Kniest dysplasia is a severe type II collagenopathy characterized by a short trunk and limbs, prominent joints and midface hypoplasia (round face with a flat nasal root).

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
The disease is apparent from birth. Cleft palate (sometimes associated with Pierre-Robin syndrome, see this term), kyphoscoliosis, premature osteoarthritis, severe myopia and deafness are common findings. Stature varies but is often severely affected. Intelligence is usually normal.
Etiology
The disease is caused by mutations in the COL2A1 gene (12q13.11-q13.2) encoding type II collagen.
Diagnostic methods
Diagnosis is made on the basis of radiologic features including large and deformed epiphyses, absence of the femoral head, enlargement of the superior metaphysis of the femur, platyspondyly and other vertebral malformations. Pathological studies of the cartilage reveal the presence of intracytoplasmic inclusions in chondrocytes and a highly vacuolated matrix.
Differential diagnosis
Forms of spondyloepiphyseal dysplasia and metatropic dysplasia (see these terms) constitute the principle differential diagnoses. In young patients, clinical and radiological features overlap with those of OSMED (see this term), but in the latter myopia is absent.
Antenatal diagnosis
Molecular prenatal diagnosis is possible for families in which the disease-causing mutation has already been identified. Micromelia may be detected during the second trimester of the pregnancy and fetal CT scan may be a useful tool for diagnosis.
Genetic counseling
The disease is transmitted as an autosomal dominant trait. Most cases are due to de novo heterozygous COL1A2 mutations but affected parents should be informed of a recurrence risk of 50%.
Management and treatment
Management is supportive only.
Prognosis
Prognosis depends on the extent of the joint malformations and vertebral anomalies

                            Last update:
                            September 2008

                            - Expert reviewer(s):
                            Dr Martine LE MERRER


A rare systemic disorder characterized by vitreoretinal and macular degeneration, as well as occipital encephalocele.

Summary:
Epidemiology
The exact prevalence of Knobloch syndrome (KS) is unknown but less than 100 cases have been reported in the literature so far.
Clinical description
KS is characterized by early-onset severe myopia (usually becoming apparent in the first year of life), vitreoretinal degeneration with retinal detachment, macular abnormalities, and midline encephalocele (mainly in the occipital region). Predisposition to hydrocephalus is frequent. Ocular abnormalities vary and may include congenital cataract, iris abnormalities, and lens subluxation. Numerous extraocular abnormalities have been described: a single umbilical artery, pyloric stenosis, a flat nasal bridge, midface hypoplasia, bilateral epicanthic folds, abnormal lymphatic vessels in the lung, patent ductus arteriosus, cardiac dextroversion, generalized hyperextensibility of the joints, unusual palmar creases, and unilateral duplication of the renal collecting system. Structural brain defects, epilepsy and cognitive abnormalities have also been frequently reported. However, the full phenotypic spectrum is yet to be defined.
Etiology
The syndrome is caused by inactivating mutations in the collagen XVIII/endostatin gene (COL18A1; 21q22.3) which is highly expressed throughout the human eye. As a mutational hot-spot the c.4063_4064delCT is the most common mutation detected in Knobloch syndrome to date. İn one reported family the locus remains unmapped.
Diagnostic methods
Diagnosis is based on ocular abnormalities and occipital encephalocele (detected by computed tomography and magnetic resonance imaging). Magnetic resonance imaging of the brain would also help to detect associated developmental brain abnormalities. Sequencing of (COL18A1) gene.
Differential diagnosis
The differential diagnosis should include the following syndromes with or without encephalocele: Stickler, Wagner, Marshall, Meckel, and Walker-Warburg syndromes.
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
Management of the ocular manifestations requires referral to an ophthalmologist specialist in retinopathies. Treatment modalities include retinal reattachment surgery, prophylactic treatment of the vitreoretinal pathology and photodynamic therapy. Encephalocele should be treated by surgical methods, aiming to restore normal anatomy with repair of the defective dura, bone and skin.
Prognosis
The eye findings in KS are severe and progressive, and regularly lead to bilateral blindness at a young age.

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Pr Ahmet CAGLAYAN


Knuckle pads-leukonychia-sensorineural deafness-palmoplantar hyperkeratosis syndrome

A rare, syndromic genetic deafness disease characterized by symmetric or asymmetric knuckle pads (typically located on the distal and interphalangeal joints), leukonychia, diffuse palmoplantar keratoderma, and congenital, mild to moderate sensorineural deafness.


Kommerell diverticulum (KD) is a developmental anomaly of the aortic arch characterized by a diverticulum at the proximal descending aorta of left or right arch configuration that gives rise to an aberrant subclavian artery. KD is primarily asymptomatic but may become symptomatic secondary to dilatation of KD, atheroma and fibrotic changes in paratracheal or paraesophageal tissue, presenting with signs of tracheal compression (more common in children), esophageal compression (dysphagia lusoria; more common in patients with a right sided aortic arch), chest pain, or blood pressure difference in the upper limbs. KD may also predispose toward aortic dissection or rupture.


A rare multisystem disorder characterized by neonatal/childhood hypotonia, mild to moderate developmental delay or intellectual disability, epilepsy, dysmorphic facial features, hypermetropia, congenital heart anomalies, congenital renal/urologic anomalies, musculoskeletal problems, and a friendly/amiable disposition.

Summary:
Epidemiology
The prevalence of this disorder is unknown; however, the prevalence of the 17q21.31 deletion is approximately 1/55,000 individuals. The prevalence of single nucleotide variants (SNVs) in KANSL1 cannot be ascertained with precision owing to the limited number of cases identified thus far. Males and females are affected equally.
Clinical description
Hypotonia is most evident between the neonatal period and infancy with poor sucking and slow feeding, but may persist throughout life. Feeding difficulties may require hospitalization and/or nasogastric tube feeding in some neonates. Tracheo/Laryngomalacia is a common feature. Global psychomotor developmental delay is noted in all individuals from an early age, although the level of developmental delay varies significantly. The majority of individuals with Koolen-de Vries syndrome (KdVS) function in the mild to moderate range of intellectual disability. Oral hypotonia and apraxia in infancy and preschool, associated with severely delayed speech development is one of the hall marks of KdVS. A history of epilepsy is noted in ~30-50% of all cases and other neurological problems may also be present. The facial dysmorphism is characterized by upslanted palpebral fissures, blepharophimosis, epicanthal folds, ptosis, a pear-shaped nose with bulbous nasal tip, and large / protruding ears. Short stature, pectus excavatum, spine anomalies, dislocation of the hip(s), long slender fingers and slender lower limbs, and positional deformities of the hands/feet have been reported. Other features include heart defects (bicuspid aortic valve, atrial and ventricular septal defects), kidney and urologic anomalies, and cryptorchidism.
Etiology
KdVS is typically a sporadic disorder caused either by a 17q21.31 deletion encompassing the KAT8 regulatory NSL complex subunit 1 (KANSL1) gene or a mutation of the KANSL1 gene.
Diagnostic methods
Molecular genetic testing approaches can include a combination of chromosomal microarray (CMA), a multigene panel, and comprehensive genomic testing (exome sequencing, exome array, genome sequencing). In individuals with normal CMA results, targeted Sanger sequencing of the KANSL1-gene testing can be considered based on the clinical findings.
Differential diagnosis
Differential diagnoses include Prader-Willi syndrome in the neonatal period and 22q11.2 deletion syndrome, fragile X syndrome, Angelman syndrome and blepharophimosis-intellectual disability syndrome, SBBYS type in older patients.
Antenatal diagnosis
Almost all cases correspond to a single occurrence in a family, but prenatal testing can be offered for at risk pregnancies.
Genetic counseling
Genetic counseling should be proposed to parents of affected individuals. Whilst almost all affected individuals represent simplex cases (i.e., a single affected individuals in the family) with a very small risk of sibling recurrence, the pattern of inheritance is autosomal dominant and thus the risk to offspring of affected individuals inheriting KdVS is 50%
Management and treatment
Affected individuals should have routine examinations by the primary care physician and pediatrician. Cardiac investigations, and kidney and urologic evaluations are warranted. Speech production requires intensive motor speech treatment in preschool years and language development requires focused intervention and augmentative (sign language) or alternative (communication device) support until oral speech and language develops. Regular check up by a dermatologist can be considered in case of multiple nevi. Referral to other specialists is indicated if neurological or other systemic problems are suspected.
Prognosis
Longitudinal data are insufficient to determine life expectancy, although survival into adulthood is typical, autonomy is likely to be limited and affected individuals will probably require life-long support from caregivers.

