Late-onset localized junctional epidermolysis bullosa-intellectual disability syndrome

A rare junctional epidermolysis bullosa subtype characterized by late-onset blistering surrounded by erythema and localized on the anterior aspect of the lower legs, associated with dystrophic toenails, tooth enamel defects and mild to severe intellectual disability. Lens subluxation and mild facial dysmorphism (with short midface, prognatism and thin upper lip vermilion) are additional reported features. There have been no further descriptions in the literature since 1992.


Late-onset retinal degeneration is an inherited retinal dystrophy characterized by delayed dark adaptation and nyctalopia and drusen deposits presenting in adulthood, followed by cone and rod degeneration that presents in the sixth decade of life, which leads to central vision loss. Anterior segment features such as peripupillary iris transillumination defects and abnormally long anterior zonular insertions are also observed. Choroidal neovascularization and glaucoma may occur in the late stages of the disease.


A rare genetic neurological disorder characterized by multiple lateral meningoceles, distinctive facial dysmorphism (including hypertelorism, downslanting palpebral fissures, posteriorly rotated ears, micrognathia, and high, narrow palate, among others), and skeletal abnormalities (e. g. vertebral anomalies, wormian bones, short stature, and scoliosis). Multiple additional features may present, such as conductive hearing impairment, hypotonia, and connective tissue and urogenital abnormalities. Cognition is usually normal.


Lathosterolosis is an extremely rare inborn error of sterol biosynthesis characterized by facial dysmorphism, congenital anomalies (including limb and kidney anomalies), failure to thrive, developmental delay and liver disease.

Summary:
Epidemiology
Only 4 cases have been reported in the literature to date.
Clinical description
Microcephaly is present at birth along with hypotonia, failure to thrive and facial dysmorphic features such as bitemporal narrowing, ptosis, puffy cheeks, and micrognathia. Limb anomalies that have been reported include postaxial polydactyly of upper or lower limbs (mainly feet), bilateral syndactyly between the 2nd and 3rd or 2nd and 4th toes and bilateral club feet. Developmental delay and learning disability starting in early childhood have been noted in all patients. Additional anomalies have also been reported such as corneal clouding, cataract, conductive hearing loss, gingival hypertrophy, ambiguous genitalia, horseshoe kidney (see this term) and neurological manifestations (i.e. myoclonus). Liver disease seen in patients ranges from hypertransaminasemia to progressive cholestasis and can lead to end stage hepatic disease, occurring in childhood.
Etiology
Lathosterolosis is due to mutations in the SC5D gene (11q23.3). A mutation in this gene leads to a deficiency in 3-beta-hydroxysteroid-delta-5-desaturase, which is necessary in the conversion of lathosterol into 7-dehydrocholesterol. This prevents the synthesis of cholesterol, which among other functions acts as a structural lipid, a precursor for bile acids and steroid hormones, and is necessary for the maturation of hedgehog morphogens during embryonic development.
Diagnostic methods
Diagnosis is based on clinical and biochemical findings. An elevation of lathosterol by gas chromatography/mass spectroscopy (GC/MS) is noted in both skin fibroblasts and plasma. The levels of 7-dehydrocholesterol and cholesterol are normal or low. Molecular genetic testing revealing mutations in the SC5D gene confirms the diagnosis.
Differential diagnosis
The main differential diagnosis is Smith-Lemli-Opitz syndrome (see this term) that shares many clinical features with lathosterolosis but that can be excluded with biochemical and genetic testing.
Antenatal diagnosis
Prenatal diagnosis is feasible if the mutations are known but it has never been performed given the rarity of the disease.
Genetic counseling
Lathosterolosis is inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes and they therefore have a 25% risk of having an affected child at each pregnancy.
Management and treatment
Treatment involves cholesterol supplementation and reduction of 7-hydrocholesterol. Simvastin, a 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitor, has been proven to be beneficial in normalizing the lathosterol level in one patient. Liver transplantation was successful in normalizing liver function and cholesterol levels in a patient who had developed end stage liver disease. Moreover, it appeared to improve neurocognitive functions. Regular opthalmological evalutations and ultrasound monitoring of the liver are recommended.
Prognosis
The prognosis is poor but treatment appears to prolong life and arrest progression of neurological damage.

                            Last update:
                            November 2014

                            - Expert reviewer(s):
                            Dr Nicola BRUNETTI PIERRI  - Pr Giancarlo PARENTI


Type I lattice corneal dystrophy (LCDI) is a frequent form of stromal corneal dystrophy (see this term) characterized by a network of delicate interdigitating branching filamentous opacities within the cornea with progressive visual impairment and no systemic manifestations.

Summary:
Epidemiology
Prevalence of this form of corneal dystrophy is unknown. It is one of the more common forms in Western countries but has been reported worldwide.
Clinical description
Lesions mostly develop bilaterally towards the end of the 1st decade of life, but may develop in middle age, or rarely in infancy. LCDI is slowly progressive and usually results in substantial discomfort and visual impairment before the 6th decade. Corneal sensation is often diminished.
Etiology
Most cases of LCDI are caused by mutations in the multifunctional TGFBI gene (5q31).
Diagnostic methods
The interwoven linear opaque filaments have some resemblance to nerves, but may not be observed in all affected members of families with the condition. Recurrent corneal erosions may precede the corneal opacities and even appear in individuals lacking recognizable stromal disease. Amyloid deposits are found throughout the corneal stroma. Linear and other shaped opaque areas accumulate particularly within the central corneal stroma, while the peripheral cornea remains relatively transparent.
Genetic counseling
An autosomal dominant pattern of inheritance has been reported.
Management and treatment
A corneal graft may be necessary by 20 years of age, but is usually not indicated until after the 4th decade. The outcome of penetrating keratoplasty (PK) is excellent, but amyloid may deposit in the grafted donor tissue after 2 to 14 years.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Dr Gordon KLINTWORTH


Laubry-Pezzi syndrome is a rare, non-syndromic, congenital heart malformation characterized by the prolapse of an aortic valve cusp into a subjacent ventricular septal defect due to Venturi effect, resulting in aortic regurgitation. Patients typically present with symptoms of progressive aortic valve insufficiency, such as shortness of breath, heart palpitations, chest pain and exercise intolerance.


A very rare genetic multisystemic disorder characterized by progressive neurological, ophthalmologic and endocrine manifestations leading to severe handicap.

Summary:
Epidemiology
The prevalence is unknown.
Clinical description
The neurological manifestations include peripheral neuropathy, spastic paraplegia and cerebellar ataxia. The symptoms progressively worsen for patients over time. The ophthalmologic manifestations are caused by chorioretinal dystrophy presenting widespread chorioretinal atrophy (thinning of the retina, loss of retinal architecture and choroid vessels) under fundus observation. The onset of visual impairment ranges widely from 1 year old to 60 years old. Hypogenitalism is present at birth due to hypogonadotrophic hypogonadism with primary amenorrhea, small penis and testes, or absence of pubic hair/breast development. Related growth delay during adolescence can also occur.
Etiology
Likely pathogenic or pathogenic variants in the PNPLA6 gene have been identified in patients with Laurence-Moon syndrome (LMS). The PNPLA6 gene codes for the patatin-like phospholipase domain-containing protein 6, also called neuropathy target esterase (NTE), a 1375 amino acids long protein (UniProt accession number: Q8IY17). The protein is composed of 5 domains including a single pass transmembrane domain (N-terminus), 3 cyclic nucleotide-binding domains (cNMP) and a NEST domain (NTE-esterase domain) at the C-terminus. The protein is a serine hydrolase that functions as a phospholipase B by catalyzing the deacylation of glycerophospholipids. It has also been shown to have a strong lysophospholipase activity. Altogether it plays a major role in phospholipid homeostasis, membrane trafficking, and axonal integrity in cells. Previously, the terms Laurence-Moon-Biedl syndrome or Laurence-Moon-Bardet-Biedl syndrome were used for this disease. However, the association Laurence-Moon/Bardet-Bield is no longer relevant given the different underlying gene mechanisms. It should be underlined that this condition is now clearly considered as part of the continuous spectrum of PNPLA6-related disorders linked to NTE activity. Recent evidence seems to inversely correlate the level of NTE activity with disease severity and tissue onset.
Diagnostic methods
Diagnosis is suspected on clinical presentation and confirmed by genetic testing including sequencing of the PNPLA6 gene (by direct Sanger sequencing or panel/exome next generation sequencing).
Differential diagnosis
The main differential diagnoses are the other PNPLA6-related disorders such as autosomal recessive spastic paraplegia type 39, cerebellar ataxia-hypogonadism syndrome, ataxia-hypogonadism-choroidal dystrophy syndrome and trichomegaly-retina pigmentary degeneration-dwarfism syndrome that share all or a subset of the clinical manifestations, sometimes with a different age of onset.
Antenatal diagnosis
Prenatal diagnosis is possible where the pathogenic variant(s) have previously been identified in an affected family member.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Treatment is only symptomatic and depends on the severity of the neurological manifestations. Optical aids can be provided to manage visual impairment.
Prognosis
Data on prognosis is limited for patients with PNPLA6-related disorders but recent evidence has shown a highly dependent relation between the NTE activity and severity of the disease and/or tissue onset.

                            Last update:
                            April 2024

                            - Expert reviewer(s):
                            Pr Hélène DOLLFUS | ERN-EYE* - Dr Jean MULLER | ERN-EYE*

                                * European Reference Network


Laurin-Sandrow syndrome (LSS) is characterised by complete polysyndactyly of the hands, mirror feet and nose anomalies (hypoplasia of the nasal alae and short columella), often associated with ulnar and/or fibular duplication (and sometimes tibial agenesis). It has been described in less than 20 cases. Some cases with the same clinical signs but without nasal defects have also been reported, and may represent the same entity. The etiology of LSS is unknown. Different modes of inheritance have been suggested.


LCAT (lecithin-cholesterol acyltransferase) deficiency is a rare lipoprotein metabolism disorder characterized clinically by corneal opacities, and sometimes renal failure and hemolytic anemia, and biochemically by severely reduced HDL cholesterol.

