestations. NS presents typically at birth as hairless yellow-pink, salmon-colored Blaschkoid plaque(s), but nevi may not appear clinically until later in infancy or early childhood. NS are found on the head and neck in two-thirds of cases, and large extensive nevi or a centrofacial location is more associated with NSS. In puberty, NS thicken and can become verrucous in appearance. Later in life, benign neoplasms may grow within the NS; rarely do malignant neoplasms grow, and the risk specifically for basal cell carcinoma is less than 1%. Central nervous system (CNS) findings are the most common extracutaneous anomalies, notably intellectual disability (nearly 80%) and seizures (57%, generalized tonic, tonic-clonic, focal motor, infantile spasms). While structural brain anomalies may occur (hemiatrophy, vascular anomalies, hemimegalencephaly, gyral or posterior fossa abnormalities), 75% of patients with CNS findings have normal imaging. Many other organ systems may also be involved in this syndrome, most commonly ophthalmologic (strabismus, lipodermoids, retinal anomalies, coloboma, cataracts, corneal vascularization) and skeletal (frontal bossing, skeletal hypoplasia, scoliosis and kyphoscoliosis, vitamin D-resistant rickets, hypophosphatemia). Other rare findings have included endocrine, cardiovascular and urogenital systems and oral anomalies (including rare neoplasms of ameloblastoma ,odontoma, giant cell granuloma).
Etiology
NSS is a sporadic disease. EN syndromes are the result of post-zygotic mutations. Mutations in KRAS, HRAS , and NRAS have been described in both isolated NS and NSS. Mutations in these same genes are seen in keratinocytic EN (KEN).
Diagnostic methods
Evaluation should include prenatal, developmental, and family histories. Cutaneous examination should evaluate all skin including areas covered by hair, mucosa, eyes (especially the conjunctiva, sclerae, and extra-ocular eye movements). Careful neurologic and ophthalmologic exams should be performed. Any child with NS on the head or neck and developmental delay should have brain imaging. Skeletal exam should evaluate for kyphoscoliosis, gait and limb length. Skin biopsies and relevant laboratory studies (serum/urine calcium and phosphate, liver and renal function tests) as appropriate. Referral to specialists guided by the above is recommended.
Differential diagnosis
Differential diagnosis includes cutaneous-skeletal hypophosphatemia syndrome, nevus comedonicus syndrome, Becker nevus syndrome, phakomatosis pigmentokeratotica, CHILD syndrome, the spectrum of PIK3CA-related overgrowth syndrome, SOLAMEN (segmental outgrowth-lipomatosis-arteriovenous malformation-epidermal nevus syndrome), and CLOVES syndrome.
Genetic counseling
NSS occurs sporadically due to a postzygotic mutation. They do not appear to be heritable, as the severity of the mutations are thought to be incompatible with life when present in the germline.
Management and treatment
NSS management is individualized and multidisciplinary based on the involved organ systems and degree of impairment. NS are no longer prophylactically excised in infancy, given low risk of malignant potential. In puberty, patients may opt for removal of the thickened lesions for cosmetic reasons. Biopsy is recommended for any growths that may occur within lesions. Tissue should be sent to an experienced dermatopathologist to prevent misdiagnosis of basal cell carcinoma.
Prognosis
The prognosis depends on the severity of the clinical manifestations and the extent of the multisystem involvement.

                            Last update:
                            February 2020

                            - Expert reviewer(s):
                            Dr Sarah ASCH  - Dr Jeffrey SUGARMAN


A rare skin disease characterized by a hamartomatous epidermal lesion presenting as a linear array of verrucous, hyperkeratotic papules that often coalesce into plaques and are formed along the lines of Blaschko. The condition is associated with involvement of other organ systems, mainly brain, eye, and skeletal system. It is the result of mosaic post-zygotic mutations and most commonly presents at birth, but may occur anytime during childhood, rarely also in adulthood.


LIPE-related familial partial lipodystrophy

A rare, genetic lipodystrophy characterized by abnormal subcutaneous fat distribution, resulting in excess accumulation of fat in the face, neck, shoulders, axillae, trunk and pubic region, and loss of subcutaneous fat from the lower extremities. Variable common additional features are progressive adult onset myopathy, insulin resistance, diabetes, hypertriglyceridemia, hepatic steatosis, and vitiligo.


A rare soft tissue tumor characterized by a lobulated, localized (lipoblastoma) or diffuse (lipoblastomatosis) lesion resembling fetal adipose tissue, composed of mature and immature adipocytes. It is most commonly found during the first years of life and presents as a slowly growing, well circumscribed mass, which may compress adjacent structures, depending on the location. Malignant transformation or metastasis does not occur, while recurrences are described especially in lipoblastomatosis.


Lipodystrophy due to peptidic growth factors deficiency

A rare genetic lipodystrophy characterized by loss of subcutaneous fat layers on the limbs, lipodystrophy in the face and trunk and scleroderma-like skin disorders (thickened skin on the palms and soles and skin pigment changes on the limbs and trunk). Additional clinical signs include joint contractures, reduced relative body weight, a bird-like facial appearance with a beaked nose, micrognathia and insulin-resistant diabetes mellitus.


A rare form of genetic lipodystrophy, reported in 3 patients from one family to date, characterized by generalized congenital lipodystrophy, low birth weight, progressive sensorineural deafness occurring in childhood, intellectual deficit, progressive osteopenia, delayed skeletal maturation, skeletal abnormalities described as slender, undermineralized tubular bones, and dense metaphyseal striations in the distal femur, ulna and radius of older patients. Autosomal recessive inheritance has been suggested.


A rare neurometabolic disease characterized by a neonatal onset of seizures (often intractable), muscular hypotonia, feeding difficulties (poor sucking and/or swallowing) and mild to severe psychomotor delay, associated with nonketotic hyperglycinemia typically revealed by biochemical analysis. Respiratory problems (apnea, acute respiratory acidosis), lethargy, hearing loss, microcephaly and spasticity with pyramidal signs may also be associated.


Lipoid proteinosis (LP) is a rare genodermatosis characterized clinically by mucocutaneous lesions, hoarseness developing in early childhood and, at times, neurological complications.