                            Last update:
                            November 2019

                            - Expert reviewer(s):
                            Dr D.A. [David] KOOLEN


A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by postnatal tall stature with long hands and feet, scoliosis, distinctive dysmorphic facial features (prominent forehead, proptosis, downslanting palpebral fissures, broad nasal bridge, thin upper lip, and pointed chin), hyperelastic, thin, and fragile skin, lipodystrophy, and variable intellectual disability and neurological deterioration. Additional reported manifestations include craniosynostosis, camptodactyly, progressive flexion contractures, joint dislocation, and cerebrovascular complications, among others. Brain MRI may show extensive periventricular white matter lesions and other anomalies.


Kostmann syndrome is a rare, severe, congenital neutropenia disorder characterized by a lack of mature neutrophils (absolute neutrophil counts less than 500 cells/mm3) associated with frequent, recurrent bacterial infections (e.g. otitis media, pneumonia, sinusitis, urinary tract infections, abscesses of skin and/or liver) and increased promyelocytes in the bone marrow. Periodontal disease, as well as neurological symptoms, such as cognitive impairment, severe neurodegeneration and epilepsy, have been reported in some patients.


A rare syndromic central nervous system malformation characterized by the association of conotruncal heart defects, myelomeningocele and craniofacial dysmorphism similar to that seen in monosomy 22q11.


A rare lysosomal disorder that affects the white matter of the central and peripheral nervous systems characterized by neurodegeneration with severity depending on the age of onset (infantile, late-infantile, juvenile, adolescent and adulthood).

Summary:
Epidemiology
It has an estimated prevalence of 1/100,000 in the Northern European population (higher in certain populations) and a worldwide incidence of 1/100,000-1/250,000 live births. The infantile form is the most common form and accounts for 85-90% of cases in the Northern European population. Later-onset forms may be more common in other populations.
Clinical description
The infantile form has an onset at 2-6 months of age and is divided into 3 stages. In the first stage, symptoms include irritability, stiffness, poor head control, feeding difficulties, intermittent thumb clasp, episodes of increased temperature, and developmental delay. In the second stage, hypertonic episodes occur with opisthotonus, myoclonic seizures, developmental regression, fisting and vision deficits. In the third stage, hypotonia, blindness and deafness occur. Patients progress into a vegetative state and usually die before the age of 2-3 years, generally due to respiratory infections. In the late infantile/juvenile (1-16 years) and adult (>16 years) forms, the presenting symptoms vary greatly and progression is variable (generally slower in older patients). Patients with late infantile /juvenile onset most resemble infantile patients, while the first signs in adult forms are often weakness, gait disturbances (spastic paraparesis or ataxia), burning paresthesias, hemiplegia, and/or vision loss, with or without peripheral neuropathy. Cognitive regression is variable and often absent in adult forms. In the later-onset forms the disease progresses at a slower rate than infantile patients with some adults living until the sixth decade with mild symptoms.
Etiology
The disease is due to mutations in the  GALC gene (14q31) encoding the lysosomal enzyme galactocerebrosidase (GALC), that catabolizes the hydrolysis of galactose from galactocerebroside and galactosylsphingosine (psychosine). The accumulation of cytotoxic psychosine leads to apoptosis of oligodendrocytes and demyelination of the CNS and PNS. Rarely, infantile Krabbe disease is caused by a mutation in the PSAP gene (10q21-q22), encoding prosaposin which is necessary for GALC activity.
Diagnostic methods
Diagnosis is suspected by the clinical picture, slow nerve conduction velocity, abnormal electroencephalogram, and brain MRI revealing white matter abnormalities (demyelination, gliosis, late-stage cerebral atrophy, cerebral calcifications). It is established by enzymatic assays in leukocytes or cultured fibroblasts that reveal, in almost all cases, a deficiency of GALC activity. Biopsy of nervous tissues is not indicated for diagnosis. Mutation analysis is sometimes done to confirm the diagnosis. Newborn screening (NBS) may be available in certain regions; however additional studies are required after an initial positive test.
Differential diagnosis
Differential diagnosis includes metachromatic leukodystrophy, GM1 gangliosidosis, GM2 gangliosidosis, Canavan disease, encephalopathy due to prosaposin deficiency, X-linked adrenoleukodystrophy, Pelizaeus-Merzbacher disease and Alexander disease.
Antenatal diagnosis
Antenatal diagnosis (enzymatic assay or mutation analysis) is possible for at-risk families. If the disease-causing mutations in the family are known, pre-implantation genetic diagnosis is also possible.
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 of the 25% chance of having an affected child.
Management and treatment
Treatment is currently limited to hematopoietic stem cell transplantation in pre-symptomatic infantile patients and mildly affected late-onset patients. It has been shown to slow the progression of the disease. Most individuals predicted to have infantile Krabbe disease and treated before 4 weeks of age can live into the second decade with mostly preserved cognitive functioning, but with difficulty in walking and in expressive language.
Prognosis
Steady neurodegeneration and early death within two to three years occur in most infantile cases. In late infantile/juvenile patients, the disease is generally fatal 2-7 years after the symptoms begin. Adult-onset patients can survive many years after symptoms present.

                            Last update:
                            March 2021

                            - Expert reviewer(s):
                            Dr Paola LUZI  - Pr David WENGER


KRT1-related diffuse nonepidermolytic keratoderma

A rare, genetic, isolated diffuse palmoplantar keratoderma characterized by diffuse, mild to thick, finely demarcated hyperkeratosis of palms and soles. Additional clinical findings include knuckle pad-like keratoses on fingers, hyperkeratosis of umbilicus and areolae, diffuse dry skin, hyperhidrosis, hangnails and frequent fungal infections. Histological examination of lesions reveals orthokeratotic hyperkeratosis, acanthosis, hypergranulosis, and mild lymphocyte infiltrations in the upper dermis with no evidence of epidermolysis.


Kufor-Rakeb syndrome (KRS) is a rare genetic neurodegenerative disorder characterized by juvenile Parkinsonism, pyramidal degeneration (dystonia), supranuclear palsy, and cognitive impairment.


A rare acquired human prion disease characterized by rapidly progressive, fatal neurodegeneration, caused by the consumption of prion-containing tissue in endocannibalistic funeral rituals in Papua New Guinea until the late 1950s. After a decades-long asymptomatic period and a non-specific prodromal phase with headaches and arthralgia, the most prominent neurological feature is ataxia, in addition to other symptoms involving the cerebellum, brain stem, mid-brain, hypothalamus, and cerebral cortex, and emotional changes including inappropriate euphoria and compulsive laughter, or depression and apprehension. The last reported patient died in 2005 with an incubation period extending over four decades.


A very rare congenital contracture disorder, reported exclusively in Yup'ik Eskimos of the Kuskokwim River delta region of Alaska, characterized by multiple contractures of large joints (predominantly the knees and ankles) that present at birth or during childhood but are lifelong; deformities of the spine, pelvis and feet; and sometimes proximally or distally displaced patellae and muscle atrophy in the limbs with contractures. Additional radiological features include mild vertebral wedging, elongation of the vertebral pedicle, and clubbing of the distal clavicle. An autosomal recessive pattern of inheritance has been suggested.


A rare infectious disease caused by the kyasanura forest disease virus and clinically characterized by an initial fever, headache and myalgia that can progress to a hemorrhagic disease and that in some cases is followed by a second phase characterized by neurological manifestations.


A rare primary bone dysplasia characterized, radiologically, by short, stubby long bones, severely angulated femurs and lesser bowing of other long bones (mild, moderate or no bowing), short and wide iliac wings with horizontal acetabular roofs, platyspondyly and a narrow thorax, clinically manifesting with severe, disproportionate short stature. Regression of femora angulation is observed with advancing age.


Kyphoscoliosis-lateral tongue atrophy-hereditary spastic paraplegia syndrome

A rare complex hereditary spastic paraplegia characterized by neonatal to infantile onset of progressive spasticity in the lower limbs, hyperreflexia, tip-toe walking, pes equinus, and delayed motor developmental milestones. Kyphoscoliosis becomes evident in older patients, and most patients show atrophy of the lateral aspects of the tongue. Additional signs may include intellectual disability, language impairment, and moderate upper limb involvement.


Kyphoscoliotic Ehlers-Danlos syndrome due to FKBP22 deficiency

A rare subtype of kyphoscoliotic Ehlers-Danlos syndrome characterized by congenital muscle hypotonia, congenital or early-onset kyphoscoliosis (progressive or non-progressive), and generalized joint hypermobility with dislocations/subluxations (in particular of the shoulders, hips, and knees). Additional common features are skin hyperextensibility, easy bruising of the skin, rupture/aneurysm of a medium-sized artery, osteopenia/osteoporosis, blue sclerae, umbilical or inguinal hernia, chest deformity, marfanoid habitus, talipes equinovarus, and refractive errors. Subtype-specific manifestations include congenital hearing impairment (sensorineural, conductive, or mixed), follicular hyperkeratosis, muscle atrophy, and bladder diverticula. Molecular testing is obligatory to confirm the diagnosis.