Summary:
Epidemiology
Prevalence of LCAT deficiency is unknown. About 125 cases have been reported to date worldwide. Most cases were reported in Europe, Japan and Canada.
Clinical description
Age of onset is variable but most patients are diagnosed during adulthood. Two familial forms of LCAT deficiency have been reported: familial LCAT deficiency (FLD, see this term) characterized by corneal opacities, anemia and renal insufficiency, and Fish-eye disease (FED, see this term) characterized by corneal opacities and sometimes atherosclerosis.
Etiology
LCAT deficiency is caused by deficient or absent catalytic activity of the LCAT enzyme, which catalyzes the formation of cholesterol esters in lipoproteins and is encoded by the LCAT gene (16q22.1). Accumulation of unesterified cholesterol in the body, e.g. in the cornea, erythrocytes and kidneys, is thought to underlie the clinical manifestations. To date, more than 85 mutations in the LCAT gene have been identified. LCAT deficiency follows an autosomal recessive pattern of inheritance.

                            Last update:
                            March 2012

                            - Expert reviewer(s):
                            Pr Laura CALABRESI  - Pr Guido FRANCESCHINI


Lead poisoning is defined as acute or chronic exposure to lead resulting in lead accumulation (blood lead concentration (BLC) >5 ug/dL) that can affect every organ system in the body and to which children are more susceptible. Clinical manifestations depend on the amount and duration of exposure and include abdominal pain, colic, constipation, lead line on gingival tissue, arthralgia, myalgia, peripheral neuropathy, fatigue, irritability, anemia, chronic nephropathy and hypertension. In children, even low levels of exposure (BLC <5 ug/dL) is reported to lead to irreversible effects such as loss of cognition, shortening of attention span, alteration of behavior, dyslexia, attention deficit disorder, hypertension, renal impairment, immunotoxicity and toxicity to the reproductive organs.


Leber congenital amaurosis (LCA) is a retinal dystrophy defined by blindness and responses to electrophysiological stimulation (Ganzfeld electroretinogram (ERG)) below threshold, associated with severe visual impairment within the first year of life.

Summary:
Epidemiology
The prevalence of LCA is 1/50,000 - 1/33,000 live births and accounts for 5% of all retinal dystrophies and 20% of blindness in school age children.
Clinical description
LCA is characterized by severely reduced visual acuity (less or equal 20/400) or blindness within in the first year of life. Sluggish pupillary responses, roving eye movement, photophobia, high hyperopia, nystagmus, convergent strabismus, or keratoconus may occur depending on the genetic cause. The Franceschetti's oculo-digital sign, comprising eye poking, pressing, and rubbing is pathognomonic. LCA may be associated with mutations in genes linked to syndromes presenting with neurodevelopmental delay, intellectual disability, oculomotor apraxia-type behavior (difficulty moving the eye) and renal dysfunction.
Etiology
To date, mutations in genes encoding retina specific proteins have been reported to cause LCA. This includes GUCY2D (17p13.1), CEP290 (12q21.33), RPGRIP1 (14q11.2), RDH12 (14q24.1), SPATA7 (14q31.3), AIPL1 (17p13.1), RD3 (1q32.3), CRB1 (1q31-q32.1), CRX (19q13.3), IMPDH1 (7q31.3-q32), IQCB1 (3q21.1), KCNJ13 (2q37), LCA5 (6q14), NMNAT1 (1p36.22), and TULP1 (6p21.3). These mutations cause severe functional impairment or are mostly related to retinal dystrophies. Mutations in CRX or IMPDH1 genes may cause an early and severe onset disease. Patients with GUCY2D mutations present with very slow progressive morphological degeneration and a mostly functional defect.
Diagnostic methods
Diagnosis relies on clinical observation which shows a pupillary response that may be sluggish or near-absent in early life; on funduscopy findings revealing attenuation of retinal vessels along with variable signs of retinal degeneration (from almost unremarkable to an overall granulated appearance). Diagnosis is confirmed by sedated ERG close to or below threshold. Molecular diagnosis is indispensable and may be performed using an arrayed primer extension (APEX) chip (tests a subset of known mutations in known LCA genes; diagnosis achieved in 50-70% of cases) and next generation sequencing (NGS) (covering the whole sequence of the known reported genes; this is the preferable method covering up to 90% of patients). Confirmation of identified mutations and segregation analysis in the parents by Sanger sequencing is the final step.
Differential diagnosis
Differential diagnosis includes retinitis pigmentosa, Alström syndrome, Joubert syndrome, Stargardt disease, Senior-Loken syndrome, Conorenal syndrome and infantile neuronal ceroid lipofuscinosis. Cortical blindness is a frequent misdiagnosis when there is limited access to functional testing or high resolution morphological examination.
Antenatal diagnosis
Prenatal diagnosis may be offered by specialized laboratories for at-risk couples with identified disease-causing mutations.
Genetic counseling
LCA is typically an autosomal recessive inherited disease. Rarely, mutations within CRX or IMPDH1 genes are inherited in an autosomal dominant manner that may overlap with the diagnosis of LCA.
Management and treatment
Currently LCA is an incurable disease. Treatment is mainly supportive and includes correction of refractive error and use of low-vision aids. Repeated poking and pressing on the eyes should be discouraged. Periodic ophthalmic evaluation and assessment of the presence of amblyopia, glaucoma, or cataract should be achieved. Therapies are presently being investigated, including gene therapy (particularly for RPGRIP and CEP290) and optogenetics (genetic targeting of light-sensing molecules to residual cells in a degenerate retina).
Prognosis
Vision commonly declines with age until complete blindness is observed most often latest by the third or fourth decade of life.

                            Last update:
                            July 2015

                            - Expert reviewer(s):
                            Pr Birgit LORENZ  - Dr Markus PREISING


A rare hereditary optic neuropathy characterized by sudden onset, painless central vision loss, loss of retinal ganglion cells and optic atrophy.

Summary:
Epidemiology
The prevalence of the disease is estimated at 1/27,000 - 1/54,000 in Europe. Lower prevalence is reported in Australia (1 in 113,300) and in Serbia (1/526,000). The disease predominantly affects males, who are 4-5 times more likely to be affected and to lose vision.
Clinical description
Whilst carriers may remain asymptomatic, there may be recognizable changes on ophthalmological examination. Clinical onset of Leber hereditary optic neuropathy (LHON) is typically in young adulthood (age 18-30) and is divided into subacute (< 6 months from onset) and dynamic (6-12 months) stages. Typically, onset is with sudden, painless central vision loss that can occur in both eyes simultaneously or sequentially with vision loss in the second eye occurring weeks to months after the first eye. Visual loss generally stabilizes within 4 to 6 months. However, many patients will continue to show expansion of their central scotoma, producing a more profound level of blindness over a period of years (chronic stage). Extraocular symptoms (motor disorders, dystonia, postural tremor and cerebellar ataxia) are uncommon, but when present are known as Leber plus disease.
Etiology
LHON is caused by mutations in the mitochondrial DNA (mtDNA). Over 90% have been identified to occur at nucleotide positions 3460, 11778 or 14484, respectively corresponding to the mtDNA respiratory chain complex I subunit genes MT-ND1, MT-ND4, and MT-ND6. Other genetic or epigenetic factors may have an effect on the development of this disease; in addition, the gene NDUFS2 (1q23.3) may be associated with a LHON-like phenotype.
Diagnostic methods
The diagnosis is based on patient and family history, in addition to an ophthalmologic examination and genetic testing for mtDNA. Baseline examination should include visual acuity, color vision, fundus examination, visual fields, and optical coherence tomography (OCT) imaging. Swelling of the optic nerve head, vascular tortuosity, peripapillary telangiectasia, microangiopathy and central scotomas on visual field testing are all signs of LHON. OCT confirms the swelling of the retinal nerve fiber layer. Red-green dyschromatopsia during color vision testing, and pseudopapilledema during fluorescein angiography are also observed. Snellen vision acuities of 20/200 or worse are typical.
Differential diagnosis
Differential diagnosis includes optic neuritis, autosomal dominant optic atrophy (DOA), Wolfram syndrome, metabolic optic neuropathies (toxic, nutritional, and combinations), chiasmal tumors, and anterior ischemic optic neuropathy.
Antenatal diagnosis
The prenatal presence of mtDNA pathogenic variant for LHON does not predict occurrence of disease, age of onset, or vision loss.
Genetic counseling
LHON is a maternally-inherited disease. Female carriers will pass the mutation to all their children, while male carriers will not pass the mutation to any children. Genetic counseling is recommended for affected families, though it is complicated by incomplete penetrance of pathogenic variants. Although, extremely rare, inheritance is autosomal recessive for NDUFS2.
Management and treatment
Low-vision aids are the primary supportive care offered to patients. It is important that patients avoid toxic exposures such as alcohol, smoke (tobacco and environmental) and certain antibiotics that interfere with mitochondrial oxidative phosphorylation. Several compounds have shown positive results in moderating the visual loss. Idebenone (approved in the USA and Europe), shows a modest visual improvement after one year, and should be started as soon as possible in patients presenting within subacute and dynamic stages of disease (< 12 months). There is insufficient evidence at this time for treatment in chronic stage patients. Multiple clinical trials for other compounds and gene therapies are ongoing; notably EPI-743 has demonstrated efficacy in a small open label study for LHON.
Prognosis
The age of symptom onset and the causative mutation are factors that determine the disease outcome. Younger patients have a more favorable prognosis. Some patients, especially with the 14484 mutation, show spontaneous partial recovery 1-2 years after onset; whilst visual field improvement is usually incomplete, the recovery in visual acuity can be dramatic. In 30 to 50 % of male carriers and 80 to 90 % of female carriers, blindness will not ensue. Complete blindness is rare.

                            Last update:
                            March 2021

                            - Expert reviewer(s):
                            Dr Elise MA  - Pr Alfredo SADUN


A rare inherited mitochondrial disease characterized by the clinical features of Leber hereditary optic neuropathy in combination with other systemic or neurological abnormalities. These abnormalities include: postural tremor, motor disorder, multiple sclerosis-like syndrome, spinal cord disease, skeletal changes, Parkinsonism with dystonia, anarthria, motor and sensory peripheral neuropathy, spasticity, mild encephalopathy, and cardiac arrhythmias.


A rare, benign, superficial fibromatosis disease characterized by single or multiple, uni- or bilateral, slow-growing, round, firm nodules typically located on the medial portion of the plantar aponeurosis, with no calcification. Patients are often asymptomatic or may present with foot pain, difficulty to walk or stand and, rarely, toe contractures. Histopathology reveals dense fibrocellular tissue with parallel and nodular arrays of fibrocytes and fibrillar collagen with a distinctive cork-screw morphology and no atypia.


A rare cardiac malformation characterized by both atrial appendages having the morphology of the left atrial appendage. It is associated with other anomalies of the heart, systemic and pulmonary veins, and other organ systems, including the gastrointestinal, respiratory, and genitourinary tract, as well as the spleen and immune system.