Summary:
Epidemiology
Incidence and prevalence are not known. More than 300 cases (ages 6 to 67 years) have been reported worldwide. Most patients are of European ancestry (Dutch or German). A founder effect is reported among large kindreds in South Africa. Many cases are also reported from the Middle East and India. The disease is more commonly seen in consanguineous unions.
Clinical description
A wide range of clinical signs is noted and disease severity is variable, while the course is usually slowly progressive. The usual presenting manifestation is a hoarse cry due to laryngeal infiltration at birth or in infancy. Subsequently, skin and mucous membrane changes develop in the first two years of life. Crusted lesions initially appear on the face and extremities and heal with scarring. Waxy, thickened and at times verrucous skin lesions may affect the face, eyelids, axillae, knees and scrotum. Eyelid beading (moniliform blepharosis) is a hallmark feature but occurs later in childhood. Patchy or diffuse hair loss may be present. The oral mucosa is often involved with cobblestone lips, tongue or gingiva, impaired tongue mobility causing speech problems, and transient swelling and ulceration of the lips and tongue. Oligodontia (see this term) may be present. Respiratory tract infiltration may cause upper respiratory tract infections, hoarseness or aphonia, dysphagia, and airway obstruction. Dystonia, seizures, behavioral changes, learning difficulties and short stature have been reported in affected children. Less commonly, the disease manifests in adulthood with subtle skin findings and possible complications due to visceral deposition. Heterozygous carriers are generally asymptomatic but may have a mild presentation including abnormal dentition.
Etiology
LP is caused by deposition of an amorphous hyaline material in the skin, mucosa, and viscera. Causative loss-of-function mutations have been found in the ECM1 gene (1q21) encoding extracellular matrix protein 1, which has a role in physiology and homeostasis of the skin and many other tissues.
Diagnostic methods
Diagnosis is based on the clinical signs (particularly hoarseness and skin manifestations). Histological findings on biopsy of affected cutaneous or mucosal sites show periodic acid-Schiff-positive deposition of amorphous hyaline material in the papillary dermis which confirms the diagnosis. Cranial magnetic resonance imaging or computed tomography reveals bean-shaped intracerebral calcifications in the temporal lobe (in up to 75% of patients). Molecular genetic testing confirms the diagnosis.
Differential diagnosis
The main differential diagnoses are hydroa vacciniforme and autosomal erythropoietic protoporphyria, but also include leprosy, lichen amyloidosis (see these terms), and xanthomas.
Antenatal diagnosis
If a family member is affected by the disease and the gene mutation has been confirmed, prenatal diagnosis is possible.
Genetic counseling
LP is inherited in an autosomal recessive manner. Genetic counseling should be provided to affected families.
Management and treatment
There is currently no known effective curative treatment and no standard treatment approach. D-penicillamine, oral dimethyl sulfoxide, acitretin, topical corticosteroids, and carbon dioxide laser have been used with varying degrees of success. Treatment of LP with acitretin has shown some efficacy for hoarseness after use over a long period, but there has been variable success in treating the skin lesions.
Prognosis
The prognosis is generally favorable. Fatal outcomes are uncommon, but the disease may strongly impact quality of life.

                            Last update:
                            October 2014

                            - Expert reviewer(s):
                            Dr Bernice KRAFCHIK  - Dr Irene LARA-CORRALES


A rare genetic renal disease characterized by the formation of intraglomerular lipoprotein thrombi due to lipid deposition in severely dilated glomerular capillaries. Laboratory examination reveals abnormal serum lipid profiles, in particular markedly elevated apolipoprotein E. Clinical manifestations include proteinuria or nephrotic syndrome with hypertension and potential progression to chronic renal failure. Systemic complications of dyslipidemia are not observed.


Liposarcoma (LS), a type of soft tissue sarcoma, describes a group of lipomatous tumors of varying severity ranging from slow-growing to aggressive and metastatic. Liposarcomas are most often located in the lower extremities or retroperitoneum, but they can also occur in the upper extremities, neck, peritoneal cavity, spermatic cord, breast, vulva and axilla.

Summary:
Epidemiology
Liposarcomas account for approximately 15-20% of all soft tissue sarcomas. The incidence is approximately 1 per 100, 000 persons/years.
Clinical description
They can affect all age groups but are most frequently seen in middle-aged and older adults. Liposarcomas are classified into 4 biological groups (encompassing five histological subtypes): well-differentiated (WDLS), dedifferentiated (DDLS), myxoid /round cell (MRCLS) and pleomorphic (PLS) (see these terms).
Etiology
The etiology is unknown but many chromosomal aberrations are found in liposarcomas.
Prognosis
The prognosis is dependent on the specific subtype, size, stage and location of the disease.

                            Last update:
                            January 2013

                            - Expert reviewer(s):
                            Dr Samuel SINGER


A rare inborn error of metabolism disorder, with a highly variable phenotype, typically characterized by neonatal to infancy-onset of seizures, psychomotor delay, and abnormal muscle tone that may include hypo- and/or hypertonia, resulting in generalized weakness, dystonic movements, and/or progressive respiratory distress, associated with severe lactic acidosis and elevated lactate, ketoglutarate and 2-oxoacids in urine. Additional manifestations may include dehydration, vomiting, signs of liver dysfunction, extrapyramidal signs, spastic tetraparesis, brisk deep tendon reflexes, speech impairment, swallowing difficulties, and pulmonary hypertension.


A rare inborn error of metabolism characterized by severe neonatal encephalopathy with EEG abnormalities, increased serum lactate, little or no psychomotor development, and sometimes death in infancy. Brain imaging may show cortical atrophy, enlarged ventricles, delayed myelination, and white matter abnormalities, among others.


Lisch epithelial corneal dystrophy (LECD) is a very rare form of superficial corneal dystrophy characterized by feather-shaped opacities and microcysts in the corneal epithelium arranged in a band-shaped and sometimes whorled pattern, occasionally with impaired vision.

Summary:
Epidemiology
Exact prevalence of this form of corneal dystrophy is not known but very few cases have been reported to date. LECD has been documented in one German family and in rare sporadic cases in Germany and the USA.
Clinical description
Lesions generally develop in childhood. Epithelial opacities are slowly progressive and painless blurred vision sometimes occurs after 60 years of age.
Etiology
The exact cause is unknown but appears to be genetic. The gene related to Lisch epithelial corneal dystrophy has been mapped to the short arm of the X chromosome (Xp22.3).
Genetic counseling
An X-linked recessive pattern of inheritance has been reported.
Management and treatment
The pathologic corneal epithelium can be removed if the symptoms demand such a treatment.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Dr Gordon KLINTWORTH


Lissencephaly due to LIS1 mutation is a cerebral malformation with epilepsy characterized predominantly by posterior isolated lissencephaly with developmental delay, intellectual disability and epilepsy that usually evolves from West syndrome to Lennox-Gastaut syndrome. Additional features include muscular hypotonia, acquired microcephaly, failure to thrive and poor control of airways leading to aspiration pneumonia.