Kyphoscoliotic Ehlers-Danlos syndrome due to lysyl hydroxylase 1 deficiency

A rare subtype of kyphoscoliotic Ehlers-Danlos syndrome characterized by congenital muscle hypotonia, congenital or early-onset kyphoscoliosis (progressive or non-progressive), and generalized joint hypermobility with dislocations/subluxations (in particular of the shoulders, hips, and knees). Additional common features are skin hyperextensibility, easy bruising of the skin, rupture/aneurysm of a medium-sized artery, osteopenia/osteoporosis, blue sclerae, umbilical or inguinal hernia, chest deformity, marfanoid habitus, talipes equinovarus, and refractive errors. Subtype-specific manifestations include skin fragility, atrophic scarring, scleral/ocular fragility/rupture, microcornea, and facial dysmorphology (like low‐set ears, epicanthal folds, down‐slanting palpebral fissures, high palate). Molecular testing is obligatory to confirm the diagnosis.


A rare systemic disease for which two subtypes exist, either related to the gene PLOD1 or FKBP22, and for which the clinically overlapping characteristics include congenital muscle hypotonia, congenital or early-onset kyphoscoliosis (progressive or non-progressive), and generalized joint hypermobility with dislocations/subluxations (in particular of the shoulders, hips, and knees). Additional features which may occur in both subtypes are skin hyperextensibility, easy bruising of the skin, rupture/aneurysm of a medium-sized artery, osteopenia/osteoporosis, blue sclerae, umbilical or inguinal hernia, chest deformity, marfanoid habitus, talipes equinovarus, and refractive errors. Gene-specific features, with variable presentation, are additionally observed in each subtype.


Kyphosis-lateral tongue atrophy-myofibrillar myopathy syndrome

A rare genetic skeletal muscle disease characterized by neonatal to childhood onset of slowly progressive muscle weakness and atrophy primarily affecting the lower limbs, joint contractures, kyphosis or lordosis of the spine, lateral tongue atrophy, and pes equinus. Progression to upper limb involvement, facial weakness, language impairment, intellectual disability, and behavioral abnormalities have been reported in addition. Muscle biopsy shows myopathic changes with increased fiber size variation, internalized nuclei, fiber atrophy, as well as rod structures and core targetoid defects.


L-2-hydroxyglutaric aciduria is a primarily neurological form of 2-hydroxyglutaric aciduria (see this term) characterized by psychomotor retardation, cerebellar ataxia and variable macrocephaly or epilepsy.

Summary:
Epidemiology
Exact prevalence and incidence of this disorder are not known but about 140 cases have been reported to date. The disorder appears to be pan-ethnic with cases reported worldwide.
Clinical description
Onset is often insidious in the first year of life. Presenting symptoms include motor retardation and epilepsy. The disease course is progressive leading to mental deterioration such as speech difficulties and motor deficits such as loss of independent walking. Most reported patients had macrocephaly. Other signs include hypotonia in the early stages and spasticity later in the course of the disease, extrapyramidal symptoms and behavioral disorders. An increased incidence of brain tumors has also been reported.
Etiology
L-2-hydroxyglutaric aciduria is thought to be caused by mutations in the L2HGDH gene (14q22.1) L-encoding mitochondrial 2-hydroxyglutarate dehydrogenase. More than 70 different mutations have been identified to date. However, several affected families did not have identifiable mutations in this gene.
Diagnostic methods
Urinary organic acid screening reveals a massive increase of 2HG, and subsequent chiral differentiation is needed establish the biochemical diagnosis of L-2-hydroxyglutaric aciduria. Diagnosis may be delayed due to the slowly progressive course of the disorder and is based on magnetic resonance imaging (MRI) or computed tomography (CT) findings, biochemical testing, and mutational analysis of the L2HGDH gene. MRI and CT findings are typically subcortical and paraventricular hyperintensities. Varying degrees of subcortical leukoencephalopathy and cerebellar atrophy have been observed.
Differential diagnosis
Urinary organic acid screening does not allow differentiation between L-2-hydroxygluratic acid and D-2-hydroxyglurac acid. Therefore, this differentiation has to be performed subsequently by a specialized laboratory.
Antenatal diagnosis
Prenatal diagnosis can be performed by mutational analysis and by the measurement of L-2-hydroxyglutaric acid in amniotic fluid.
Genetic counseling
L-2-hydroxyglutaric aciduria follows an autosomal recessive pattern of inheritance.
Management and treatment
There is currently no specific treatment for L-2-hydroxyglutaric aciduria. Supportive and symptomatic measures are therefore recommended.
Prognosis
Prognosis is poor but most patients reach adulthood.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Pr G.S. [Gajja] SALOMONS  - Dr E.A. [Eduard] STRUYS


L-Arginine:glycine amidinotransferase (AGAT) deficiency is a very rare type of creatine deficiency sydrome characterized by global developmental delay, intellectual disability, and myopathy.

Summary:
Epidemiology
Less than 20 patients have been described with AGAT deficiency to date.
Clinical description
AGAT deficiency is characterized by global developmental delay, appearing in infancy, which can be associated with language impairment and autistic behavior in some, as well as a mild to moderate intellectual disability. Progressive muscle weakness and fatigability have been reported in older patients. Seizures and failure to thrive have also been described. If creatine supplementation is administered early enough, psychomotor delay may be avoided.
Etiology
AGAT deficiency is caused by mutations in the L-arginine:glycine amidinotransferase gene (GATM) located to chromosome 15q15.1. This gene encodes AGAT, which converts arginine and glycine to ornithine and guanidinoacetate in the creatine cycle pathway.
Genetic counseling
AGAT deficiency is transmitted in an autosomal recessive manner and genetic counseling is possible.

                            Last update:
                            December 2014

                            - Expert reviewer(s):
                            Dr Sylvia STOCKLER


A rare genetic hematologic disease characterized by decreased or undetectable serum L-ferritin with otherwise normal laboratory parameters. Clinical signs and symptoms include generalized seizures, atypical restless leg syndrome, mild neuropsychologic impairment, and progressive hair loss. Asymptomatic cases have also been reported.


A rare, congenital X-linked developmental disorder characterized by hydrocephalus of varying degrees of severity, intellectual deficit, spasticity of the legs, and adducted thumbs. The syndrome represents a spectrum of disorders including: X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS), MASA syndrome, X-linked complicated hereditary spastic paraplegia type 1, and X-linked complicated corpus callosum agenesis.

Summary:
Epidemiology
L1 syndrome primarily affects males. HSAS is the most common genetic form of congenital hydrocephalus, with a prevalence of approximately 1/30,000. The prevalence and incidence of the other disorders in the spectrum are not known.
Clinical description
Presentation is commonly in the antenatal or neonatal period but, depending on the severity of condition, may present later in life with developmental delay and other neurological features such as spasticity. Affected males have varying degrees of hydrocephalus (frequently present in the prenatal period) ranging from subclinical to severe. Intellectual deficit ranges from mild to severe. Patients develop generalized hypotonia and spasticity of the legs at an early age and the condition appears to progress over time, leading to leg muscle atrophy causing a shuffling gait. Adducted thumbs are a characteristic feature of the syndrome, present in about 50% of cases. Some patients also experience seizures. A small number of patients (< 20) have been reported to have a combination of L1 syndrome and Hirschsprung disease. Female carriers may have minor features such as adducted thumbs or mild intellectual deficit but they rarely have the severe manifestations of the syndrome.
Etiology
L1 syndrome is caused by mutations in the L1CAM gene (Xq28) encoding the L1 cell adhesion molecule that is expressed mainly in the developing nervous system. More than 240 different mutations have been reported to date, possibly explaining the wide clinical spectrum. About 7% of mutations have been reported to occur de novo.
Diagnostic methods
Diagnosis in male patients is made on the basis of the characteristic clinical and neuropathologic findings and a family history consistent with X-linked transmission. Bilateral absence of the pyramids (corticospinal tract) detected by magnetic resonance imaging (MRI) or autopsy is practically a pathognomonic feature of the syndrome. The diagnosis can be confirmed by molecular genetic testing of the L1CAM gene.
Differential diagnosis
The differential diagnosis is broad. Other hydrocephalus and spastic paraplegia disorders should be ruled out. A pediatric/neurologic/clinical genetics work-up enables diagnosis of the possible individual diseases.
Antenatal diagnosis
Prenatal testing can be performed in female carriers if an L1CAM disease-causing mutation has been identified in a family member. Genetic counseling is important; fetal gender determination can be part of the prenatal workup. Fetal cells, obtained by chorionic villus sampling or by amniocentesis, can be studied for the known disease-causing mutation. Girls may be affected, and ultrasound at 20 weeks is recommended in female fetuses. Normal fetal ultrasound at 20 weeks does not however rule out the disorder: absence of hydrocephalus at this stage does not guarantee that a male fetus is not affected.
Genetic counseling
L1 syndrome is inherited in an X-linked manner. Genetic counseling should be provided to affected families. For carrier females, there is a 50% chance that male offspring will be affected; for female offspring there is 50% risk of inheriting the mutation. Carrier females may be asymptomatic or express a milder phenotype.
Management and treatment
Treatment requires a multidisciplinary team including specialists in pediatrics, child neurology, neurosurgery, rehabilitation, and medical genetics. Shunting of cerebrospinal fluid (CSF) can be carried out to lower intracranial pressure. Corrective surgery for adducted thumbs is not indicated. Monitoring should include developmental progress and neurological symptoms.
Prognosis
Hydrocephalus may result in stillbirth or death in early infancy. Prognosis is dependent on the severity of the manifestations.