A rare cardiomyopathy characterized anatomically by prominent left ventricular trabeculae and deep intratrabecular recesses causing progressive systolic and diastolic dysfunction, conduction abnormalities, and occasionally thromboembolic events.


A rare disorder characterized by uni- or bilateral avascular necrosis (AVN) of the femoral head in children.

Summary:
Epidemiology
Reported annual incidences vary greatly, from 1/250,000 in Hong Kong and 1/18,000 in the UK, to 1/3,500 in the Faroe Islands. Legg-Calvé-Perthes disease (LCPD) affects children between 2 and 12 years of age, but it is more prevalent among children of 5-6 years, and more common in boys.
Clinical description
The initial symptoms are usually a limping gait, pain in the hip, thigh or knee, and a reduced range of hip motion. Later in the disease course, leg length discrepancy, as well as atrophy of musculature around the hip can be observed. The active phase of the disease can last for several years, and during this phase the femoral head becomes partially or completely necrotic and gradually deformed. This is followed by new bone formation (re-ossification) in the epiphysis and eventual healing. The final deformity can vary from a nearly normal joint configuration to an extensive deformation with severe flattening and subluxation of the femoral head, broadening of the femoral neck, and a deformed and dysplastic acetabulum, which in turn can lead to early-onset osteoarthritis.
Etiology
The etiology of LCPD remains obscure. It is generally accepted that one or more infarctions of the femoral head due to interruption of vascular supply eventually cause the deformity, however, there are several theories concerning the cause of this interruption. Several contributory factors have also been suggested: delayed skeletal maturity, impaired and disproportionate growth, short stature, low birth weight, social and economic deprivation and trauma, as well as an association with congenital anomalies. It has also been proposed that coagulation system disorders could cause thrombophilia and/or hypofibrinolysis and lead to thrombotic venous occlusion with subsequent AVN of the femoral head in children. Mutations in the COL2A1 gene (12q12-q13.2) have recently been identified in familial cases of AVN of the femoral head (see this term) and LCPD.
Diagnostic methods
Diagnosis is made by conventional radiography in frontal and lateral projections. Scintigraphy and ultrasound can be of value in selected cases and MRI can be useful in the early stages of the disease to distinguish LCPD from other hip disorders.
Differential diagnosis
Differential diagnoses include Meyers dysplasia, multiple epiphyseal dysplasia and spondyloepiphyseal dysplasia (see these terms).
Management and treatment
The main aim of treatment is to contain the femoral head within the acetabulum, either using an abduction brace or through surgical interventions (femoral or pelvic osteotomy). A recent study suggested that femoral osteotomy gives significantly better results than treatment with braces (specifically the Scottish Rite abduction orthosis).
Prognosis
Prognosis is variable and several factors are of prognostic importance, such as the extent of femoral head necrosis and residual deformity. The more deformed the femoral head is during healing, the greater the risk of osteoarthritis later in life. Total hip replacement in early adulthood may be required in some cases. A younger age at diagnosis is generally accepted to be associated with a better outcome.

                            Last update:
                            March 2009

                            - Expert reviewer(s):
                            Dr Ola WIIG


A rare form of Legionellosis characterized by a severe, potentially fatal, pneumonia.

Summary:
Epidemiology
The annual notification rate in 2009 from 25 EU Member States amounted to approximately 1/90,000. In France the annual incidence is around 1/50,000.
Clinical description
LD has an incubation period of 2-10 days with fatigue and weakness often being the first signs of the disease. It manifests as pneumonia characterized by fever, cough, sputum production and shortness of breath. Other symptoms can include diarrhea, myalgia, headaches, confusion/delirium and nausea. LD is most severe in elderly and immunocompromised people (due to immunosuppressive therapy, especially with corticosteroids, transplants, hematologic malignancy or cancer), who are an ever-increasing risk group for infection. Other risk factors for LD include cigarette smoking, age over 50, male gender, diabetes, and chronic heart, lung or kidney disease.
Etiology
LD is caused by Legionella pneumophila (most commonly serogroup 1), a bacteria found in water and wet soil. Humans are infected by inhaling aerosols containing the bacteria, most commonly from showers, hot tubs, saunas or other bathing facilities. The same bacteria are responsible for Pontiac fever (PF; see this term) a mild form of LD. LD occurs sporadically and in outbreaks, with the sporadic form accounting for 65 to 80% of cases. Outbreaks are predominantly linked to contaminated aerosols from wet cooling systems or occur in hospitals, nursing homes or hotels.
Diagnostic methods
EU case definitions have been agreed upon associating clinical and laboratory criteria for case confirmation. Any person with pneumonia and one of the following criteria: isolation of Legionella spp.  from respiratory secretions or any normally sterile site, detection of L. pneumophila antigen in urine or L. pneumophila serogroup 1-specific antibody response, are given a diagnosis of LD. Detection of Legionella spp.  nucleic acid in a clinical specimen has been added as criteria for probable cases.
Differential diagnosis
The disease has no particular clinical features that clearly distinguish it from other types of pneumonia. Other bacterial (Streptococcus pneumonia, Staphylococcus aureus and Haemophilus influenza) or viral infections that cause pneumonia need to be ruled out.
Management and treatment
Treatment involves antibiotics (usually macrolides and quinolones). Hospitalization is often required. Ventilatory support may be necessary in those with serious breathing difficulties. Legionella surveillance programs are based on notification of cases at a national and European level and on legislation for controlling the development of the bacteria in the aquatic environment.
Prognosis
In most cases, LD is treated and cured with antibiotics but in those with compromised immune systems or underlying health conditions the prognosis can be poor. The overall case fatality rate is around 10-15%.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Dr Sophie JARRAUD


Legius syndrome, also known as NF1-like syndrome, is a rare, genetic skin pigmentation disorder characterized by multiple café-au-lait macules with or without axillary or inguinal freckling.

Summary:
Epidemiology
The prevalence of Legius syndrome is not known. Fewer than 200 cases have been reported to date. Prevalence may be higher than expected due to misdiagnosis of cases as neurofibromatosis type 1 (NF1, see this term). The incidence of NF1 is reported to be 1/3000, and about 2% of patients fulfilling diagnostic criteria for NF1 are found to have the genetic mutation underlying Legius syndrome (SPRED1).
Clinical description
The clinical presentation of Legius syndrome is very similar to that of NF1. Patients typically present with multiple café-au-lait spots sometimes associated with intertriginous freckling, but lack Lisch nodules, optic pathway gliomas, bone abnormalities, neurofibromas or other tumor manifestations. The number of café-au-lait macules tends to increase with age during childhood. Other less common manifestations include short stature, macrocephaly, Noonan-like facies, pectus excavatum/carinatum, lipomas, hypopigmented macules, vascular lesions, learning disabilities, attention deficit/hyperactivity disorder (ADHD), and developmental delay.
Etiology
Legius syndrome is caused by heterozygous inactivating mutations in the SPRED1 gene (15q14), involved in regulation of the RAS-MAPK signal transduction pathway. Nearly 100 different mutations in this gene have been identified. The proportion of cases related to de novo mutations is not yet known. No genotype-phenotype correlations have been found.
Diagnostic methods
About 50% of patients with Legius syndrome fulfill the diagnostic criteria for NF1, but they have a far milder phenotype compared to NF1 patients. Diagnosis based solely on the presence of clinical features is difficult, given the overlap with other disorders characterized by multiple café-au-lait spots. The presence of characteristic clinical signs in parents of affected individuals is supportive of diagnosis. However, molecular genetic testing is required to confirm the diagnosis and testing is available on a clinical basis.
Differential diagnosis
Legius syndrome is differentiated from NF1 by the absence of the non-pigmentary clinical manifestations seen in this disorder (i.e. Lisch nodules, neurofibromas, optic glioma, bone abnormalities). Correct diagnosis is essential because of the differences in prognosis and long-term monitoring between Legius syndrome and NF1. Other disorders to consider include Noonan syndrome, Noonan syndrome with lentigines (LEOPARD syndrome), and McCune-Albright syndrome (see these terms).
Antenatal diagnosis
Prenatal diagnosis is possible and requires prior identification of the disease-causing mutation in the family.
Genetic counseling
Legius syndrome follows an autosomal dominant pattern of inheritance. Genetic counseling should be provided to affected families.
Management and treatment
Drug therapy should be considered for the behavioral manifestations of the disorder (ADHD). Physical, speech, and occupational therapy is recommended for those with developmental delay and educational support for those with learning difficulties.
Prognosis
Given the current knowledge of disease manifestations and complications, the prognosis for patients with Legius syndrome is considered to be very good.

                            Last update:
                            July 2014

                            - Expert reviewer(s):
                            Pr Eric LEGIUS


A progressive neurological disease defined by specific neuropathological features associating brainstem and basal ganglia lesions.