Lissencephaly (LIS) due to TUBA1A mutation is a congenital cortical development anomaly due to abnormal neuronal migration involving neocortical and hippocampal lamination, corpus callosum, cerebellum and brainstem. A large clinical spectrum can be observed, from children with severe epilepsy and intellectual and motor deficit to cases with severe cerebral dysgenesis in the antenatal period leading to pregnancy termination due to the severity of the prognosis.


Lissencephaly syndrome, Norman-Roberts type is characterised by the association of lissencephaly type I with craniofacial anomalies (severe microcephaly, a low sloping forehead, a broad and prominent nasal bridge and widely set eyes) and postnatal growth retardation.

Summary:
Epidemiology
The prevalence is unknown.
Clinical description
Severe intellectual deficit, spasticity and epilepsy are also present.
Etiology
Mutations in the RELN gene (7q22) have been identified in some patients.
Genetic counseling
Transmission is autosomal recessive.

                            Last update:
                            March 2008


Lissencephaly type 1 due to doublecortin gene mutation

Type 1 lissencephaly due to doublecortin (DCX) gene mutations is a semi-dominant X-linked disease characterised by intellectual deficiency and seizures that are more severe in male patients.

Summary:
Epidemiology
The prevalence is unknown.
Clinical description
Boys presenting with lissencephaly show an abnormally thick cortex with very few gyri (pachygyria) or even none (agyria). Clinical manifestations include swallowing and feeding difficulties, abnormal muscular tone, seizures and severe to profound psychomotor retardation. Female patients display a less severe malformation referred to as ''doublecortex'' or subcortical laminar heterotopia (SCLH) and present with clinical signs of variable severity ranging from mild epilepsy, beginning in childhood or adolescence with difficulties at school, to refractory epileptic seizures and severe intellectual deficiency.
Etiology
The condition is caused by doublecortin (DCX, located at Xq22.3-q23) gene mutations. These mutations lead to a specific defect of neuronal migration during embryogenesis, affecting all the neurons in males (lissencephaly) or only a population of neurons in heterozygous females, explaining why affected females display the less severe SCLH malformation. The DCX gene is linked to 50% of the cases of agyria, 33% of frontal pachygyria cases and 75% of SCLH cases. There is no correlation between the type of mutation and the severity of the disease. The group of type I lissencephalies includes Miller-Dieker syndrome and isolated lissencephalies linked to a deletion or point mutation in the LIS1 gene located on chromosome 17 (see these terms). In contrast to lissencephaly resulting from mutations in DCX, these types of lissencephaly are never familial.
Diagnostic methods
The diagnosis of subcortical laminar heterotopia and lissencephaly relies on magnetic resonance imaging (MRI). There seems to be a correlation between the degree of pachygyria of the cortex, widening of the ventricles, and thickness of laminar heterotopia on the one hand, and early onset of attacks and severity of intellectual deficiency on the other hand.
Differential diagnosis
SCLH should be distinguished from periventricular nodular heterotopia (see this term), which is also observed in girls, and is caused by a mutation in the filamin A gene, also located on the X chromosome. The clinical picture is milder with later onset and moderate epilepsy occurring in the young adult.
Genetic counseling
The molecular diagnosis of SCLH and lissencephaly is useful for genetic counselling and potential early antenal diagnosis of this very severe epileptogenic encephalopathy, before the stage when gyri normally appear (15 weeks of amenorrhea). If the mother carries the mutation, her risk of having a child with the mutation is 50%. Even when the mutation fails to be detected in the mother's blood, a risk nevertheless exists for future pregnancies, due to germinal mosaicism (5% to 10% of the cases).
Management and treatment
Antiepileptic medication generally succeeds in controlling epilepsy, although in some cases seizures do not completely resolve despite the use of several drugs. A gastric catheter or even a gastrotomy may be necessary to prevent complications linked to swallowing and feeding difficulties (malnutrition, regurgitation-induced pneumopathy). Orthopaedic problems (hip luxation, progressive scoliosis) can be prevented by posture correction and use of a surgical corset, which allow surgery to be delayed or avoided.
Prognosis
The prognosis depends on the degree of cerebral involvement. Lissencephaly is a severe disease, potentially associated with multiple impairments. The prognosis of SCLH is more variable, and depends on the severity of learning difficulties and epilepsy.

                            Last update:
                            January 2007

                            - Expert reviewer(s):
                            Pr Vincent DES PORTES


Lissencephaly type 3-familial fetal akinesia sequence syndrome is characterised by the association of microencephaly, agenesis of the corpus callosum, brainstem hypoplasia, cystic cerebellum and foetal akinesia sequence. Less than 10 cases have been described so far. The syndrome is transmitted as an autosomal recessive trait and may be an allelic variant of Neu-Laxova syndrome and lissencephaly type III with metacarpal bone dysplasia (see these terms).


Lissencephaly type 3-metacarpal bone dysplasia syndrome

A rare syndromic form of lissencephaly characterized by severe microcephaly, agyria, agenesis of the corpus callosum, cerebellar hypoplasia, facial dysmorphology and epiphyseal stippling of the metacarpal bones. The syndrome may be an allelic variant of Neu-Laxova syndrome and Lissencephaly type III with cystic dilations of the cerebellum and foetal akinesia sequence.


Lissencephaly with cerebellar hypoplasia type A

A rare, genetic, lissencephaly with cerebellar hypoplasia subtype characterized by classical lissencephaly with thickened cortical gray matter (with either no discernable gradient, a predominantly posterior gradient, or a predominantly anterior gradient) associated with variable, predominantly midline, cerebellar hypoplasia.


Lissencephaly with cerebellar hypoplasia type B

A rare form of lissencephaly with cerebellar hypoplasia characterized by subtle microcephaly, hypotonia and neurological and cognitive development delay. Hippocampal malformation is a characteristic imaging feature of this disorder.