                            Last update:
                            November 2020

                            - Expert reviewer(s):
                            Pr C.T.R.M. [Connie] STUMPEL | ITHACA* - Dr Y.J. [Yvonne] VOS

                                * European Reference Network


An acute arboviral infection caused by the La Crosse bunyavirus transmitted by an infected mosquito, usually observed in infants, children or adolescents (6 months to 16 years), and characterized by the onset of flulike symptoms such as fever, chills, nausea, vomiting, headache, and abdominal pain, followed by the onset of encephalitis characterized by somnolence, obtundation, and even seizures, focal neurologic signs (asymmetrical reflexes or Babinski signs), paralysis or even coma. CE can leave sequelae such as residual epilepsy and neurocognitive deficits.


A rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by hypoplasia, aplasia or atresia of the lacrimal system, anomalies of the ears with sensorineural or mixed hearing loss, hypoplasia, aplasia or atresia of the salivary glands, dental anomalies, and digital malformations. Patients present obstruction of the nasal lacrimal ducts that can lead to epiphora, and chronic conjunctivitis due to alacrimia. Aplasia or hypoplasia of the salivary glands lead to dry mouth and early onset of severe dental caries. Dental features include late tooth eruption, small and peg-shaped lateral maxillary incisors and mild enamel dysplasia. The digital features are variable and include fifth finger clinodactyly, duplication of the distal phalanx of the thumb, triphalangeal thumb, and/or syndactyly. Unilateral radial aplasia and radial-ulnar synostosis have also been reported in association.


A rare, inherited, severe, progressive myoclonic epilepsy characterized by myoclonus and/or generalized seizures, visual hallucinations (partial occipital seizures), and progressive neurological decline.

Summary:
Epidemiology
The prevalence varies: LD is seen worldwide but is more common in geographic isolates and areas with a high degree of inbreeding. In Western countries, prevalence is estimated to be below 1/1,000,000.
Clinical description
Onset occurs during adolescence, with generalised tonic-clonic or clonic-tonic-clonic seizures, action and resting myoclonus, negative myoclonus, and focal occipital seizures with transient amaurosis. The course is marked by prominent and rapid cognitive deterioration (the primary symptoms of which may precede the motor anomalies), and by the progressive increase in intensity of the seizures and myoclonus.
Etiology
LD is genetically heterogeneous. Mutations/deletions of the EPM2A gene, localised in 1995 to 6q24 (product: laforin), are found in 80% of cases. The less common EPM2B variant is localised on 6p22 (product: malin). However, these two localisations do not account for all cases of LD.
Diagnostic methods
The diagnosis of LD may be suspected on the basis of the family history, age at onset, typical appearance of symptoms, rapid worsening of cognitive function and detection of fairly typical electroencephalogram (EEG) features. It can easily be confirmed by axillary skin biopsy with detection of Lafora bodies (polyglucosan aggregates) in the sweat duct cells. Other biopsies, such as brain biopsy, are generally not necessary. Molecular biology is useful for diagnosis but the genetic heterogeneity does not allow LD to be excluded when none of the known mutations are detected.
Genetic counseling
Transmission is autosomal recessive. Genetic counselling and prenatal diagnosis are theoretically possible when the genetic anomaly has been documented in an affected member of the family.
Management and treatment
The treatment of LD with antiepileptic and antimyoclonic drugs remains purely symptomatic. Drugs that may aggravate myoclonus must be avoided. Psychological and social management is of utmost importance in LD.
Prognosis
Death occurs 4 to 10 years after onset in typical forms.

                            Last update:
                            February 2007

                            - Expert reviewer(s):
                            Dr Pierre GENTON


A rare autosomal dominant distal myopathy characterized by preferential weakness of the great toe, ankle dorsiflexor, finger extensor and neck flexor. Progression is slow with variations in age of onset, severity, weakness, cardiac, and respiratory involvement.

Summary:
Epidemiology
Worldwide prevalence is unknown. A founder variant in La Safor region (Spain) causes a local prevalence of 1/5,000. De novo variants cause 30% of cases.
Clinical description
Onset is usually from 4-5 years to the early 20s but may be in the 50s. The disease initially involves the dorsiflexors of the ankles and great toes, with foot drop causing high step walking and tripping, then spreads to finger extensors. Some patients present with neck flexion weakness. Mild involvement of the face (particularly the orbicularis oculi and oris) is frequent. Proximal and axial weakness may develop with variable severity and progression ranging from loss of ambulation in the 4th decade to symptomless old age. Exercise myalgia and backpain are occasional complaints. Atypical congenital or childhood forms with spinal rigidity, bent spine, dropped head or scapuloperoneal distribution may occur. Cleft palate, scoliosis, pes cavus, tendon contractions and calf hypertrophy may present. Cardiopathy occurs in one third of patients. Respiratory involvement is less common.
Etiology
The disease is caused by missense, deletion and insertion pathogenic variants (PVs) of the MYH7 gene (14q11), in the beta-myosin heavy chain rod domain. PVs alter the heptad amino acid repeat forming the coiled coil tail, or change its charge, hindering thick filament assembly and perturbing interaction with other sarcomeric proteins. Recent findings indicate altered myosin head function despite the PVs being in the myosin tail.
Diagnostic methods
Diagnosis is based on molecular genetic testing (exome, gene panel or Sanger sequencing). Serum creatine kinase concentration is normal to mildly increased. Electromyography demonstrates myopathy but occasional neurogenic features may mislead diagnosis. Muscle MRI grades muscle impairment and confirms the pattern of involvement with constant fatty replacement of anterior lower leg muscles and variable extension to other muscles independent of disease duration. Muscle pathology includes nonspecific myopathic/dystrophic features, type I fiber predominance and atrophy, cores or minicores, sarcoplasmic inclusions, occasional rimmed vacuoles and ragged-red fibres. Abundant fibers express both fast and slow myosin. Electron-microscopy shows focal sarcomeric disorganization, granular electrodense deposits like reducing bodies or lipofuscin material, aberrant mitochondria, and disorganized triads.
Differential diagnosis
Differential diagnosis is broad including: congenital myopathies and cardiomyopathies (RYR1 or MYH7-related); muscular dystrophies (due to PVs in LMNA/B, FHL1, SELENON, DUX4); Udd, Markesbery-Griggs, and Welander distal myopathies; GNE myopathy; distal nebulin myopathy; and neuropathy.
Antenatal diagnosis
Prenatal diagnosis may be performed using standard methods of preimplantation genetic testing or chorionic villus sampling and analysis.
Genetic counseling
Transmission is autosomal dominant. PV carriers have a 50% chance of transmitting it to their offspring.
Management and treatment
Management includes physiotherapy and lightweight ankle splinting for footdrop. Orthopedic and surgical management should be considered for scoliosis, rigid spine and tendon contractions. Annual neurologic evaluation, monitoring (electrocardiogram and echocardiogram) for cardiac involvement and spirometry for respiratory complications are recommended. There is no disease modifying therapy.
Prognosis
Life expectancy is normal for typical Laing distal myopathy. Patients with cardiac, spinal and respiratory complications should be evaluated accordingly.

                            Last update:
                            June 2024

                            - Expert reviewer(s):
                            Pr Nigel LAING  - Pr Phillipa LAMONT  - Dr Nuria MUELAS  - Pr Juan Jesús VILCHEZ PADILLA


A rare genetic systemic or rheumatologic disease characterized by infantile onset of skin anomalies (such as delayed wound healing with atrophic scars and mild alopecia with dry and brittle hair), retinal rod degeneration with night blindness, degenerative myopathy with muscle weakness, myalgia, and cramps, osteoarthritis, joint laxity, prolapse of internal organs, floating kidney syndrome, malabsorption syndrome, and hypothyroidism. The phenotype has been reported to be more severe in women than in men.