Summary:
Epidemiology
Its prevalence at birth has been estimated at approximately 1 in 36 000.
Clinical description
Typical onset of symptoms occurs before the age of 12 months but, in rare cases, the disease may manifest during adolescence or even early adulthood. Loss of motor milestones, hypotonia with poor head control, recurrent vomiting, and a movement disorder are common initial symptoms. Pyramidal and extrapyramidal signs, nystagmus, breathing disorders, ophthalmoplegia and peripheral neuropathy are often noted later. Epilepsy is relatively uncommon.
Etiology
Leigh syndrome has multiple causes, all of which imply a defect in aerobic energy production, ranging from the pyruvate dehydrogenase complex to the oxidative phosphorylation pathway. Most mutations are located in the nuclear genome. The genes identified to-date encode either one of the subunits of the pyruvate dehydrogenase (PDH) complex, one of the subunits of respiratory complexes I or II, or a protein involved in the assembly of respiratory complex IV. Between 10 and 30% of individuals with Leigh syndrome carry mitochondrial DNA mutations, the most common of which are the 8993T>G or 8993T>C mutations in the MTATP6 gene encoding a subunit of ATP synthase. These individuals are often referred to as having maternally inherited Leigh syndrome (MILS). They harbor very high proportions (above 95%) of the mitochondrial DNA mutation. Lower proportions of this mutation are associated with a milder phenotype such as the NARP syndrome (Neurogenic Ataxia and Retinitis Pigmentosa). The genetic cause of a number of cases of Leigh syndrome remains unknown, despite the presence of a specific biochemical defect in some of the cases.
Diagnostic methods
Diagnosis of the syndrome relies on brain imaging showing the specific topology of the lesions in the brainstem and basal ganglia, often in association with leucodystrophy and cerebral atrophy. Lactate levels are constantly increased in cerebrospinal fluid, and often in the blood. The etiological diagnosis relies on biochemical investigations looking for the underlying defect in energy production. Pyruvate dehydrogenase is assayed in leucocytes or in cultured skin fibroblasts, whereas oxidative phosphorylation is more completely analyzed in muscle or liver.
Antenatal diagnosis
Prenatal diagnosis may be possible in cases with a known genetic anomaly in a nuclear gene. It is much more difficult when the alteration involves a mitochondrial DNA gene due to heteroplasmy (coexistence of mitochondria with altered genome and normal mitochondria). When only the biochemical defect has been identified, prenatal diagnosis is made complex by potential technical difficulties in biochemical analysis of amniocytes, as well as the possibility that these cells do not express the defect detected in skin fibroblasts.
Genetic counseling
In the majority of cases, Leigh syndrome is transmitted in an autosomal recessive manner. However, PDH defects due to subunit E1alpha anomalies are X-linked and the mitochondrial DNA alterations are maternally transmitted. Genetic counseling depends on the identification of the cause of the disease.
Management and treatment
There is no specific treatment for Leigh disease. Several different vitamins or cofactors, including vitamin B1 (thiamine), vitamin B2 (riboflavin) and coenzyme Q10, have been proposed and may be tried systematically. Their efficacy depends upon the underlying defect. A ketogenic diet has been proposed for patients with pyruvate dehydrogenase deficiency.
Prognosis
The prognosis of Leigh syndrome is poor, with a life expectancy reduced to only a few years for most patients.

                            Last update:
                            July 2006

                            - Expert reviewer(s):
                            Dr Anne LOMBES


Small bowel leiomyosarcoma is a rare type of small bowel malignancy, originating in the smooth muscle cells within the muscularis propria or the muscularis mucosa, most often found in the jejunum, and presenting with gastrointestinal bleeding and anemia and sometimes with other non-specific symptoms such as vomiting, nausea, abdominal pain and weakness and spreading to regional lymph nodes in 14% of cases.


Leiomyosarcoma of the cervix uteri is a rare, malignant mesenchymal tumor of smooth muscle origin, macroscopically appearing as a large, poorly circumscribed mass, often protruding from the cervical canal or expanding it circumferentially. The most common presenting symptoms are vaginal discharge or bleeding, pain in the lower abdomen and a bulky cervical mass. There is a reported tendency to metastatsize hematogenously, especially to the lungs, peritoneum, bones and the liver.


Leiomyosarcoma of the corpus uteri is a rare, malignant, mesenchymal tumor of smooth muscle origin characterized, histologically, by spindle and/or pleomorphic cells, often forming disorganized fascicles, with tumor cell necrosis and, macroscopically, by a large, soft, usually intramural mass with irregular borders and necrotic and hemorrhagic areas, located in the uterus. Presenting signs and symptoms typically include dysfunctional vaginal bleeding, vaginal discharge, palpable pelvic mass and/or pelvic pain/pressure. Changes in bowel habits, frequent or painful urination and hematuria may also be associated.


A rare soft tissue sarcoma characterized by a malignant space-occupying lesion most commonly located in the retroperitoneum or the inferior vena cava, but also other soft tissues, and composed of cells showing distinct features of smooth muscle cells. The tumor presents with mass effect depending on the location. It is capable of both local recurrence and distant metastasis, while lymph node metastasis is rare. Prognosis largely depends on tumor location and size.


A parasitic disease caused by different species of the genus Leishmania, transmitted through the bite of hematophagous female phlebotomine sand flies. The clinical spectrum ranges from asymptomatic to clinically overt disease which can remain localized to the skin or disseminate to the upper oral and respiratory mucous membranes or throughout the reticulo-endothelial system. Three main clinical syndromes have been described: visceral (or Kala-Azar; with fever, weight loss, hepatosplenomegaly), cutaneous, and mucocutaneous leishmaniasis (cutaneous or mucocutaneous ulceration).


Lelis syndrome is characterised by the association of ectodermal dysplasia (hypotrichosis and hypohidrosis) with acanthosis nigricans.

Summary:
Epidemiology
So far, only eight cases have been described in the literature.
Clinical description
Other clinical features may include palmoplantar hyperkeratosis, nail dystrophy, intellectual deficit and hypodontia.
Genetic counseling
Transmission is autosomal recessive.

                            Last update:
                            July 2008


Lemierre syndrome is a rare, potentially lethal, oropharyngeal infectious disease occurring in immunocompetent adolescents and young adults that is mainly due to Fusobacterium necrophorum and that is characterized by septic thrombophlebitis of the internal jugular vein that leads to septic, usually pulmonary, embolism, associated with ENT (ear, nose, and throat) infection that manifests with fever, neck pain, and tonsillopharyngitis.


A rare, severe early-onset developmental epileptic encephalopathy characterized by the triad of intellectual impairment, multiple seizure types, and typical electroencephalography (EEG) abnormalities.

Summary:
Epidemiology
The incidence of Lennox-Gastaut syndrome (LGS) is estimated at 0.1 to 0.28 per 100,000 people per year, the lifetime prevalence at the age of ten years amounts to 0.26 per 1000 children. Although rare, it represents 1-10% of childhood epilepsies, and 1-2% of all epilepsy patients. Males are slightly more affected.
Clinical description
Characteristic seizure types include atypical absences and tonic seizures during sleep, but atonic seizures during wakefulness, myoclonic, tonic-clonic, and focal seizures as well as non-convulsive status epilepticus commonly occur. Tonic, myoclonic, or atonic seizures can lead to sudden falls (drop attacks). The interictal EEG typically shows slow spike-wave complexes (< 3/s), paroxysmal fast rhythms (10-20/s) during non-REM (rapid eye movement) sleep, and a slowing of the background activity. The disease begins mostly between 3 and 5 years of age and the full triad develops over time. In more than half of the patients, intellectual impairment is present at disease-onset and worsens over time. Behavioral problems are commonly observed and may complicate the treatment.
Etiology
The etiology is heterogeneous including prenatal or perinatal infarctions, central nervous system infections, metabolic disorders, traumatic lesions, and cortical malformations. Genetic de-novo mutations are increasingly identified, such as in GABRB3 (15q12), CHD2 (15q26.1) DNM1 (9q34.11), SCN1A (2q24.3), MAPK10 (4q21.3), CUX2 (12q24.11-q24.12), and CACNA1A (19p13.13). LGS can evolve from early epileptic encephalopathies like West syndrome. In about one fourth of cases, the etiology remains unclear.
Diagnostic methods
The presence of typical clinical features and EEG abnormalities confirms the diagnosis. Magnetic resonance imaging identifies structural abnormalities in more than two thirds of the patients. Genetic testing helps to distinguish between LGS and other disease entities and should be performed in selected cases (e.g. suspected tuberous sclerosis complex, late infantile neuronal ceroid lipofuscinosis, ring chromosome 20 syndrome).
Differential diagnosis
In principle, all epilepsies with frequent and brief motor seizures occurring in childhood may be considered; the most relevant differential diagnoses include myoclonic atonic epilepsy, Dravet syndrome, and focal epilepsies with secondary bilateral synchrony.
Genetic counseling
If a monogenetic etiology is suspected, genetic counseling is recommended.
Management and treatment
Seizures in LGS are difficult to treat and the treatment should aim to improve the quality of life and reduce the burden of seizures with falls. Sodium valproate is recommended as a first line anti-seizure medicine. Randomized controlled trials with lamotrigine, felbamate, clobazam have demonstrated efficacy in all seizure types. The use of felbamate is limited by adverse side effects. Topiramate, rufinamide, and cannabidiol proved effective in reducing drop attacks. Other anti-seizures medicines levetiracetam, zonisamide, perampanel as well as a ketogenic diet, vagus nerve stimulation, corpus callosotomy, and resective brain surgery in candidate cases, should be considered. In some cases, seizure worsening was reported with carbamazepine, lacosamide, oxcarbazepine, phenytoin, and vigabatrin.
Prognosis
The prognosis of children with LGS is poor. 80-90% of the patients have recurrent seizures and the mortality rate is 14 times higher than in the general population, mainly due to epilepsy-related events (e.g. status epilepticus, sudden unexpected death in epilepsy). Cognitive and behavioral problems are present in nearly all affected individuals. The severity of the disease has a significant impact on family members.

                            Last update:
                            April 2021

                            - Expert reviewer(s):
                            Pr Alexis ARZIMANOGLOU | EpiCARE* - Pr Rima NABBOUT | EpiCARE* - Pr Rainer SURGES | EpiCARE*

                                * European Reference Network


An extremely rare syndrome associating dwarfism, characteristic facial appearance, cutis laxa and progressive bone sclerosis.

Summary:
Epidemiology
Nine cases have been reported in the literature.
Clinical description
Marked hypertelorism and broad forehead are noted in all patients as well as large ears. Loose and wrinkled atrophic skin with prominent veins is also apparent, giving the patient a progeroid appearance. Increasing generalized osteosclerosis of tubular bones, vertebrae and cranial bones is a characteristic feature. Cutaneous syndactyly of 2nd to 5th fingers was observed in all patients, as well as brachydactyly (see this term) and proximal symphalangism (see this term). All patients have moderate to severe intellectual deficit.
Genetic counseling
The elevated age of some patient's fathers of the reported families is suggestive of an autosomal dominant de novo mutation.

                            Last update:
                            March 2010


Leprechaunism is a congenital form of extreme insulin resistance (a group of syndromes that also includes Rabson-Mensenhall syndrome, type A insulin-resistance syndrome, and acquired type B insulin-resistance syndrome; see these terms) characterized by intrauterine and mainly postnatal severe growth retardation.

Summary:
Epidemiology
It is a very rare condition with less than 1 case in every million births.
Clinical description
Leprechaunism is associated with a characteristic dysmorphic facies (resembling that of the 'leprechauns' in Irish folk traditions), atrophic subcutaneous adipose tissue (lipoatrophy) and muscular hypotrophy. Signs of virilization are often observed in young girls. Biologically, episodes of hypo- and hyperglycemia are observed along with marked hyperinsulinemia due to an extreme resistance to insulin.
Etiology
The syndrome is associated with homozygous or compound heterozygous mutations in the insulin receptor gene (INSR; 19p13.3-p13.2).
Diagnostic methods
A positive diagnosis requires identification of one mutation in each allele of this gene.
Differential diagnosis
The differential diagnosis should include the other forms of extreme insulin resistance.
Genetic counseling
The disorder is transmitted as an autosomal recessive trait.
Management and treatment
Treatment with recombinant insulin-like growth factor 1 (IGF1) may be considered. A combination treatment with insulin-like growth factor binding protein 3 (IGF-BP3) resulted in an increased lifespan in one case.
Prognosis
Prognosis is uncertain, growth is severely affected and life expectancy rarely exceeds a few months.