Lissencephaly with cerebellar hypoplasia type C

A severe form of lissencephaly with cerebellar hypoplasia characterized by severe microcephaly, cleft palate, and severe cerebellar and brainstem hypoplasia leading to neonatal death.


Lissencephaly with cerebellar hypoplasia type D

A rare form of lissencephaly with cerebellar hypoplasia characterized by pronounced microcephaly (≤ -3 SD), intellectual disability, spastic diplegia and moderate to severe cerebellar hypoplasia involving both vermis and hemispheres.


Lissencephaly with cerebellar hypoplasia type E

A rare, genetic, lissencephaly with cerebellar hypoplasia subtype characterized by the presence of lissencephaly with an abrupt transition, near the boundary between the frontal and parietal cortex, from frontal agyria to posterior gyral simplification, associated with cerebellar hypoplasia which predominantly affects the midline vermis.


Lissencephaly with cerebellar hypoplasia type F

A severe form of lissencephaly with cerebellar hypoplasia, characterized by a microcephaly of at least - 3 SD and a thick cortex associated with complete absence of the corpus callosum.


Lissencephaly with cerebellar hypoplasia (LCH) is a variant form of lissencephaly and involves a heterogeneous group of cortical malformations without severe congenital microcephaly (>-3 SD). LCH is characterized by cerebellar underdevelopment ranging from vermian hypoplasia to total aplasia with classical or cobblestone lissencephaly. The phenotypic features of LCH include small head circumference (between -2 and -3 standard deviations (SD) forage) at birth and postnatally, moderate to severe intellectual disability, hypotonia and spasticity. Seizures are often observed and infantile spasms have been reported in some rare cases. LCH has been classified into six subgroups according to neuroradiographic properties and are classified LCH type A to F.


A rare bacterial infectious disease caused by the foodborne pathogen Listeria monocytogenes, characterized by a febrile gastroenteritis, which is usually mild and self-limiting in otherwise healthy persons, but can progress to severe illness in at-risk groups like pregnant women, elderly people, immunocompromised people, and neonates. Complications include sepsis, meningitis, and encephalitis. Listeriosis during pregnancy usually occurs during the third trimester and may lead to preterm labor, miscarriage, stillbirth, or intrauterine infection of the unborn child.


A rare vascular skin disease characterized by recurrent focal non-inflammatory thrombosis of dermal venulae, predominantly of the lower extremities, resulting in a cutaneous response manifested as pruritus and painful papules and erythematous plaques. The lesions evolve into hemorrhagic vesicles or bullae, which rupture and turn into painful ulcers merging into reticulate, confluent, geometric, and painful ulcerations. During a period of a few months, the ulcerations change to porcelain-white atrophic scars with punctate telangiectasia (so-called atrophie blanche). In active disease, lesions in different stages coexist.


A rare neoplastic disease characterized by the presence of ten or more hepatocellular adenomas in a background of normal appearing hepatic parenchyma. The majority of reported cases are female. There is no association with steroid use. The condition is considered benign, although the risk of complications (such as malignant transformation or spontaneous rupture with intraperitoneal hemorrhage) is much higher than in isolated hepatic adenoma. Hepatocellular carcinoma develops in less than 10% of cases.


LMNA-related cardiocutaneous progeria syndrome is a rare, genetic, premature aging syndrome characterized by adulthood-onset cutaneous manifestations that result in a prematurely aged appearance (i.e. premature thinning and graying of scalp hair, loss of subcutaneous fat, tightening of skin) associated with prominent cardiovascular manifestations, such as accelerated atherosclerosis, calcific valve disease, and cardiomyopathy. Patients present loss of eyebrows and eyelashes in childhood and have a predisposition to develop malignancies.


A form of holoprosencephaly characterized by separation of the right and left cerebral hemispheres and lateral ventricules with some continuity only across the frontal neocortex, especially rostrally and ventrally. Craniofacial features are variable may include ocular hypotelorism, midline cleft lip (complete or partial) and/or flat nose amongst other features.


Localized dystrophic epidermolysis bullosa, acral form

A form of localized dystrophic epidermolysis bullosa characterized by trauma-induced blistering confined primarily to the hands and feet. Healing of blisters is associated with milia formation, atrophic scarring and dystrophic nails. There is no extracutaneous involvement.


Localized dystrophic epidermolysis bullosa, nails only

A form of localized dystrophic epidermolysis bullosa characterized by dystrophic nails in the absence of blistering. The nail deformity is often limited to toenails which can appear thickened and shortened, or may be absent. No other cutaneous or extracutaneous symptoms are observed.


Localized dystrophic epidermolysis bullosa, pretibial form

A form of localized dystrophic epidermolysis bullosa characterized by the development of blisters, erosions, and lichenoid lesions predominantly in the anterior lower legs (pretibial areas and feet), the hands and nails. Individual lesions, which tend to be papular or plaque-like, are often violaceous. Pruritus is possible. Healing of blisters is associated with hypertrophic scarring and milia formation. Dystrophy of both fingernails and toenails is characteristic.


Localized dystrophic epidermolysis bullosa

A localized form of dystrophic epidermolysis bullosa characterized by blisters confined primarily to the hands and feet (acral form) or to the pretibial region (pretibial form). Nail dystrophy or loss is common and may be an isolated finding (nail only form).

Summary:
Epidemiology
The prevalence is unknown.
Clinical description
The disorder manifests at birth or during infancy with trauma-induced blisters but in some cases may be delayed until the adolescence. Blisters are limited to the extremities or the anterior lower legs. Healing of blisters is associated with milia formation, atrophic scarring and dystrophic nails. There is no extracutaneous involvement. Individual lesions, which tend to be papular or plaque-like, are often violaceous, suggesting the clinical diagnosis of lichen planus. Some patients complain of pruritus. Dystrophy of both fingernails and toenails is characteristic.
Etiology
The disorder is caused by mutations within the type VII collagen gene (COL7A1; 3p21.31). Mutations in this gene lead to an alteration in function of collagen VII. This impairs its assembly into anchoring fibrils that anchor the basement membrane to the underlying dermis.
Diagnostic methods
Diagnosis is suspected on clinical presentation and confirmed by genetic testing. Immunofluorescence antigen mapping and/or transmission electron microscopy on skin samples may show only discrete changes.
Differential diagnosis
The differential diagnosis includes localized subtypes of epidermolysis bullosa simplex or junctional EB and lichen planus.
Antenatal diagnosis
Antenatal diagnosis is not recommended.
Genetic counseling
The disorder can be autosomal dominant or recessive. Genetic counseling will depend on the type of inheritance or if the disease occurs sporadically. The nail only form is usually autosomal dominant.
Management and treatment
Management is preventive: protective padding of the skin and appropriate lifestyle measures reduce blistering, and careful wound care prevents secondary infection and reduces scarring.
Prognosis
Prognosis is very good, life expectancy is not influenced by this form of EB.