A rare genetic syndromic intellectual disability characterized by global developmental delay and speech delay, variable degrees of intellectual disability, and dysmorphic facial features (such as frontal bossing, epicanthal folds, strabismus, depressed nasal bridge, short philtrum, auricular abnormalities, micrognathia, or crowded teeth, among others). Additional reported manifestations are behavioral problems (stereotypies, aggression, anxiety, autism spectrum disorder), skeletal anomalies (scoliosis, pectus carinatum, clinodactyly of fingers and toes, among others), and seizures.

Summary:
Epidemiology
Lamb-Shaffer syndrome (LAMSHF) is a rare disorder reported in less than 100 patients worldwide. The prevalence is not known.
Clinical description
In most cases, pregnancy and delivery are unremarkable and the neonatal period is uneventful. Developmental delay (delayed independent walking and speech) and truncal hypotonia during infancy are the usual first manifestations. In older children, mild-to-moderate intellectual disability is the main clinical feature, with some patients having either more severe or milder cognitive impairment. Behavioral disturbances are frequent, including autism spectrum disorder, stereotypies, isolation, tantrums and hyperactivity. Seizures may occur but epilepsy is relatively infrequent (<10%). Height, weight and occipitofrontal circumference are within normal ranges. Mild dysmorphological features are noted in most patients, including broad/full nasal tip, thin upper lip or full lips, small jaw or chin, strabismus, long face and/or epicanthus. Optic atrophy is a rare feature. Malformations of organs are infrequent, skeletal malformations mainly involve the spine (scoliosis, thoracic kyphosis, fused cervical vertebrae).
Etiology
LAMSHF is an autosomal dominant disorder caused by haplo-insufficiency of the SOX5 gene (12p12.1) due to either a 12p12.1 microdeletion encompassing the gene or heterozygous point variants. Points variants are either truncating variants or missense variants affecting functional domains of the protein.
Diagnostic methods
LAMSHF diagnosis may be suspected on clinical presentation and confirmed by micro-array analysis (SOX5 deletion) or sequencing of SOX5 (gene panel, exome sequencing, genome sequencing).
Differential diagnosis
Many differential diagnoses may be considered, i.e. developmental disorders with mild-to-moderate intellectual disability and mild morphological features.
Antenatal diagnosis
Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Genetic counseling
The disorder is autosomal dominant and whilst most cases arise sporadically, parental mosaicism is not exceptional. Genetic counseling should be offered to i) couples with an affected child informing them that there is a risk of having another affected child, ii) affected individuals informing them that there is a 50% risk of transmission.
Management and treatment
There is no specific treatment for LAMSHF. Management of patients requires medical and social care as for other patients with intellectual disability, including special schooling, speech therapy, etc.
Prognosis
Life expectancy of individuals with LAMSHF does not seem to be affected. The functional prognosis depends on the severity of intellectual disability.

                            Last update:
                            March 2021

                            - Expert reviewer(s):
                            Dr Cyril MIGNOT | ITHACA*

                                * European Reference Network


A very rare syndrome described in four sibs of one French family and characterized by branchial dysplasia (malar hypoplasia, macrostomia, preauricular tags and meatal atresia), club feet, inguinal herniae and cholestasis due to paucity of interlobular bile ducts and intellectual deficit.


Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune, presynaptic disorder of neuromuscular transmission characterized by fluctuating muscle weakness and autonomic dysfunction frequently associated with small-cell lung cancer (SCLC).

Summary:
Epidemiology
The prevalence is estimated to be between 1/250,000- 1/333,300 worldwide.
Clinical description
The age of onset is typically over 40 years old, although it may occur at any age. LEMS is characterized by the clinical triad of proximal muscle weakness, autonomic disturbance, and depressed tendon reflexes. Tumors, mostly SCLC (see this term), are present in fifty to sixty percent of LEMS patients. Cerebellar ataxia can occur, in which case it is almost always accompanied by SCLC.
Etiology
Around 90% of LEMS patients have pathogenic antibodies against the presynaptic P/Q-type voltage-gate calcium channel (VGCC). Dysfunction or decrease in number of these channels inhibits release of acetylcholine from the presynaptic endplate, resulting in impaired neuromuscular transmission and muscle weakness.
Diagnostic methods
In addition to the classical clinical triad (although all three features are not always present), the diagnosis of LEMS is based on the detection of VGCC antibodies by using radioimmunoprecipitation assays and/or typical abnormalities of the repetitive nerve stimulation (RNS) test: a low amplitude compound muscle action potential (CMAP), a decremental response to low rate stimulation, and an incremental response to high rate stimulation or after brief exercise (postexercise facilitation). Abnormal single fiber EMG (SFEMG) can confirm a disorder of the neuromuscular junction, but is non-specific.The diagnosis of LEMS almost invariably precedes the discovery of SCLC.
Differential diagnosis
In 60% of LEMS patients, a different diagnosis was initially made such as myasthenia gravis (MG), inclusion body myositis, Guillain-Barré syndrome (GBS), amyotrophic lateral sclerosis (ALS) (see these terms), lumbar canal stenosis, early-phase Parkinson's disease and lower body parkinsonism.
Management and treatment
There is no cure for LEMS and treatment is mainly symptomatic. This includes 3, 4-diaminopyridine phosphate (DAP) which is usually well tolerated and effective. In some patients, the combination of pyridostigmine with 3,4-DAP has been suggested to have an additional positive effect. If symptomatic treatment is insufficient, immunosuppressive therapy with prednisone, alone or in combination with azathioprine, can achieve long-term control of the disorder. Plasmapheresis and high dose administration of intravenous immunoglobulins (IVIGs) have a short effect. An effective treatment against any tumor present is mandatory, both to control the tumor and to improve the clinical symptoms of LEMS.
Prognosis
In general, LEMS responds well to symptomatic and immunosuppressive treatments. However, LEMS can affect every day activities and quality of life of individual patients. Life expectancy depends on the presence of lung cancer. Without cancer, the life expectancy is considered normal. As SCLC (see this term) is a very aggressive cancer, prognosis of patients with LEMS and SCLC is often rather poor. Median survival is 17-24 months, although the amount of patients with long-standing remission or cured is approximately 20% (compared to <2% of patients with a SCLC without LEMS).

                            Last update:
                            November 2013

                            - Expert reviewer(s):
                            Dr M.J. [Maarten] TITULAER


A rare autosomal recessive congenital ichthyosis characterized by the presence of large scales all over the body without significant erythroderma.

Summary:
Epidemiology
It is the most common variant of autosomal recessive congenital ichthyosis (ARCI). Prevalence in Europe is estimated at approximately 1/100,000-1/300,000 individuals.
Clinical description
Newborns are often encased in a collodion membrane (taut, shiny, translucent membrane appearing as an extra skin layer) with ectropion and eclabium. Once the membrane has been shed (after one to two weeks), scales covering the whole body become apparent. In classic lamellar ichthyosis (LI), scales are large, dark and plate-like. Milder forms with lighter and thinner scales are possible. Contrarily to congenital ichthyosiform erythroderma (CIE), there is no significant erythroderma. Nevertheless, LI and CIE are the two extremities of the same spectrum, with many patients exhibiting intermediate phenotypes. Furthermore, patients' phenotypes may change over time or under treatment. Skin is usually itchy or painful (with cracks), mobility can be reduced due to skin stiffness over the joints, and cutaneous barrier function is impaired, which can result in increased transepidermal water loss and a proneness to dehydration. Other associated features include: persistent ectropion and associated eye complications (keratitis, corneal scarring), nail dystrophy, scarring alopecia, palmoplantar keratoderma, failure to thrive, short stature, hypohidrosis with heat intolerance, and impaired hearing (due to the accumulation of scales in the external ear).
Etiology
LI is a genetically heterogeneous disease within the disease spectrum of autosomal recessive congenital ichthyosis (ARCI) generally due to mutations in the genes TGM1, ABCA12, ALOX12B, and NIPAL4. Most mutations are found in the TGM1 gene encoding transglutaminase 1, involved in the formation of the epidermal cornified cell envelope. ABCA12 encodes an ATP-binding cassette (ABC) transporter, involved in lipid transport, ALOX12B and NIPAL4 encode arachidonate 12(R)-lipoxygenase and ichthyn respectively and are involved in lipid metabolism. There is no clear genotype-phenotype correlation. There also exists an autosomal dominant lamellar ichthyosis with palmoplantar keratoderma due to mutations in ASPRV1, which encodes a protease involved in Filaggrin processing.
Diagnostic methods
The diagnosis is based on the clinical appearance of the skin and can be confirmed by genetic testing. Histological features include orthohyperkeratosis, a normal to slightly widened stratum granulosum, acanthosis, and papillomatosis of the epidermis. Immunohistochemistry using antibodies directed against transglutaminase 1 or transglutaminase 1 enzyme activity measurement is available in some centers. Molecular testing (such as gene panel diagnosis) is possible in national reference laboratories.
Differential diagnosis
Differential diagnosis includes syndromic forms of ichthyosis, recessive X-linked ichthyosis and semidominant ichthyosis vulgaris, and CIE in case of erythroderma.
Antenatal diagnosis
Prenatal diagnosis is based on DNA analysis of amniocentesis and chorion villus sampling materials.
Genetic counseling
Genetic counseling should be offered to the affected families.
Management and treatment
Newborns presenting with collodion baby are usually admitted to a neonatal intensive care unit for 2 to 4 weeks. In later life, management is based on daily applications of emollients and/or keratolytics. Oral retinoids are useful in severe forms. Acitretin is the only retinoid approved by the European Medical Agency (EMA). Usually dosages of 0.5 mg/kg/day are sufficient. Doses should be maintained as low as 10-25 mg/day.
Prognosis
Prognosis is variable. During the neonatal period, there is a risk of sepsis and electrolyte imbalance. The disease often remains stable throughout life, with periods of exacerbation. Life expectancy is normal after the somewhat critical neonatal period. LI has a strong impact on quality of life due to altered physical appearance, troublesome symptoms, and the many constraints due to the disease and its treatment.