                            Last update:
                            January 2009

                            - Expert reviewer(s):
                            Pr Jacqueline CAPEAU


A chronic infectious disease affecting primarily the skin and peripheral nervous system.

Summary:
Epidemiology
Worldwide annual incidence is estimated at 250,000 cases, with a large majority in India and Brazil.
Clinical description
A wide clinical spectrum has been described from a polar tuberculoid (localized) form (TT) to a polar lepromatous (disseminated) one (LL). Borderline forms exist: borderline tuberculoid, borderline borderline and borderline lepromatous (BT, BB, BL). Tuberculoid leprosy (TLep) or paucibacillary form includes TT and BT and lepromatous leprosy (LLep) or multibacillary form includes LL, BL and BB. The incubation time ranges from several months to more than 20 years and does not exceed 5 years in TLep. After contact with Mycobacterium leprae, only 5% of patients develop the disease, almost all with cutaneous lesions and variably severe peripheral neuropathy. In TLep, initially a few large lesions are found (1 to 10). They appear as well demarcated hypopigmented, macules or erythematous plaques. A characteristic loss of sensation at the skin lesion is always present. In LLep, the cutaneous lesions are numerous (10 to 100 or more), normoesthesic, poorly demarcated hypopigmented macules or erythematous papules or nodules and sometimes plaques and may induce diffuse infiltration causing a leonine facies. Mucosas are affected leading in severe cases to nasal destruction, and corneal or laryngeal impairment. Visceral involvement (adenopathies, hepato-splenomegaly or orchiepididymitis) may be present. Neural involvement affects especially the ulnar, median, radial, external popliteal and tibial posterior nerves, with a greater risk in TLep than LLep of distal (hands and feet) anesthesia, palsy (foot drop or clawed hands) and amyotrophy. About 40% of patients may develop 2 types of reactional states: 1) reversal reaction (RR; inflammation of the skin lesions and severe acute neuritis) or down-grading reaction (increased number of lesions) and 2) erythema nodosum leprosum (ENL; vasculitis with painful and eruptive erythematous nodules, fever, neuritis and joint swelling) or Lucio's phenomenon (granulomatous vasculitis with painful necrotic macules).
Etiology
The disease is caused by M. leprae, a mycobacterium for which the main reservoir is humans and some species of armadillos. Recently M. lepromatosis was identified as causing some LLep cases. Possible predisposing genetic factors have been found.
Diagnostic methods
Diagnosis is based on clinical, histopathological and bacteriological findings. Skin biopsy is used to determine the form. Examination of slit skin smears enables quantitative evaluation of the bacterial load, usually low or nil in TLep and always high in LLep. PCR assays in tissue may accurately detect M. leprae's 16s rRNA in LLep cases and gene mutations inducing antibiotic resistance. It is generally negative in TLep and only gives a qualitative score.
Differential diagnosis
Differential diagnosis includes hypochromic eczematides, annular granuloma, annular erythema, dermatophyties and annular sarcoidosis in TLep, and pityriasis versicolor, post-inflammatory hypomelanosis, hypochromic or papulo-nodular sarcoidosis, Kaposi sarcoma, syphilis, lymphoma, cutaneous leukemia in LLep.
Management and treatment
There are 2 treatment groups: paucibacillary (PB; up to 5 skin lesions) and multibacillary (MB; more than 5). The recommended therapy combines 2 antibiotics (for PB) or 3 (for MB): rifampicin, dapsone and clofazimine. In some cases, other drugs can be used (ofloxacin, minocycline, clarithromycin). Treatment duration is 6 months for PB and at least 1 year for MB. Reactional states can be treated with systemic corticosteroids and sometimes surgical neurolysis for RR, and thalidomide, corticosteroids or pentoxifylline for ENL.
Prognosis
Prognosis is favorable when antibacillary and anti-reactional treatments are rapidly instituted. If not, the disease may lead to definitive neurological disabilities.

                            Last update:
                            September 2011

                            - Expert reviewer(s):
                            Dr Béatrice FLAGEUL


An anthropozoonosis, rare in Europe, clinically characterized by an initial presentation of flu-like symptoms rapidly progressing into life-threatening multisystem failure (notably hepatonephritis) caused by spiral-shaped bacteria belonging to the genus Leptospira. Leptospirosis is a widespread zoonosis with a worldwide distribution and has emerged as a major public health problem in developing countries in South-East Asia and South America.

Summary:
Epidemiology
Estimations from the World Health Organization (WHO) indicate that over 1 million cases of leptospirosis are thought to occur each year, with a mortality rate ranging from 5 to 20% depending on the country. However, the incidence in Europe is much lower with, for example, 600-700 cases in France which is the country with the highest incidence in Europe.
Clinical description
Initial signs of infection include fever associated with shivering and pain (myalgia, headaches and abdominal pain). The disease progresses over several days with severity varying from flu-like symptoms to rapidly life-threatening multisystem failure, with the most characteristic manifestation being hepatonephritis. Marked jaundice, renal insufficiency, neurologic signs, respiratory involvement, myocarditis, painful hepatomegaly with splenomegaly, and bleeding may also occur. Laboratory investigations reveal polynuclear hyperleucocytosis, cholestasis that is in some cases severe and isolated (without or with only limited cytolysis), and occasionally rhabdomyolysis and thrombopenia.
Etiology
Animal hosts (generally rodents) excrete leptospires in their urine. Humans become infected through skin or mucosal contact with contaminated soft water. The incubation period lasts around 10 days.
Diagnostic methods
The diagnosis relies on PCR results and serology. PCR analysis of blood or urine samples can be used to detect leptospire DNA and allows early diagnosis within the first week following disease onset. Antibodies can become detectable by the 6th to 10th day of the onset of symptoms by IgM ELISA or microscopic agglutination test (MAT). However, leptospirosis is often diagnosed late due to its wide spectrum of symptoms ranging from a flu-like syndrome to renal failure.
Differential diagnosis
The symptoms mimic the clinical presentations of many other diseases, including dengue fever and malaria.
Management and treatment
Leptospira remain sensitive to penicillin G and therefore treatment is based on administration of antibiotics. Antibiotic therapy is beneficial but must be administered in the early stage of the disease. Disease prevention revolves around eradication of rodents and the use of proper precautions. In some countries, such as France, a vaccine is also available but is reserved for those in at-risk professions, such as sewerage workers.
Prognosis
Leptospirosis may lead to pulmonary hemorrhages and irreversible multiple organ failure and death in 5 to 20% of cases.

                            Last update:
                            July 2024

                            - Expert reviewer(s):
                            Dr Mathieu PICARDEAU


Leri pleonosteosis is characterized by broadening and deformity of the thumbs and great toes in a valgus position (a 'spade-shaped' appearance), flexion contracture of the interphalangeal joints, generalized limitation of joint mobility, short stature, and often mongoloid facies. Additional malformations include genu recurvatum, enlargement of the posterior neural arches of the cervical vertebrae, and thickening of the palmar and forearm fasciae. A few multigenerational families have been reported so far. The disease is inherited in an autosomal dominant manner.


Lesch-Nyhan syndrome (LNS) is the most severe form of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency (see this term), a hereditary disorder of purine metabolism, and is associated with uric acid overproduction (UAO), neurological troubles, and behavioral problems.

Summary:
Epidemiology
Estimated prevalence at birth is between 1/380,000 and 1/235,000 live births. Males are generally affected and heterozygous females are carriers (usually asymptomatic).
Clinical description
Patients are normal at birth. Psychomotor delay becomes evident within 3 to 6 months with a delay in head support and sitting, hypotonia and athetoid movements. Sandy urine in diapers or crystalluria with urinary tract obstruction are common forms of presentation. Patients have severe action dystonia with baseline hypotonia that may lead to an inability to stand up and walk, and involuntary movements (choreoathetosis and ballismus) associated with voluntary movements increased by stress but not evident at rest. Dysarthria, dysphagia, and opisthotonus are frequent. Spasticity, hyperreflexia and extensor plantar reflex appear later. Patients usually show mild to moderate intellectual deficit. Obsessive-compulsive self-mutilation (lip biting or finger chewing) can appear as soon as teeth are present, does not result from lack of sensation and may be associated with or aggravated by psychological stress. Aggressive behavior (i.e. spitting, abusive language) may be directed against family and friends. Megaloblastic anemia is frequent and may be severe. Microcytic anemia may occur. UAO may result in joint inflammation, gouty arthritis and urolithiasis. Renal failure or acidosis occur rarely.
Etiology
LNS is caused by complete HPRT deficiency due to mutations in the HPRT1 gene (Xq26). UAO is due to deficient recycling and enhanced synthesis of purine bases. Megaloblastic anemia is supposed to be due to increased folic acid consumption but it does not respond to folic supplementation. The cause of neurological and behavioral symptoms is unknown. Several neurotransmitter disorders and a toxic effect of hypoxanthine excess have been advocated.
Diagnostic methods
Diagnosis is suspected when psychomotor delay occurs in a patient with elevated UA in blood and urine. Undetectable HPRT enzyme activity in peripheral blood or in intact cells (erythrocyte, fibroblast) and molecular genetic testing confirm the diagnosis.
Differential diagnosis
Differential diagnoses include cerebral palsy, other causes of intellectual deficit, dystonia and self-injury including autism, Tourette syndrome, Cornelia de Lange syndrome (see these terms), idiopathic intellectual deficit, and severe psychiatric disorders.
Antenatal diagnosis
Prenatal diagnosis by amniocentesis or chorionic villus sampling is possible if the mutation has been identified in the family.
Genetic counseling
Inheritance is X-linked recessive and genetic counseling is essential.
Management and treatment
UAO is managed with allopurinol, urine alkalinization, and hydration. Doses must be adjusted to avoid xanthine urolithiasis. There is no treatment for the neurological dysfunction. Spasticity and dystonia can be managed with benzodiazepines (diazepam, alprazolam) and gamma-aminobutyric acid inhibitors (baclofen, tizanidine). Physical rehabilitation (i.e. management of dysarthria and dysphagia), devices to enable hand control, walking aids, and posture management to prevent deformities are recommended. Self-injury requires physical restraints, behavioral and pharmaceutical treatment (gabapentin, carbamazepine).
Prognosis
Patients may die from aspiration pneumonia or complications from chronic nephrolithiasis and renal failure. With optimal care, few patients live beyond 40 years and most are confined to a wheelchair.