                            Last update:
                            May 2021

                            - Expert reviewer(s):
                            Pr Cristina HAS | ERN-Skin*

                                * European Reference Network


Localized epidermolysis bullosa simplex, formerly known as EBS, Weber-Cockayne, is a basal subtype of epidermolysis bullosa simplex (EBS, see this term). The disease is characterized by blisters occurring mainly on the palms and soles, exacerbated by warm weather.

Summary:
Epidemiology
Reported prevalence ranges from 1/318,000 for localized EBS in the United States to 1/35,000 for localized EBS and non-Dowling-Meara generalized EBS (combined) in Scotland. About two-thirds of EBS patients have the localized basal form.
Clinical description
Onset is usually in late infancy or early childhood. The usual distribution of blisters in these patients is on the palms and soles, although other skin surfaces may also blister if subjected to significant trauma. Milia and scarring are rare in localized EBS, and dystrophic nails are uncommon. Focal keratoderma of the palms and soles may occur by adulthood in some patients. The only common extracutaneous finding in localized EBS, i.e. localized intraoral erosions or blisters, tends to be asymptomatic, occurs in about one third of patients, and is usually seen only during infancy.
Etiology
Localized EBS is caused by dominant negative mutations within either the KRT5 (12q13.13) or KRT14 (17q12-q21) genes, encoding keratin 5 and keratin 14, respectively.
Genetic counseling
Transmission is autosomal dominant and sporadic cases are frequent.
Prognosis
Although the disease can be disabling, life-expectancy is normal.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Pr Giovanna ZAMBRUNO


Localized junctional epidermolysis bullosa

A form of junctional epidermolysis bullosa characterized by neonatal onset of localized blistering, and dystrophic or absent nails. Skin blistering is mainly confined to hands, feet, lower legs and face. Additional findings may include dental enamel hypoplasia and an increased incidence of caries.


Localized lichen myxedematosus with mixed features of different subtypes

Localized lichen myxedematosus (LM) with mixed features of different subtypes is a form of atypical lichen myxedematosus (see this term), characterized by mixed features of the 5 subtypes of localized LM which are: discrete papular LM, acral persistent papular mucinosis, self-healing papular mucinosis, papular mucinosis of infancy, and nodular LM (see these terms).

Summary:
Epidemiology
Localized LM with mixed features of different subtypes is a rare disease and to date only a few cases have been described in the literature.
Clinical description
The disease affects middle age adults and manifests with mixed features of the 5 subtypes of localized LM (discrete papular LM, acral persistent papular mucinosis, self-healing papular mucinosis, papular mucinosis of infancy, and nodular LM). One case is reported as having features of both acral persistent papular mucinosis and self-healing juvenile cutaneous mucinosis (see this term) with carpal tunnel syndrome.
Etiology
As all primitive mucinosis, the pathogenesis of localized LM with mixed features of different subtypes is still unknown.

                            Last update:
                            June 2014

                            - Expert reviewer(s):
                            Dr Elisa CINOTTI  - Pr Franco RONGIOLETTI


Localized lichen myxedematosus with monoclonal gammopathy or systemic symptoms is a form of atypical lichen myxedematosus (see this term), characterized by the appearance of several 2-4 mm erythematous waxy papules confined to a few sites that may be associated with either an immunoglobulin A (IgA) nephropathy in patients with acral persistent papular mucinosis; discrete papular lichen myxedematosus (see these terms); a scleromyxedema-like involvement, with dysphagia, hoarseness, pulmonary involvement, and carpal tunnel syndrome; myositis without skin sclerosis; or paraproteinemia.


A group of skin diseases characterized by the development of papules, nodules and/or plaques with mucin deposits and a variable degree of fibrosis in the absence of thyroid disease. The group comprises five sub-forms: nodular lichen myxedematosus, discrete papular lichen myxedematosus, papular mucinosis of infancy, acral persistent papular mucinosis and self-healing papular mucinosis.


A rare group of acquired lipodystrophies that are characterized by loss of subcutaneous tissue from generally small regions of the body, either single or multiple areas, and are not typically associated with metabolic complications. Some cases may involve lipohypertrophy (insulin). This group includes pressure-induced localized lipoatrophy, drug-induced localized lipodystrophy, panniculitis- induced localized lipodystrophy, centrifugal lipodystrophy, and idiopathic localized lipodystrophy.

Summary:
Epidemiology
The term covers a heterogeneous group of conditions for which the prevalence varies according to the cause.
Clinical description
Localized lipohypertrophy involves small body areas, manifesting as either a soft bump or a depression in the soft tissue, and are not usually accompanied by a metabolic syndrome. They are most frequently observed in association with repeated mechanical microtraumatism (pressure induced localized lipoatrophy) such as drug injection, but may also be seen as the sequelae of an inflammation (panniculitis-induced localized lipodystrophy). Drug-induced localized lipodystrophy is often observed in diabetes associated with steroid or antiretroviral treatment leading to possible android obesity, and sometimes a lipoatrophy of Bichat balls under antiretroviral drugs. Centrifugal lipodystrophy is characterized by fat loss spread in a centrifugal pattern from abdomen and groin area and is associated with peripheral panniculitis. It begins in infancy, stops spreading between the ages of 3 and 8 and then in most cases, resolves by itself. Panniculitis-induced localized lipodystrophy is characterized by an initial development of panniculitis followed by localized fat loss when these lesions heal. The disease is associated with serum ANA and anti dsDNA antibodies, patients may also have concurrent autoimmune diseases. Localized lipoatrophy is not painful but can induce discomfort, especially when they are localized in a support zone such as the bottom, or dressing difficulties or aesthetic prejudice.
Etiology
Localized lipodystrophy is generally iatrogenic and secondary to medication injections (somatostatin analogs, pegvisomant, insulin), vaccines or repetitive pressure trauma. In addition certain medications can induce localized lipodystrophy such as steroids or antiretroviral treatment, or it can be triggered by panniculitis (such as nodular non-suppurative panniculitis, Weber-Christian syndrome). The etiology for idiopathic localized lipodystrophy and centrifugal localized lipodystrophy remains unknown.
Differential diagnosis
Differential diagnoses may include scleroderma, idiopathic dermal atrophy, idiopathic atrophoderma of Pasini and Pierini, and Gowers panatrophy.
Antenatal diagnosis
Not applicable.
Genetic counseling
Not applicable.
Management and treatment
Treatment should revolve around elimination of the cause whenever possible: modification of the injection technique or plastic surgery if necessary. Localized lipodystrophy associated with insulin therapy usually resolves in a few weeks after changing the site of injection and modification of the length of the needle.
Prognosis
The prognosis depends on the cause but is more severe in case of panniculitis.