                            Last update:
                            December 2022

                            - Expert reviewer(s):
                            Dr Kira SÜßMUTH | ERN-Skin*

                                * European Reference Network


Laminin subunit alpha 2-related congenital muscular dystrophy

Congenital muscular dystrophy type 1A (MCD1A) belongs to a group of neuromuscular disorders with onset at birth or infancy characterized by hypotonia, muscle weakness and muscle wasting.

Summary:
Epidemiology
MCD1A represents 30-40% of congenital muscular dystrophies, with some regional variation. Prevalence is estimated at 1/30,000.
Clinical description
The disease presents at birth or in the first few months of life with hypotonia and muscle weakness in the limbs and trunk. Respiratory and feeding disorders can also occur. Motor development is delayed and limited (sitting or standing is only possible with help). Infants present with early rigidity of the vertebral column, scoliosis, and respiratory insufficiency. There is facial involvement with a typical elongated myopathic face and ocular ophthalmoplegia disorders can appear later. Epileptic attacks are possible, although they occur in less than a third of patients. Intellectual development is normal.
Etiology
MCD1A is caused by mutations in the LAMA2 gene coding for the alpha-2 laminin chain.
Diagnostic methods
Diagnosis is based on muscular biopsy, as merosin deficiency can be detected in the muscle and skin. MRI reveals diffuse abnormalities in brain white matter, typically sparing the corpus callosum, capsula interna and cerebellum. In the initial phase of the disease there is a four-fold increase in levels of serous creatine kinase.
Differential diagnosis
Differential diagnoses include other forms of congenital muscular dystrophy, linked particularly with glycosylation and alpha-dystroglycan anomalies, as well as congenital structural myopathies (central core disease, multi-minicore myopathy, centronuclear myopathy), of which the causative genes have been identified in the majority of cases (see these terms).
Antenatal diagnosis
Prenatal diagnosis is possible in the ninth week by chorionic villus sampling for evidence of merosin deficiency, and by evidence of mutation in the LAMA2 gene.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to families.
Management and treatment
Treatment is symptomatic. It consists of a multidisciplinary approach, including physiotherapists, occupational therapists and speech-language therapists, with the objective of optimizing each patient's abilities. Seizures or other neurological complications require specific treatment.
Prognosis
The prognosis of these muscular dystrophies is very severe as a large proportion of affected children do not reach adolescence. Currently, the prognosis can only be improved by attentive multidisciplinary (particularly orthopedic and respiratory) management.

                            Last update:
                            April 2009

                            - Expert reviewer(s):
                            Pr Michel FARDEAU


Laminin subunit alpha 2-related limb-girdle muscular dystrophy R23

A rare autosomal recessive limb-girdle muscular dystrophy characterized by childhood to adult onset of slowly progressive limb girdle muscular weakness, often accompanied by calf hypertrophy, and moderately elevated creatine kinase levels. Patients remain ambulatory but may variably present mild intellectual disability, seizures, migraine, or cardiopulmonary involvement. Occurrence of dilated cardiomyopathy has been reported. Brain MRI typically shows hyperintensity in T2-weighted sequences. Muscle biopsy commonly reveals dystrophic features.


Landau-Kleffner syndrome (LKS) is an age-related epileptic encephalopathy where developmental regression occurs mainly in the language domain and the electroencephalographic (EEG) abnormalities are mainly localized around the temporal-parietal regions. The term acquired epileptic aphasia describes the main features of this condition.

Summary:
Epidemiology
The prevalence is difficult to estimate because of heterogeneous definitions. The male-to-female ratio is 2:1.
Clinical description
LKS only affects children and adolescents. The age of onset is thought to range from the ages of 2-8 years. Acquired aphasia in previously normal children is the defining feature of this disorder and it usually presents as verbal auditory agnosia. Expressive aphasia follows the receptive aphasia and spontaneous speech becomes limited. Behavioral problems such as attention deficits, hyperactivity, impulsivity, and distractibility often accompany the language regression. Seizures occur in 2/3 of patients and are generally easy to control and remit spontaneously before adolescence. Approximately 1/3 of patients do not have seizures. Seizure types observed include partial motor (most common), generalized clonic and atypical absence. The disease course is progressive with spontaneous fluctuations in severity over time.
Etiology
The exact etiology is unknown. Structural brain lesions are very infrequent in LKS patients. Genetic factors may be involved, with GRIN2A (16p13.2) mutations appearing to be causal.
Diagnostic methods
Diagnosis is based on clinical (acquired aphasia) and EEG findings. EEG findings include bilateral centro-temporal, posterior temporal, and parieto-occipital spikes during wakefulness that become much more diffuse and intense during non-rapid eye movement (non-REM) sleep, leading in occasions to electrical status epilepticus in sleep (ESES). ESES is characterized by marked potentiation of epileptiform discharges during the transition from wakefulness to sleep leading to (near-) continuous, bilateral or occasionally lateralized slow spikes and waves that occur during a significant proportion of non-REM sleep. The pattern of ESES in LKS is unilateral or bilateral. A reduction of volume in language development areas of the brain may be observed with MRI volumetric analysis. As of now it is not routine clinical practice to perform genetic tests for GRIN2A in LKS, but testing is available in certain specialized centers.
Differential diagnosis
The differential diagnosis includes any epileptic syndrome with sleep potentiation of epileptiform activity such as continuous spikes and waves during sleep, Panayiotopoulos and Gastaut types of benign childhood occipital epilepsy and rolandic epilepsy (see these terms). It is important to rule out a hearing defect and/or autism that may present initially in a similar way.
Genetic counseling
An autosomal dominant transmission has been proposed in families with a GRIN2A mutation.
Management and treatment
In those with seizures, several antiepileptic drugs (AEDs) are often effective and seizure control is generally not an issue. Corticosteroids have also been linked to improvements or at least stabilization of language abilities. Subpial transections, a surgical approach that seeks to disrupt the epileptic network while preserving eloquent cortex, have been successful in selected cases. Carbamazepine, oxcarbacepine, phenytoin and phenobarbital are generally avoided due to a risk of exacerbation of epileptiform discharges of ESES. Follow-up with an audiologist is recommended and special education may be necessary.
Prognosis
The prognosis is good in regards to seizures as they are easy to control and remit spontaneously around puberty. Language outcome is characterized by a variable improvement with treatment and/or at around puberty, but without ever returning to the pre-disease state.

                            Last update:
                            April 2014

                            - Expert reviewer(s):
                            Dr Tobias LODDENKEMPER  - Dr Iván SÁNCHEZ FERNÁNDEZ


A rare, genetic skeletal dysplasia characterized by severe disproportionate short stature with mesomelic and rhizomelic shortening of the upper and lower limbs.