                            Last update:
                            April 2010

                            - Expert reviewer(s):
                            Dr Juan GARCÍA PUIG  - Dr Rosa TORRES JIMÉNEZ


Lethal acantholytic epidermolysis bullosa is a suprabasal subtype of epidermolysis bullosa simplex (EBS, see this term) characterized by generalized oozing erosions, usually in the absence of blisters.

Summary:
Epidemiology
Prevalence is unknown but 3 cases have been reported to date.
Clinical description
Onset of the disease is at birth. Erosions are associated with absent nails, universal alopecia, and, in one patient, neonatal teeth. Extracutaneous involvement is always present, involving erosions of the soft tissues of the oral cavity, and gastrointestinal, genitourinary and respiratory tract abnormalities. Cardiomyopathy has been reported in one case.
Etiology
This form of EBS is due to mutations in the DSP (6p24) gene encoding desmoplakin. A homozygous nonsense mutation in the JUP gene (17q21) has been reported in a patient with a very similar phenotype.
Genetic counseling
Transmission is autosomal recessive.
Prognosis
In reported cases, death occurred within the first month of life from multiorgan failure secondary to huge transcutaneous fluid loss or airway obstruction due to mucosal sloughing.

                            Last update:
                            September 2012

                            - Expert reviewer(s):
                            Pr Giovanna ZAMBRUNO


Lethal arteriopathy syndrome due to fibulin-4 deficiency

A rare, genetic, vascular disorder characterized by severe aneurysmal dilatation, elongation, and tortuosity of the thoracic aorta, its branches and pulmonary arteries with stenosis at various typical locations, typically resulting in infantile demise. Variable associated features may include cutis laxa, long philtrum with thin vermillion border, hypertelorism, sagging cheeks, arachnodactyly, joint laxity and pectus deformities.


Lethal ataxia with deafness and optic atrophy (also known as Arts syndrome) is characterized by intellectual deficit, early-onset hypotonia, ataxia, delayed motor development, hearing impairment and loss of vision due to optic atrophy.

Summary:
Epidemiology
It was initially described in 12 male members from five generations of a Dutch family. Arts syndrome has also been described in one Australian family.
Clinical description
Other manifestations included floppiness, susceptibility to infections, and later, flaccid tetraplegia and areflexia.
Etiology
It is caused by missense mutations in the phosphoribosyl pyrophosphate synthetase 1 gene (PRPS1) localized to Xq22.1-q24, leading to impaired purine biosynthesis.
Genetic counseling
Arts syndrome is transmitted as an X-linked recessive trait.
Management and treatment
Treatment with S-adenosylmethionine may be beneficial and is currently under evaluation.
Prognosis
The disease has a fatal course during childhood (the majority of patients die before the age of 5 years) due to the high susceptibility of the patients to infections, especially of the upper respiratory tract.

                            Last update:
                            September 2008


Lethal brain and heart developmental defects

A rare genetic lethal multiple congenital anomalies/dysmorphic syndrome characterized by early intrauterine growth retardation, generalized edema, craniofacial dysmorphism (such as microcephaly, brachycephaly, frontal bossing, hypertelorism, short palpebral fissures, or absent nasal bone), cerebellar hypoplasia, sex reversal in male fetuses, congenital heart defects (including septal and valve defects and cardiomegaly), and late fetal loss.


Lethal congenital contracture syndrome type 1 is a rare, genetic arthrogryposis syndrome characterized by total fetal akinesia (detectable since the 13th week of gestation) accompanied by hydrops, micrognathia, pulmonary hypoplasia, pterygia and multiple joint contractures (usually flexion contractures in the elbows and extension in the knees), leading invariably to death before the 32nd week of gestation. Lack of anterior horn motoneurons, severe atrophy of the ventral spinal cord and severe skeletal muscle hypoplasia are characteristic neuropathological findings, with no evidence of other organ structural anomalies.


Lethal congenital contracture syndrome type 2 is a rare arthrogryposis syndrome characterized by multiple congenital contactures (typically extended elbows and flexed knees), micrognathia, anterior horn cell degeneration, skeletal muscle atrophy (mainly in the lower limbs), presence of a markedly distended urinary bladder and absence of hydrops, pterygia and bone fractures. Other craniofacial (e.g. cleft palate, facial palsy) and ocular (e.g. anisocoria, retinal detachment) anomalies may be additionally observed. The disease is usually neonatally lethal however, survival into adolescence has been reported.


Lethal congenital contracture syndrome type 3 is a rare arthrogryposis syndrome characterized by clinical features identical to Lethal congenital contracture syndrome type 2 (i.e. multiple congenital contactures (typically extended elbows and flexed knees), micrognathia, anterior horn cells degeneration, skeletal muscle atrophy (mainly in the lower limbs), in the absence of hydrops, pterygia or bone fractures), but without bladder enlargement.


A group of rare arthrogryposis syndromes characterized by fetal akinesia, multiple congenital contractures, anterior horn cell degeneration, skeletal muscle atrophy, and other features, depending on the subtype. All types are lethal in the fetal or neonatal period.


An extremely rare polymalformative syndrome.

Summary:
Epidemiology
It was described only once, in 1975, in 3 affected males in a sibship of 13, from second-cousin parents.
Clinical description
Patients were all of low birth weight, had microretrognathia, microstomia, and microglossia, hypoplasia of the radius and ulna with radial deviation of the hands, simian creases and hypoplasia of fingers I and V, hypoplasia of the fibula and tibia with talipes and wide space between toes I and II, and severe malformation of the left heart which may have been responsible for death of all 3 in the first week or so of life.

                            Last update:
                            December 2011


Lethal fetal brain malformation-duodenal atresia-bilateral renal hypoplasia syndrome

A rare genetic lethal multiple congenital anomalies/dysmorphic syndrome characterized by mid-gestation lethality and features of a ciliopathy. Clinical manifestations include hydrocephalus, cerebellar vermis hypoplasia, corpus callosum agenesis, duodenal atresia, gastrointestinal malrotation, bilateral renal hypoplasia, and dysmorphic craniofacial features (such as microcephaly, hypertelorism, low-set ears, prominent nose, short columella, cleft palate, micrognathia, and wide mouth).


Lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome is a rare, genetic developmental defect during embryogenesis malformation syndrome characterized by intrauterine growth restriction, flexion arthrogryposis of all joints, severe microcephaly, renal cystic dysplasia/agenesis/hypoplasia and complex malformations of the brain (cerebral and cerebellar hypoplasia, vermis, corpus callosum and/or occipital lobe agenesis, with or without arhinencephaly), as well as of the genitourinary tract (ureteral agenesis/hypoplasia, uterine hypoplasia and/or vaginal atresia), leading to fetal demise.


Lethal hemolytic anemia-genital anomalies syndrome

A rare genetic disease characterized by lethal non-spherocytic, non-immune hemolytic anemia, in association with abnormalities of the external genitalia (such as micropenis and hypospadias). Reported dysmorphic features include flat occiput, dimpled earlobes, deep plantar creases, and increased space between the first and second toes. There have been no further descriptions in the literature since 1995.


Lethal hydranencephaly-diaphragmatic hernia syndrome is a rare, genetic, lethal, multiple congenital anomalies syndrome characterized by hydranencephaly and diaphragmatic hernia, as well as macrocephaly, a widely open anterior fontanel, scaphoid abdomen and hypotonia. Additionally, congenital heart defects, polyhydramnios and pulmonary hypertension have also been associated.


Lethal infantile mitochondrial myopathy is a rare mitochondrial oxidative phosphorylation disorder characterized by progressive generalized hypotonia, progressive external ophthalmoplegia and severe lactic acidosis, which results in early fatality (days to months after birth). Patients may present with lethargy and areflexia and may associate additional features, such as cardiomyopathy, renal dysfunction, liver involvement and seizures.


Lethal intrauterine growth restriction-cortical malformation-congenital contractures syndrome

A rare and fatal central nervous system malformation occurring during embryogenesis, presenting prenatally with holoprosencephaly and fetal hypokinesia as major features. Other manifestations include microcephaly, multiple contractures and intrauterine growth restriction. There have been no further descriptions in the literature since 1988.


A rare, lethal, congenital, chondrodysplasia disorder characterized by dumbbell-shaped long bones with markedly shortened diaphyses and metaphyseal irregularities associated with a 'Swiss cheese' appearance of the cartilage matrix, as well as distinctive changes in the growth plate and resting cartilage, resulting in death in the neonatal period. There have been no further descriptions in the literature since 1983.


A rare developmental defect with connective tissue involvement characterized by multiple joint dislocations, flattened facial appearance, abnormal palmar creases, laryngotracheomalacia, and pulmonary hypoplasia. Additional signs may include a bifid tongue, micrognathia, non-immune hydrops fetalis, and brain dysplasia. The disease is lethal shortly after birth due to respiratory insufficiency.


Lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndrome is rare, genetic, neurometabolic disease characterized by global developmental delay, severe hypotonia, seizures, cataracts, cardiomyopathy (including left or bi-ventricular hypertrophy, dilated cardiomyopathy) and left ventricular non-compaction, typically resulting in infantile or early-childhood death. Patients usually present metabolic lactic acidosis, failure to thrive, head lag, respiratory problems and decrease in respiratory chain complex activity. Highly variable cerebral abnormalities have been reported and include microcephaly, prominent extra-axial cerebrospinal fluid spaces, diffuse neuronal loss and cortical/white matter gliosis.


A rare genetic multiple pterygium syndrome characterized by intrauterine growth retardation, fetal akinesia, multiple joint contractures causing severe arthrogryposis and pterygia (webbing) across multiple joints. Cystic hygroma and/or fetal hydrops are almost invariably present.