                            Last update:
                            September 2019

                            - Expert reviewer(s):
                            Pr Marie-Christine VANTYGHEM


A rare variant of mycosis fungoides (MF), a form of cutaneous T-cell lymphoma, characterized by the presence of localized patches or plaques with epidermal hyperplasia and intraepidermal proliferation of neoplastic T-cells, usually involving one extremity.

Summary:
Epidemiology
The annual incidence of MF and its variants is estimated at between 1/350,000 and 1/110,000, with localized pagetoid reticulosis accounting for less than 2% of MF cases. Exact data on the male to female ratio are unavailable.
Clinical description
Onset usually occurs in the 4th to 5th decade of life, but younger patients may be affected in rare cases. Patients present with solitary psoriasiform or hyperkeratotic patches or plaques. Extracutaneous involvement is exceptional in the solitary variant, but rarely the disease may progress to "conventional" MF.
Etiology
The etiology remains unknown.
Diagnostic methods
The diagnosis is based on clinical presentation and is confirmed by a skin biopsy. Histological findings reveal a hyperplastic epidermis with marked infiltration by atypical "haloed" lymphocytes that have medium-sized, pleomorphic nuclei. Immunohistology shows either a memory T-helper (CD3+, CD4+, CD8-) or a T-cytotoxic (CD3+, CD4-, CD8+) phenotype. CD30 may be positive.
Differential diagnosis
The differential diagnosis includes other epidermotropic lymphomas, such as CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (aggressive cutaneous T-cell lymphoma: see this term).
Management and treatment
Radiotherapy and surgical excision are the main treatment options. Topical steroids may also be effective.
Prognosis
Localized pagetoid reticulosis is slowly progressive. Prognosis is favorable: disease-related death has never been reported in these patients.

                            Last update:
                            June 2009

                            - Expert reviewer(s):
                            Pr Lorenzo CERRONI


A rare skin disease characterized by inflammatory and sclerosing disease affecting the skin and underlying connective tissues (subcutaneous tissue, fascia, muscle or bone). It causes cutaneous patches or bands of skin inflammation and thickness affecting the head, neck region, trunk and extremities.

Summary:
Epidemiology
The incidence of localized scleroderma has been estimated at 1/37,000-625,000 people per year depending on the country. Women are predominantly affected (F/M sex ratio around 3:1). The mean age at diagnosis ranges from 8 to 47 years. In two-thirds of cases, it occurs in adults. Localized scleroderma is called ''juvenile'' when occurring in childhood (peak incidence between 7 and 11 years).
Clinical description
Localized scleroderma is classified into several subtypes (there is no consensual classification) that include limited (circumscribed or plaque morphea), generalized (≥4 lesions and/or ≥2-3 anatomical sites) or pansclerotic morphea, and linear morphea. Linear morphea tends to affect children and adolescents, while plaque morphea is more common in adults. However, both can coexist in the same patient (mixed morphea). First, areas of hard and dry skin develop in the hands, arms, face, or leg in an ipsilateral fashion. Then, plaques that spread centrifugally or wide strips (linear scleroderma) appear. Plaques are round or oval, often with a white appearance and a violaceous border. Linear scleroderma mainly develops on the face, thorax, arms, and legs. In the case of facial involvement, some strips developing on the forehead may be hollow and lead to a sabre-cut appearance (termed ''en coup de sabre''). Linear scleroderma tends to involve the underlying fat and muscles and may lead to muscle atrophy, ophthalmologic or neurological disorders such as headaches, seizures or uveitis. Localized scleroderma can result in major facial or limb asymmetry, flexion contractures, and disability. Raynaud's phenomenon is usually absent. It is important to note that localized scleroderma does not evolve into systemic sclerosis (rarely, systemic sclerosis and localized scleroderma can co-exist).
Etiology
The exact cause of localized scleroderma is unknown. The disease originates from a combination of genetic predisposition and environmental factors, implies vascular and autoimmune pathways which lead to localized overproduction of extracellular matrix (collagen).
Diagnostic methods
Diagnosis is based on clinical presentation. A skin biopsy may help to confirm the diagnosis by revealing abnormal accumulation of collagen, thickening of the vessel walls, and the presence of inflammatory infiltrates in the papillary dermis and around the vessels. Blood tests are usually normal. Some patients may have antinuclear antibodies excluding systemic sclerosis-associated specificities (anti-topoisomerase, anti-centromere or anti-RNA polymerase III antibodies).
Differential diagnosis
The differential diagnosis includes (but is not limited to): lichen sclerosus, granuloma annulare, erythema chronicum migrans, drug-induced dermatitis, eosinophilic fasciitis or systemic sclerosis, especially in case of generalized/pansclerotic morphea.
Management and treatment
Management is symptomatic and includes the use of topical steroids, tacrolimus, vitamin D derivates or imiquimod for morphea lesions, and systemic steroids, methotrexate or phototherapy for linear scleroderma of the neck and extremities with potential functional/esthetic consequences, or for generalized morphea. Treatment should be initiated promptly to prevent irreversible tissue damage. Physical therapy may be helpful to limit cutaneous indurations and muscle retraction.
Prognosis
Prognosis is usually favorable within 5 years but some patients may present with chronic disease and recurrences. Localized scleroderma is only rarely life threatening but can severely affect quality of life, particularly in children. Linear lesions tend to persist longer than plaque lesions.

                            Last update:
                            February 2024

                            - Expert reviewer(s):
                            Pr Vincent SOBANSKI


A rare neurologic disease characterized by severe paralysis of the limbs and the oral structures causing the person to be completely dependent on help in all activities of daily living and communication, while having preserved cognition. Most commonly, the term locked-in syndrome (LIS) is used when the condition is caused by acquired brain injury (as in this text), but sometimes also when referring to the advanced stage of certain neurodegenerative disorders.