Summary:
Epidemiology
The exact prevalence is unknown. More than 100 cases have been described in the literature to date, with most of the patients being reported from populations with a high level of consanguinity.
Clinical description
Langer mesomelic dysplasia (LMD) is a more severe form of Léri-Weill dyschondrosteosis (LWD) and presents at birth with a severely shortened long bones of the limbs (involving both the middle and proximal segments), deformity of the humeral head, angulation of the radial shaft, carpal distortion, a short femoral neck, and absence or hypoplasia of the proximal half of the fibula. Mild hypoplasia of the mandible has been reported in some cases. In contrast to LWD, Madelung deformity is not typically present in LMD. Associated malformations are rare and intellect is normal in almost all reported LMD cases.
Etiology
LMD is inherited in a pseudoautosomal recessive manner and is associated with homozygous or compound heterozygous mutations and deletions of the Short stature HomeobOX (SHOX) gene (which maps to the pseudoautosomal region 1 (PAR1) of the sex chromosomes; Xp22.33 and Yp11.32) or of the upstream or downstream PAR1 (where SHOX enhancer elements are located). LMD is part of a spectrum of disorders (ranging from the most severe, LMD, to LWD, isolated Madelung deformity and so-called idiopathic short stature), all associated with SHOX/PAR1 anomalies. The prevalence of SHOX/PAR1 mutations is estimated at 1/1000.
Diagnostic methods
Diagnosis of LMD may be suspected on the basis of the clinical and radiologic findings and can be confirmed by molecular analysis (preferably multiplex ligation-dependent probe amplification for PAR1 deletions and DNA sequencing for point mutations, small deletions and insertions of SHOX).
Differential diagnosis
During the antenatal period differential diagnosis includes femur-fibula-ulna complex and the Reinhardt-Pfeiffer mesomelic dysplasia.
Antenatal diagnosis
LMD may be suspected by ultrasound at 20 weeks of gestation. Prenatal genetic testing is available; however, requests for testing for these disorders are uncommon but are more frequent for LMD.
Genetic counseling
Genetic counseling should be proposed and families should be informed that SHOX/PAR1 anomalies are inherited in a pseudoautosomal dominant manner. Each child of an individual with LWD has a 50% risk of inheriting the mutation. If both parents have LWD, the offspring have a 50% risk of having LWD, a 25% risk of having LMD, and a 25% risk of having neither condition. All children of an individual with LMD and an unaffected parent will present with LWD.
Management and treatment
There is no effective treatment for LMD. The symptomatic medical management of children with LMD begins at birth and continues into adulthood. Careful monitoring of height, weight, and head circumference is essential.
Prognosis
The short stature and limb deformities are severe but life expectancy is normal.

                            Last update:
                            January 2020

                            - Expert reviewer(s):
                            Dr Karen HEATH


A rare systemic disease characterized by the accumulation (usually organized in granulomas) of macrophage, bearing the features of Langerhans cells in various tissues.

Summary:
Epidemiology
Its prevalence is estimated at 1-2/100,000. More than 60% of the cases occur before age of 2. But the disease may be diagnosed in adults.
Clinical description
Bone is the most frequently affected organ (80% of cases), followed by the skin (35% of cases) and then the pituitary gland (25% of cases). However, involvement of these organs does not affect the vital prognosis. Involvement of the hematopoietic system (cytopenia), lungs and liver is much less common (15-20% of cases) but results in more severe disease. The aggressive nature of the hematological forms in young children, the long-term sequelae associated with lung and liver (sclerosing cholangitis) involvement, and the neurodegenerative manifestations (2-5% of cases) make LCH a severe disease. The disease may occur as one or several crises. It may result in aesthetic or functional sequelae with variable expression depending on the sites involved (deafness, respiratory or hepatic failure, diabetes insipidus, growth hormone deficiency, and cerebellar syndrome). In adults, the clinical picture is characterized by isolated lung disease, with a strong association with smoking.
Etiology
The origin of the LCH lesions, originally thought to be neoplastic proliferation of Langerhans cells, was found to instead be similar to proliferation of immature myeloid precursors, with activation of one gene of the MAPK/ERK pathway (most frequently BRAF) involving the macrophagic cells.
Diagnostic methods
Diagnosis of LCH usually relies on histological and immunohistochemical analysis of the affected tissues. A thoracic CT scan showing typical radiological findings may allow diagnosis in adults with isolated lung involvement.
Differential diagnosis
A large range of alternative diagnoses may be considered, depending on the associated clinical picture and radiological findings.
Management and treatment
The choice of therapeutic approach depends on the extent of disease, determined by routine examinations (clinical examination, hemogram, liver function tests, and bone and chest radiographs). Local treatment is usually effective for forms limited to one organ. In children, treatment of the systemic forms relies on the combination of corticosteroids and vinblastine. Smoking cessation is necessary for adults with lung involvement. Second-line treatments are available in specialized centers for patients with progressive disease. Given the polymorphic and chronic nature of the disease, management of LCH should be multidisciplinary. Treatment protocols for adult forms of the disease are less well established than those for patients with childhood onset. Long-term follow-up is needed for detection and management of later-onset sequelae.
Prognosis
The vital prognosis is not usually affected in childhood forms, except in cases with hematological involvement resistant to first-line therapies.

                            Last update:
                            July 2023

                            - Expert reviewer(s):
                            Dr Jean DONADIEU


A rare dendritic cell tumor characterized by an aggressive, high-grade neoplasm derived from Langerhans cells, most commonly extranodal and multifocal, involving the skin and underlying soft tissue, as well as lung, liver, spleen, and bone. Primary nodal involvement is seen in a minority of patients. Immune-phenotyping and the presence of Birbeck granules on ultrastructural examination reveal the Langerhans cell derivation of the neoplastic cells. Prognosis is generally poor.


A rare skin hamartoma characterized by at least one pigmented skin lesion present at birth of more than 20 cm (large congenital melanocytic nevus; LCMN) or 40 cm (giant; GCMN) projected adult diameter. The primary lesion is composed of mutated melanocytes and often locally disorganized epidermal annexes or dermis, and presents with an elevated risk of malignant transformation to melanoma or, more rarely, other neoplasms in skin or central nervous system.

Summary:
Epidemiology
LCMN has a prevalence of about 1/20,000, while GCMN is estimated to occur in 1/50,000 to 1/500,000 births, becoming increasingly rare as more body surface is implicated. It is present in all ethnic groups examined to date and in both genders, with a slight female predominance.
Clinical description
CMN develop during pregnancy as at least one darkly colored, circumscribed area of the skin sometimes covered with dense hair or proliferative nodules, often accompanied by multiple small satellite nevi at birth or pigmenting during early childhood (tardive nevi). Three or more ''multiple medium CMN'' present a total surface, when summed, similar to that of other LCMN but are more frequently associated with complications. The term ''CMN syndrome'' covers these additional neurological (epilepsy, hydrocephalus, neurocutaneous or diffuse leptomeningeal melanocytosis, spinal meningeal cysts or tethered spinal cord) or endocrine symptoms. All LCMN/GCMN patients present an elevated risk of pediatric melanoma and other neuroectodermal tumors of varying severity (rhabdomyosarcoma, schwannoma, malignant peripheral nerve sheath tumor, lipoma, neurofibroma).
Etiology
CMN are disorders of embryonic neural crest development caused by somatic mutations in genes involved in the MAP kinase signaling pathway. Multiple and L/GCMN are often associated with NRAS mutations while BRAF mutations are more frequent in small to medium CMN. BRAF-mutated GCMN may be linked to higher frequency of co-morbidities (vascular malformations or benign proliferative nodules). No strict phenotype-genotype relationship has been confirmed, and further genetic heterogeneity is supported by rare reports of other activating mutations, fusion events or duplications in these and other pathway genes.
Diagnostic methods
Diagnosis is clinical, based on size, delimitation, depth and location of the lesions. Magnetic resonance imaging (MRI) and neurological evaluations are also performed in order to screen for complications. Pigmentation is darkest at the epidermal surface, in contrast to dermal (''blue'') nevi. When malignant transformation is suspected, biopsy is necessary.
Differential diagnosis
Differential diagnoses include Becker nevus syndrome, malignant melanoma, neurofibroma, nevus of Ota, Spitz nevus, blue nevus, epidermal nevus and congenital smooth muscle hamartoma.
Antenatal diagnosis
Reported cases of antenatal diagnosis are unusual.
Genetic counseling
CMN is nearly always sporadic despite rare familial reports (in siblings and cousins).
Management and treatment
Regular periodic dermatological follow-up is necessary. In some cases, excision may be advisable by an experienced plastic surgeon. Dermabrasion, curettage and laser treatments are inferior to full-thickness removal or to simple surveillance. Neurological involvement requires a multidisciplinary approach. Psychological support should be proposed to affected patients and families.
Prognosis
Most patients have normal lives. The incidence of complications increases with nevus size. Malignant transformation may occur at any age with no correlation to sun exposure, in approximately 2-3% of multiple and LCMN patients, and up to 5% of GCMN patients. Prophylactic surgery is not known to reduce cancer risk.

                            Last update:
                            August 2023

                            - Expert reviewer(s):
                            Dr Heather ETCHEVERS


This syndrome is characterized by severe growth retardation associated with immunodeficiency.