Summary:
Epidemiology
To date, less than 50 fetuses have been reported in 28 families. Of these cases, approximately 60% were male and 40% were female. Half of the families had affected males only, including five with multiple affected males.
Clinical description
Lethal multiple pterygium syndrome (LMPS) is characterized by growth deficiency of prenatal onset, pterygia present in multiple areas (chin to sternum, cervical, axillary, humero-ulnar, crural, popliteal and the ankles) and flexion contractures giving rise to severe arthrogryposis. Subcutaneous edema varies from mildly edematous skin to fetal hydrops with cystic hygroma, lung hypoplasia, and oligo or polyhydramnios. Facial anomalies include hypertelorism, down-slanting palpebral fissures, epicanthic folds, flat nasal root, microretrognathism, microstomia, low-set malformed ears and cleft palate. Other anomalies include a small chest, reduced muscle bulk, cryptorchidism, central nervous system abnormalities (in particular cerebellar hypoplasia, ventricular dilatation and polymicrogyria), hypoplastic dermal ridges and creases, and less frequently a mid-forehead hemangioma, intestinal malrotation, cardiac hypoplasia, diaphragmatic hernia, obstructive uropathy, rocker bottom feet, microcephaly and/or cerebellar and pontine hypoplasia.
Etiology
Causal mutations have been identified in subunits of the acetylcholine receptor encoded by CHRNA1  (2q31.1), CHRND (2q37.1), CHRNG (2q37.1), as well as in the nebulin gene (NEB, 2q23.3), and the ryanodine receptor (RYR1, 19q13.2).
Diagnostic methods
Diagnosis is suspected based on characteristic clinical features and ultrasound findings observed during routine pregnancy examination (for more details see the section on antenatal diagnosis).
Differential diagnosis
Differential diagnoses include other disorders which present with prenatal ultrasound features of reduced or absent fetal movements in association with an abnormal fetal posture and other arthrogrypotic conditions. These may include fetal akinesia deformation sequence (FADS), Bartsocas-Papas syndrome, Escobar variant multiple pterygium syndrome, arthrogryposis multiplex congenita, and maternal myasthenia gravis, as well as trisomy 18, severe neural tube defects, caudal regression sequence and vertebral anomalies, limb body wall complex, fetal neck masses, fetal hypoxia, constriction rings syndrome and fetal constraint.
Antenatal diagnosis
Fetal akinesia may be detected as early as 12 weeks. Prenatal ultrasound findings with LMPS include intrauterine growth retardation, flexion contractures of the limbs, multiple pterygia, cystic hygroma, fetal hydrops, hypoplastic lungs, a cleft palate and other structural abnormalities. Additional findings of hypoplastic skeletal development may help in distinguishing LMPS from other conditions with FADS, and detailed ultrasound scans and fetal MRI may identify a central nervous system abnormality which may be a feature in LMPS or suggest an alternative etiology. Molecular prenatal genetic testing can be undertaken if early scans are inconclusive and the mutation has been identified. LMPS should also be considered in patients with a history of recurrent mid-trimester losses.
Genetic counseling
The inheritance is autosomal recessive. The sibling recurrence risk is 25%. X-linked inheritance has also rarely been reported and is also suggested by the excess of males with LMPS.
Management and treatment
As the condition is lethal, termination of the pregnancy may be proposed.
Prognosis
LMPS is typically fatal during the second or third trimester.

                            Last update:
                            October 2019

                            - Expert reviewer(s):
                            Dr Julie VOGT


Lethal neonatal spasticity-epileptic encephalopathy syndrome

A rare genetic neurological disorder characterized by neonatal onset of rigidity and intractable seizures, with episodic jerking already beginning in utero. Affected infants have small heads, remain visually inattentive, do not feed independently, and make no developmental progress. Frequent spontaneous apnea and bradycardia usually culminate in cardiopulmonary arrest and death in infancy, although some cases were described with a milder clinical course and survival into childhood.


Lethal occipital encephalocele-skeletal dysplasia syndrome is a rare, genetic, bone development disorder characterized by occipital and parietal bone hypoplasia leading to occipital encephalocele, calvarial mineralization defects, craniosynostosis, radiohumeral fusions, oligodactyly and other skeletal anomalies (arachnodactyly, terminal phalangeal aplasia of the thumbs, bilateral absence of the great toes, pronounced bilateral angulation of femora, shortened limbs, advanced osseous maturation). Fetal death in utero is associated.


Lethal omphalocele-cleft palate syndrome

A rare multiple congenital anomalies/dysmorphic syndrome characterized by the association of omphalocele and cleft palate. Other reported features include cleft lip, bifid uvula, bilateral talipes equinovarus, bicornuate uterus, and hydrocephalus internus. The condition is lethal in infancy.


Lethal polymalformative syndrome, Boissel type

A rare, genetic, lethal, multiple congenital anomalies/dysmorphic syndrome characterized by failure to thrive, severe developmental delay, severe postanatal microcephaly, frequent congenital cardiac defects and characteristic facial dysmorphysm (including coarse face with anteverted nostrils, thin vermillion, prominent alveolar ridge and retro- or micrognatia). Additional common features include neurologic abnormalities (hyper-/hypotonia, sensorineural deafness, hydrocephalus, cerebral atrophy, seizures), as well as brachydactyly, cutis marmorata and genital anomalies.


Lethal recessive chondrodysplasia is an extremely rare lethal form of chondrodysplasia characterized by severe micromelic dwarfism, short and incurved limbs with normal hands and feet, facial dysmorphism (disproportionately large skull, frontal prominence, slightly flattened nasal bridge and short neck), muscular hypotonia, hyperlaxity of the extremities, and a narrow thorax. Most patients die of respiratory distress during the first hours or weeks of life. There have been no further descriptions in the literature since 1988.


Leukocyte adhesion deficiency type I (LAD-I) is a form of LAD (see this term) characterized by life-threatening, recurrent bacterial infections.

Summary:
Epidemiology
LAD-I affects 1 individual per million.
Clinical description
Usually the first signs occur in infancy or early childhood. Patients present recurrent, life-threatening bacterial infections of the skin, mouth, and respiratory tract. Delayed umbilical cord separation is common. Skin infections may evolve into large ulcers. Severe periodontitis is often present later in life and leads to early tooth loss. A lack of swelling, redness, heat, or pus is observed in the area of infection.
Etiology
LAD-I is caused by mutations in the ITGB2 gene (21q22.3), encoding the beta-2-integrin, CD18, which is essential for firm adhesion of leukocytes to the endothelium. Severity of the disease correlates with the degree of CD18 deficiency.
Diagnostic methods
Diagnosis is based on complete blood counts revealing neutrophilic leukocytosis. Flow cytometric analyses reveal reduced CD18 expression on leukocytes. Genetic analyses of mutations in the ITGB2 gene confirm the diagnosis.
Differential diagnosis
Differential diagnoses include IRAK-4 deficiency, autosomal dominant hyper IgE syndrome, chronic granulomatous disease, other primary immunodeficiencies (see these terms) and a leukemoid reaction.
Antenatal diagnosis
Antenatal diagnosis is possible through biochemical or molecular analysis of chorionic villus cells or amniocytes in affected families for which the mutation has been identified. Flow cytometry can be performed at 20 weeks of gestation.
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Management should focus on controlling infections and includes antibiotics. Hematopoietic cell transplantation represents the only cure for LAD-I, but gene therapy may be available in the future.
Prognosis
Prognosis depends on the severity of the disease. Without hematopoietic stem cell transplantation, death in patients with severe LAD-I occurs from infection within the first 2 years of life, whereas patients with a moderate form of the disease have abetter chance of surviving into adulthood. Survival rate after bone marrow transplantation is 75%.

                            Last update:
                            May 2009

                            - Expert reviewer(s):
                            Pr Amos ETZIONI


Leukocyte adhesion deficiency type II (LAD-II) is a form of LAD (see this term) characterized by recurrent bacterial infections, severe growth delay and severe intellectual deficit.

Summary:
Epidemiology
LAD-II is extremely rare: less than 10 cases have been reported so far.
Clinical description
The first signs usually occur in infancy or early childhood. Patients present recurrent bacterial infections, severe growth delay resulting in short stature, and severe intellectual deficit. Patients have the Bombay phenotype (they do not express the H antigen). Facial dysmorphism is common, characterized mainly by a depressed nasal bridge. Severe periodontitis is often present later in life and leads to early tooth loss. In adulthood, intellectual deficit and growth retardation, rather than infections, dominate the clinical picture.
Etiology
LAD-II is a carbohydrate-deficient glycoprotein syndrome (CDG syndrome; see this term) and is therefore also referred to as CDG IIc. It results from mutations in the SLC35C1 gene (11p11.2), encoding the guanosine 5'-diphosphate (GDP)-fucose transporter localized in the Golgi apparatus. This is a specific fucose transporter that translocates GDP-fucose from the cytosol to the Golgi where it is used as a substrate for fucosylation.
Diagnostic methods
Diagnosis is based on clinical findings and complete blood counts revealing leukocytosis with neutrophilia. Blood typing is essential to look for the Bombay blood group, which is present in all patients with LAD-II and is extremely rare in the general population. Final diagnosis is based on genetic analysis.
Differential diagnosis
There is no differential diagnosis as the clinical symptoms of recurrent infections, leukocytosis, the Bombay blood group, and severe growth and intellectual deficit are unique to LAD-II.
Antenatal diagnosis
Antenatal diagnosis through biochemical or molecular analysis of chorionic villus cells or amniocytes is possible in families for which the mutation has been identified.
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Management should focus on controlling infections and includes antibiotics. Fucose replacement may improve phagocytic function in some cases.
Prognosis
Infections in LAD-II are rarely life-threatening and thus patients may live to adulthood.

                            Last update:
                            May 2009

                            - Expert reviewer(s):
                            Pr Amos ETZIONI


Leukocyte adhesion deficiency type III (LAD-III) is a form of LAD (see this term) characterized by both severe bacterial infections and a severe bleeding disorder.

Summary:
Epidemiology
LAD-III is extremely rare: only 17 patients have been reported so far.
Clinical description
Usually the first signs occur in infancy or early childhood. Patients present LAD-I life-threatening infections and a Glanzmann thrombasthenia-like bleeding disorder (see these terms). A lack of pus is observed in infected areas.
Etiology
LAD-III is caused by mutations in the FERMT3 gene (11q13.1), which encodes kindlin-3 in hematopoietic cells. The FERMT3 mutations lead to an activation defect of all beta-integrins.
Diagnostic methods
Diagnosis is based on clinical findings and complete blood counts revealing leukocytosis with neutrophilia. Platelet aggregation assays and genetic analysis confirm the diagnosis.
Differential diagnosis
Differential diagnoses include LAD-I, Glanzmann thrombasthenia (see these terms), and leukemoid reaction. Antenatal diagnosis may be confirmed through biochemical or molecular analysis of chorionic villus cells.
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Management should focus on controlling infections and includes symptomatic treatment with antibiotics and blood transfusions. Bone marrow transplantation is the only available curative treatment option.
Prognosis
Prognosis is poor and death occurs in early infancy if bone marrow transplantation is not performed.