Summary:
Epidemiology
LIS is a very rare condition. No prevalence studies have been published. A study published in 1986 identified 139 cases in the literature. A recent (2023) national population-based study from Norway reported 16 cases living with LIS in a population of approximately 5.425 million (1 out of 339,000 individuals).
Clinical description
LIS can be classified into 3 categories: classic, where patients are quadriplegic and anarthric with preserved consciousness and upper eyelid and vertical eye movements; incomplete, where patients have limited voluntary movements in addition to vertical eye movements; total, where patients show complete immobility including eye movements.
Etiology
The most common cause of LIS is vascular lesions; trauma, infection, myelinolysis, polyneuropathy and demyelination are rare etiologies.
Diagnostic methods
Diagnosis is based on clinical features. The presence of cognitive abilities and willingness to communicate is frequently noticed by patient's relatives or caregivers. Eye movement response to verbal commands should systematically be searched for in apparent vegetative state cases. Unambiguous but limited signs of consciousness (voluntary eye movements or blinking), fluctuations of vigilance and cognitive or sensory deficits lead to diagnostic difficulties. A normal and reactive EEG rhythm should alert the physician but is not sufficient to disentangle LIS from unconscious patients. Brain imaging (ideally MRI) usually shows isolated lesions of the ventral portion of the pons or midbrain, but cerebral lesions outside the brain stem might occur in as much as 80% of the cases.
Differential diagnosis
Differential diagnoses include coma, vegetative state/unresponsive wakefulness and minimally conscious states.
Management and treatment
Initial management is based on respiratory assistance, gastrostomy and prevention of any immobility, dysphagia and incontinence complications. It is important to establish a mode of communication; eye movements are preferred rather than blinking. As the individual is completely dependent on help, one needs to assure the patient feels safe. Rehabilitation should start in the acute phase and be continued throughout the subacute stage. Cornerstones are chest physiotherapy, recovery of independent swallowing and continence, and motor rehabilitation. Motor progress should be accurately monitored as even small movements might be used for interaction by switches etc. Often, communication methods can be gradually refined as a number of technical solutions are available. Brain-computer interfaces (BCI) are of growing help to provide more direct and spontaneous ways of communication.
Prognosis
In the acute phase, patients may rarely experience a transient LIS, while some patients do not survive. Further prognosis varies. Usually some motor improvement occurs. Almost 9 out of 10 patients who are ''locked in'' for at least 6 weeks remain highly dependent on help while 1 in 20 experiences complete motor recovery. Young age at onset and early intensive rehabilitation are probably favorable prognostic factors. LIS caused by a non-vascular brain injury seems to have better motor recovery.

                            Last update:
                            February 2024

                            - Expert reviewer(s):
                            Dr Frank BECKER


A rare restrictive cardiomyopathy characterized by hypereosinophilia and fibrous thickening of the endocardium, with usually large thrombi against the ventricle walls, that can lead to cardiovascular complications such as heart failure and thromboembolism. It manifests with symptoms like edema, fatigue and shortness of breath. It is usually secondary to eosinophil-associated tissue damage and is associated with idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, carcinoma, or lymphoma.


Loeys-Dietz syndrome is a rare genetic connective tissue disorder characterized by a broad spectrum of craniofacial, vascular and skeletal manifestations with four genetic subtypes described forming a clinical continuum.


Logopenic progressive aphasia (lv-PPA) is a form of primary progressive aphasia (PPA; see this term), characterized by impaired single-word retrieval and naming and impaired repetition with spared single-word comprehension and object knowledge.


Loiasis is a form of filariasis (see this term), caused by the parasitic worm Loa loa, endemic to the forest and savannah regions of Central and Western Africa. Loiasis may either be asymptomatic or manifest as a large, transient area of localized, non-erythematous subcutaneous edema (Calabar swellings), adult worm migration through the sub-conjunctiva (''African eye worm'') and pruritus. Generalized itching, hives, muscle pains, arthralgias, fatigue, and adult worms visibly migrating under the surface of the skin may be observed. Severe complications such as encephalopathy have been reported in highly infected individuals receiving ivermectin during mass drug administration programs for the control of onchocerciasis and lymphatic filariasis (see these terms).


Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency

A mitochondrial disorder of long chain fatty acid oxidation characterized in most patients by onset in infancy/ early childhood of hypoketotic hypoglycemia, metabolic acidosis, liver disease, hypotonia and, frequently, cardiac involvement with arrhythmias and/or cardiomyopathy.

Summary:
Epidemiology
The worldwide birth prevalence is estimated at 1/250,000. However around the Baltic Sea the frequency is higher; birth prevalence is predicted to be 1/120,000 in Poland and 1/20,000 in the Pomeranian district.
Clinical description
Most patients display a severe phenotype that presents in infancy, usually from the neonatal period up until 12 months of age. The disease manifests as hypoketotic hypoglycemia, metabolic acidosis, hypotonia, liver involvement with hepatic encephalopathy, cardiomyopathy and arrhythmias. Clinical presentation is frequently preceded by fasting and/or intercurrent illness and often presents with hypoketotic hypoglycemia. Chronic peripheral neuropathy and pigmentary retinopathy develop over time in many surviving patients. Rarer presentations of LCHADD are sudden cardiac arrest or sudden infant death. HELLP syndrome (see this term) often occurs in pregnant women carrying a fetus affected with LCHADD.
Etiology
LCHADD is caused by the isolated deficiency of long chain 3-hydroxyacyl-CoA dehydrogenase, an enzyme of the mitochondrial trifunctional protein complex (TFP). TFP is a heterooctamer of 4 alpha and 4 beta subunits. LCHADD is due to mutations in the HADHA gene (2p23) which encodes for the alpha subunit of TFP. The majority of patients with LCHADD of European origin are homozygous for the common LCHADD alpha-subunit mutation 1528G>C, that is located at the catalytic site of the LCHAD domain.
Diagnostic methods
Urine organic acids show a C6-C14 (hydroxy) dicarboxylic aciduria. Blood acylcarnitine analysis shows increased long chain hydroxyacylcarnitine species (C14-OH, C16-OH, C18-OH, and C18:1-OH). Confirmation is by molecular analysis of the HADHA gene that frequently demonstrates homozygocity for the 1528G>C mutation. Enzyme analysis of cultured fibroblasts or lymphocytes shows isolated deficiency of long chain 3-hydroxyacyl-CoA dehydrogenase activity. Newborn screening for LCHADD is available in Austria, Czech Republic, Denmark, Germany, Hungary, Iceland, Netherlands and Portugal.
Differential diagnosis
Mitochondrial trifunctional protein deficiency (TFPD; see this term) is clinically indistinguishable from LCHADD. Some patients present as sudden infant death so this also needs to be excluded.
Antenatal diagnosis
Prenatal diagnosis is by molecular analysis for established mutation(s) within the family and/or by measuring enzyme activity in chorionic villi samples.
Genetic counseling
LCHADD is inherited autosomal recessively and genetic counseling is available.
Management and treatment
Treatment involves strict adherence to a low fat diet with restriction of long chain fatty acid intake and substitution with medium chain fatty acids and avoidance of fasting as well as limitation of exercise or exposure to environmental extremes. An emergency regimen should be available for all patients and medical attention should be sought at the first sign of any decompensation. Treatment is lifelong.
Prognosis
The prognosis for clinically detected LCHADD patients was generally poor but due to early detection and current treatments, it is improving, with a significant number of patients surviving into adulthood.

                            Last update:
                            February 2014

                            - Expert reviewer(s):
                            Dr Simon OLPIN


A rare vaginal malformation characterized by the presence of a complete or incomplete septum dividing the vagina into two parallel cavities, resulting from failure of reabsorption of the midline uterine septum between the two fused Müllerian ducts during embryogenesis. Patients are often asymptomatic, but may present with menorrhagia, dysmenorrhea, dyspareunia, infertility, or spontaneous abortion. The condition may occur as an isolated malformation or in association with other Müllerian duct anomalies (such as septate uterus or uterus didelphys) or renal abnormalities.


Loose anagen syndrome is a rare benign hair disorder affecting predominantly blond females in childhood and characterized by the presence of hair that can be easily and painlessly pulled out. Most of the hair is in the anagen phase and lacks an external epithelial sheath. Hair grows back quickly and the condition improves spontaneously with aging. Loose anagen hair can be associated with other anomalies, such as coloboma.


A rare genetic hepatic disease characterized by low biliary phospholipid concentration with symptomatic and recurring cholelithiasis which develops before the age of 40 years.

Summary:
Epidemiology
This syndrome is infrequent and corresponds to a small subgroup of patients with symptomatic gallstone disease.
Clinical description
Patients with LPAC syndrome present typically with the following main features: age less than 40 years at onset of symptoms, recurrence of biliary symptoms after cholecystectomy, intrahepatic hyperechoic foci or sludge or microlithiasis along the biliary tree.
Etiology
A defect in ABCB4 function causes the production of bile with low phospholipid content, increased lithogenicity and high detergent properties leading to bile duct luminal membrane injuries and resulting in cholestasis with increased serum gamma-glutamyltransferase (GGT) activity.
Diagnostic methods
Intrahepatic gallstones may be detected by ultrasonography (US), computing tomography (CT), abdominal scan or magnetic resonance cholangiopancreatography. Intrahepatic hyperechogenic foci along the biliary tree may be detected by US, and hepatic bile composition (phospholipid content) may be determined by duodenoscopy.
Management and treatment
In all cases where ABCB4 genotyping confirms the diagnosis of LPAC syndrome in young adults, long-term curative or prophylactic therapy with ursodeoxycholic acid (UDCA) should be initiated early to prevent the occurrence or recurrence of the syndrome and its complications. Cholecystectomy is indicated in the case of symptomatic gallstones. Biliary drainage or partial hepatectomy may be indicated in the case of symptomatic intrahepatic bile duct dilatations filled with gallstones. Patients with end-stage liver disease may be candidates for liver transplantation.

                            Last update:
                            July 2007


A rare urogenital condition characterized by a persistent unwanted painful erection that lasts more than 4 hours, caused by obstruction of the normal drainage of blood from the erectile tissues, leading to ischemia. It may be due to hematological diseases, metabolic or neurological disorders, and some erectile dysfunction medications. If the condition continues for several days, abnormal thickening and scarring of the erectile tissue may develop, causing permanent erectile dysfunction.


Low-grade neuroendocrine tumor of the corpus uteri is an extremely rare uterine cancer typically characterized by a well demarcated, solid, frequently pedunculated tumor originating from neuroendocrine cells scattered within the endometrium, often associated with ectopic hormone production. Patients usually present with vaginal bleeding or discharge and a pelvic mass with a polypoid tumor sometimes protruding through the cervical canal. Symptoms related to ectopic hormone production (flushing, sweating, diarrhea, bronchospasm) may also develop.


Lowe-Kohn-Cohen syndrome is an extremely rare anorectal malformation syndrome characterized by imperforate anus, closed ano-perineal fistula, preauricular skin tag and absent renal abnormalities and pre-axial limb deformities. There have been no further descriptions in the literature since 1983.


A rare, genetic, non-syndromic developmental defect during embryogenesis disorder characterized by uni- or bilateral overgrowth of lower limbs involving bones and/or soft tissues and resulting in an abnormal increase in leg length and/or width. Hypertrophy presents either as a proportionate overgrowth of entire limb or involves only the proximal or distal parts of it. Phenotype ranges from mild hypertrophy without functional disability to massively hypertrophied limb with knee flexion and ankle equinus contractures and macrodystrophia lipomatosa. Patients may also present vascular abnormalities (e.g. cutaneous angiomas, varicose veins) and myalgia.


Lower limb malformation-hypospadias syndrome is a rare developmental defect during embryogenesis characterized by severe, uni- or bilateral lower limb malformations (incl. tibial hypoplasia, split and rocker bottom-shaped feet, and oligosyndactyly), normal upper limbs and hypospadias. Additional dysmorphic features (e.g. short neck and low-set, large ears), atrial septal defect, ureteropelvic junction stenosis and slight septation of the spleen, have also been reported. There have been no further descriptions in the literature since 1977.


A rare otorhinolaryngological malformation characterized by congenital, typically bilateral and paramedian, symmetric or asymmetric fistulae in the lower lip, which are lined by labial mucosa. The malformation is usually asymptomatic, although it may communicate with accessory salivary glands and then result in secretion of saliva from the opening. Infections may also occur.