                            Last update:
                            May 2009

                            - Expert reviewer(s):
                            Pr Amos ETZIONI


Leukocyte adhesion deficiency (LAD) is a primary immunodeficiency characterized by defects in the leukocyte adhesion process, marked leukocytosis and recurrent infections.

Summary:
Epidemiology
Prevalence is unknown, but less than 350 cases have been reported so far.
Clinical description
Usually the first signs occur in infancy or early childhood. Three distinct defects in the leukocyte adhesion cascade have been defined leading to three distinct entities. LAD-I (see this term) is characterized by life-threatening, recurrent bacterial infections. LAD-II (see this term) presents with leukocytosis, recurrent infections, severe growth delay and intellectual deficit. LAD-III (see this term; also called LAD-I variant) is characterized by both severe bacterial infections and a severe bleeding disorder.
Etiology
LAD results from an impaired step in the inflammatory process, namely, the migration of leukocytes from the blood vessels to sites of infection, which requires adhesion of leukocytes to the endothelium. LAD-I is caused by mutations in the ITGB2 gene (21q22.3), encoding the beta-2-integrin CD18. LAD-II results from mutations in the SLC35C1 gene (11p11.2), encoding the guanosine 5'-diphosphate (GDP)-fucose transporter. LAD-III is caused by mutations in the FERMT3 gene (11q13.1), encoding kindlin-3 in hematopoietic cells.
Diagnostic methods
Diagnosis is based on the clinical symptoms and on a complete blood count revealing neutrophilia. In LAD-I and LAD-II, flow cytometry should be performed for CD18 and CD15 respectively. In LAD-III, platelet aggregation assays should be performed. In all cases, a genetic analysis confirms the diagnosis.
Differential diagnosis
Differential diagnoses include IRAK-4 deficiency, autosomal dominant hyper IgE syndrome, chronic granulomatous disease (see these terms), neutrophil dysfunction and a leukemoid reaction.
Antenatal diagnosis
Antenatal diagnosis is feasible by genetic analysis of chorionic villus samples.
Genetic counseling
In all cases, transmission is autosomal recessive. Genetic counseling should always be offered to the patients and their families.
Management and treatment
Management depends on the type of LAD. Treatment should focus on controlling infections and includes antibiotics and, in many cases, bone marrow transplantation. Without hematopoietic stem cell transplantation, patients with severe LAD-I and LAD-III usually die from infection within the first 2 years of life.
Prognosis
The survival rate in patients with LAD-I who undergo bone marrow transplantation is 75%. Some patients with LAD-II survive to adulthood.

                            Last update:
                            May 2009

                            - Expert reviewer(s):
                            Pr Amos ETZIONI


Leukoencephalopathy with bilateral anterior temporal lobe cysts

A rare, nonprogressive, neurological disorder marked by intellectual deficit, spasticity and motor retardation associated with characteristic MRI findings of anterior bilateral temporal lobe cysts and multilobar leukoencephalopathy. So far, around 30 cases have been reported in the literature. Onset occurs in the first few months of life. Sensorineural deafness and microcephaly have also been reported. The etiology is unknown but an autosomal recessive mode of inheritance has been suggested.


Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome

This disease is characterised by progressive cerebellar ataxia with pyramidal and spinal cord dysfunction, associated with distinctive MRI anomalies and increased lactate in the abnormal white matter.

Summary:
Epidemiology
So far, 38 cases have been reported.
Clinical description
Onset occurs in early childhood. Epilepsy and cognitive decline have also been described.
Etiology
The syndrome is caused by mutations in the DARS2 gene, which encodes mitochondrial aspartyl-tRNA synthetase.
Diagnostic methods
MRI reveals inhomogeneous periventricular and deep white matter anomalies, with involvement of the cerebellar connections, the entire length of the pyramidal and sensory tracts.
Genetic counseling
Transmission is autosomal recessive.

                            Last update:
                            April 2008


Leukoencephalopathy with calcifications and cysts

A rare genetic cerebral small vessel disease characterized by leukoencephalopathy and cerebral calcification and cysts due to diffuse cerebral microangiopathy resulting in microcystic and macrocystic parenchymal degeneration. The condition can present at any age from early childhood to late adulthood and manifests as a progressive cerebral degeneration. Symptoms are variable, but restricted to the central nervous systems, and include, among others, slowing of cognitive performance, seizures, and movement disorder with a combination of pyramidal, extrapyramidal, and cerebellar features.


Leukoencephalopathy with mild cerebellar ataxia and white matter edema

A rare neurologic disease characterized by a specific pattern of white matter abnormalities on brain imaging (magnetic resonance imaging, MRI), as well as mild ataxia, headaches, mild visual impairment, learning difficulties and cases of male infertility.


Leukoencephalopathy-dystonia-motor neuropathy syndrome is a peroxisomal neurodegenerative disorder characterized by spasmodic torticollis, dystonic head tremor, intention tremor, nystagmus, hyposmia, and hypergonadotrophic hypogonadism with azoospermia. Slight cerebellar signs (left-sided intention tremor, balance and gait impairment) are also noted. Magnetic resonance imaging (MRI) shows bilateral hyperintense signals in the thalamus, butterfly-like lesions in the pons, and lesions in the occipital region, whereas nerve conduction studies of the lower extremities shows a predominantly motor and slight sensory neuropathy.


Leukoencephalopathy-palmoplantar keratoderma syndrome is a rare, genetic epidermal disease characterized by early childhood-onset of punctate palmoplantar keratoderma in association with adult-onset leukoencephalopathy manifested by progressive tetrapyramidal syndrome and cognitive deterioration.


A rare genetic neurological disorder characterized by the association of hypomyelinating leukodystrophy with spondylometaphyseal dysplasia. Patients present in infancy with absent or delayed ability to walk independently, slowly progressive motor deterioration, spasticity, ataxia, proximal weakness, and joint contractures. Additional manifestations include mild cognitive impairment, short stature, scoliosis, enlarged and deformed joints, dysarthria, nystagmus, visual defects, and mildly dysmorphic features, among others. Mode of inheritance is X-linked recessive.


Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome

A rare, genetic neurological disorder defined by early-onset of neurologic symptoms, biphasic clinical course, unique MRI features (incl. extensive, symmetrical, deep white matter abnormalities), and increased lactate in body fluids. The severe form is characterized by delayed psychomotor development, seizures, early-onset hypotonia, and persistently increased lactate levels. The mild form usually presents with irritability, psychomotor regression after six months of age, and temporary high lactate levels, with overall clinical improvement from the second year onward.


Leukomelanoderma-infantilism-intellectual disability-hypodontia-hypotrichosis syndrome is a rare ectodermal dysplasia syndrome characterized by congenital generalized melanoleukoderma, hypodontia and hypotrichosis associated with infantilism, intellectual disability and growth delay. There have been no further descriptions in the literature since 1961.


Leukonychia totalis-acanthosis-nigricans-like lesions-abnormal hair syndrome is a rare, syndromic nail anomaly disorder characterized by the association of leukonychia totalis with acanthosis-nigricans-like lesions (occurring in the neck, axillae and abdomen regions) and hair dysplasia, manifesting with dry, brittle hair which presents an irregular pattern of complete or incomplete twists and an irregular surface with londitudinal furrows on electronic microscopy.


Leukonychia totalis is a rare nail anomaly disorder characterized by complete white discoloration of the nails. Patients typically present white, chalky nails as an isolated finding, although other cutaneous or systemic manifestations could also be present.


A rare, congenital, non-syndromic, developmental defect during embryogenesis characterized by the heart located in the normal (levo) position associated with abdominal viscera located in the dextro position. Cardiac (e.g. interrupted inferior vena cava with azygous continuation) and/or splenic (asplenia, polysplenia) anomalies, as well as intestinal malrotation, are frequently associated.


A rare acquired demyelinating polyneuropathy characterized by asymmetrical distal weakness of the upper or lower extremities and motor dysfunction with adult onset. It is considered to be a variant of chronic inflammatory demyelinating polyneuropathy.


A rare 46,XY difference of sex development due to impaired androgen production characterized by impaired normal male sexual development. The severity of the disorder varies and can manifest in its severe form with complete 46,XY male pseudohermaphroditism, including low testosterone and high luteinizing hormone levels, absent development of secondary male sex characteristics and lack of breast development. Patients with the milder form can have a wider range of phenotypes, ranging from micropenis to severe hypospadias.


A rare developmental defect during embryogenesis characterized by abnormal development and enlargement of the cerebellum, and an increased intracranial pressure. The tumors can be characterized by the abnormal growth of ganglion cells that regulate activities in the cerebellum.

Summary:
Epidemiology
Approximately 230 cases of Lhermitte-Duclos disease (LDD) have been reported in literature to date, there is no sex or race preference. It typically presents between ages of 30-50, although it may occur in infants and adults over age of 60.
Clinical description
It manifests, most commonly in the third and fourth decades of life, with headache, nausea, cerebellar dysfunction, occlusive hydrocephalus, ataxia, visual disturbances and other cranial nerve palsies. Various associated abnormalities may be present (megalencephaly, microgyria, hydromyelia, polydactyly, partial gigantism, macroglossia). Co-existing conditions include Cowden syndrome.
Etiology
The etiology is uncertain; germline mutations in tumor suppressor gene PTEN have been identified in some patients with LDD.
Diagnostic methods
Diagnosis of LDD is confirmed by magnetic resonance imaging (MRI) and genetic testing for germline PTEN pathogenic variant.
Differential diagnosis
Differential diagnosis include Cowden syndrome as LDD can co-manifest along with Cowden syndrome features.
Antenatal diagnosis
Antenatal diagnosis is possible if the pathogenic variant has previously been identified in the family, but was never described in the literature.
Genetic counseling
This is an autosomal dominant condition which may occur sporadically or in a familial form. Genetic counseling should be offered to at-risk family members to inform them of the 50% risk of transmission for each pregnancy.
Management and treatment
Management includes decompressive surgical intervention.
Prognosis
There is no data regarding the prognosis of this disease.

                            Last update:
                            December 2023

                            - Expert reviewer(s):
                             Manasadevi KARTHIKEYAN  - Dr Joanne NGEOW