Summary:
Epidemiology
Less than 10 cases have been described in literature.
Clinical description
The patients present typical clinical and biochemical features of Laron syndrome such as post-natal growth retardation, delayed bone age and facial dysmorphism (prominent forehead, hypoplastic nasal bridge), and low serum IGF-1 concentrations with normal or high GH concentrations. Immunodeficiency is characterized by moderate lymphopenia which leads to recurrent infections of the skin and respiratory tract. Severe chronic lung disease, chronic diarrhea, juvenile idiopathic arthritis (see these terms), generalized eczema, pulmonary infections and respiratory distress have already been described.
Etiology
The syndrome is due to mutation in the signal transducer and activator of transcription 5b gene (STAT5b). Transmission is autosomal recessive. There have been reports of STAT5b mutations resulting in Laron symptoms but not associated with immunodeficiency.

                            Last update:
                            February 2010

                            - Expert reviewer(s):
                            Pr Juliane LEGER


Laron syndrome is a congenital disorder characterized by marked short stature associated with normal or high serum growth hormone (GH) and low serum insulin-like growth factor-1 (IGF-I) levels which fail to rise after exogenous GH administration.

Summary:
Epidemiology
The disease has been described in more than 250 cases and is more frequent in Semitic or Mediterranean populations. Males and females are equally affected.
Clinical description
Intrauterine growth and birth size are usually normal. Postnatal growth is slowed and generally disproportional with delayed bone age; adult stature ranges from -3 to -12 SD. Motor development is delayed because of diminished muscle mass. Newborns often present with hypoglycemia and a micropenis. Puberty is often delayed. Facial dysmorphism is common and includes protruding and high forehead, shallow orbits, hypoplastic nasal bridge and small chin. Sparse hair may be observed in infancy. Relative obesity, delayed tooth eruption, high-pitched voice, thin bones and skin, and decreased sweating are often present. Patients occasionally have blue sclera and hip degeneration.
Etiology
The disease is due to mutations in the GHR gene (5p14-p12). Mutations affecting the extracellular domain of the growth hormone receptor result in low growth hormone binding protein levels (GHBP, structurally identical to the extracellular domain of GHR) and defective IGF-I production. A Laron syndrome-like phenotype has been described which is associated with immunodeficiency and is due to gene dysfunction of the signal transducer and activator of transcription 5b (STAT5b deficiency; see this term). A mutation in STAT5B has also been observed in a patient suffering from typical Laron syndrome.
Diagnostic methods
Diagnosis is based on clinical and biological findings. Hormonal tests reveal normal or increased level of GH and low IGF-1 levels, which fail to rise after exogenous GH administration. GHBP levels are low in cases with mutations in the extracellular domain of the GHR and normal in cases with mutations in the intracellular domain. Genetic tests should be performed to make a precise etiological diagnosis.
Differential diagnosis
The differential diagnosis should include severe growth hormone deficiency (GHD) and growth delay due to IGF-I resistance (see this term), as well as secondary IGF-I deficiency mostly due to nutritional problems or chronic pediatric diseases.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be proposed to parents of an affected individual before any further pregnancy, informing them of the risks and the available diagnostic methods.
Management and treatment
Management aims at improving growth and includes treatment with daily subcutaneous injections of mecasermin, recombinant human IGF-I, and diet with adequate caloric intake. Frequent feeding is necessary in order to avoid hypoglycemia. In August 2005, mecasermin was granted EC orphan drug designation. There is no treatment that cures or prevents the disease.
Prognosis
Prognosis seems good but with age, patients may develop obesity, hypercholesterolemia and have increased risk of fractures due to osteopenia.

                            Last update:
                            November 2009

                            - Expert reviewer(s):
                            Pr Juliane LEGER


An orofacial clefting syndrome characterized by congenital dislocation of large joints, foot deformities, cervical spine dysplasia, scoliosis, spatula-shaped distal phalanges and distinctive craniofacial abnormalities, including cleft palate.

Summary:
Epidemiology
Larsen syndrome (LS) birth prevalence is estimated to be less than 1 in 100,000 in Europe.
Clinical description
Primary clinical characteristics of LS are congenital dislocations of hip, knee and elbow joints with equinovarus or equinovalgus foot deformities (club feet). Other frequent manifestations include spinal deformities such as scoliosis and cervical spine kyphosis, sometimes associated with cervical myelopathy and short, broad, spatula-shaped distal phalanges with the thumb almost always affected. Recurrent craniofacial abnormalities include a prominent forehead, depressed nasal bridge, flattened midface and ocular hypertelorism. Midline cleft palate and conductive hearing loss have also commonly been reported.
Etiology
The syndrome is due to missense mutations or small in frame deletions in the FLNB gene (localized to 3p14.3) that encodes cytoskeletal protein filamin B.
Diagnostic methods
Diagnosis is established by clinical assessment, and skeletal X-rays displaying, amongst other factors, supernumerary carpal and tarsal bone ossification centers and is confirmed by genetic testing.
Differential diagnosis
Differential diagnosis includes other more severe and lethal FLNB-related disorders: atelosteogenesis type I, atelosteogenesis type III and boomerang dysplasia as well as otopalatodigital syndrome type I and spondyloepiphyseal dysplasia, CHST3 type; chondrodysplasia with joint dislocations, gPAPP type; Larsen-like syndrome, B3GAT3 type; Reunion island's Larsen syndrome and Desbuquois syndrome.
Antenatal diagnosis
Prenatal diagnosis is available for those with a family history of LS.
Genetic counseling
LS is transmitted in an autosomal dominant manner. The autosomal recessive cases reported in the past may perhaps correspond to parental germline mosaicism, but are more likely to represent more recently defined recessive syndromes with similar but still distinct presentations. Genetic counseling should be proposed to individuals having the disease causing mutation informing them that there is 50% risk of passing the mutation to offspring.
Management and treatment
Management should be adapted to each patient and may involve orthopedic treatment and monitoring, surgical procedures, especially for hip dislocation, and physiotherapy. In case of hearing loss, a multidisciplinary team with pediatric expertise is recommended. It is essential that all infants with a clinical diagnosis of LS have their cervical spine evaluated as soon as practicable after birth to exclude life threatening cervical spine instability.
Prognosis
LS does not affect life expectancy.

                            Last update:
                            December 2019

                            - Expert reviewer(s):
                            Pr Stephen ROBERTSON  - Dr Emma WADE


Larsen-like osseous dysplasia-short stature syndrome is a rare primary bone dysplasia characterized by a Larsen-like phenotype including multiple, congenital, large joint dislocations, craniofacial abnormalities (i.e. macrocephaly, flat occiput, prominent forehead, hypertelorism, low-set, malformed ears, flat nose, cleft palate), spinal abnormalities, cylindrical fingers, and talipes equinovarus, as well as growth retardation (resulting in short stature) and delayed bone age. Other reported clinical manifestations include severe developmental delay, hypotonia, clinodactyly, congenital heart defect and renal dysplasia.


Larsen-like syndrome, B3GAT3 type is a rare, genetic, primary bone dysplasia characterized by laxity, dislocations and contractures of the joints, short stature, foot deformities (e.g. clubfeet), broad tips of fingers and toes, short neck, dysmorphic facial features (hypertelorism, downslanting palpebral fissures, upturned nose with anteverted nares, high arched palate) and various cardiac malformations. Severe disease is associated with multiple fractures, osteopenia, arachnodactyly and blue sclerae. A broad spectrum of additional features, including scoliosis, radio-ulnar synostosis, mild developmental delay, and various eye disorders (glaucoma, amblyopia, hyperopia, astigmatism, ptosis), are also reported.


Laryngeal abductor paralysis-intellectual disability syndrome

A rare X-linked syndromic intellectual disability characterized by congenital and permanent vocal cord paralysis causing severe congenital laryngeal stridor, associated with intellectual disability in male patients. Other presenting symptoms may include weak cry, cough, cyanosis, neonatal asphyxia, feeding difficulty, aspiration, and bronchiectasis. Microcephaly, tone abnormalities, visual and hearing impairment may also be associated features.


A rare head and neck tumor characterized by an epithelial neoplasm with evidence of neuroendocrine differentiation, typically located in the supraglottic larynx. The tumor can be well, moderately, or poorly differentiated, the latter group being subdivided into small cell or large cell neuroendocrine carcinomas. There is a strong association with tobacco use. Patients present with hoarseness, dysphagia, sore throat, airway obstruction, hemoptysis, and rarely a paraneoplastic syndrome due to aberrant hormone production. Poorly differentiated tumors are highly aggressive with high rates of regional and distant metastasis.


LOC syndrome is a subtype of junctional epidermolysis bullosa (JEB, see this term) characterized by an altered cry in the neonatal period and by aberrant production of granulation tissue in particular affecting the upper airway tract, conjunctiva and periungual/subungual sites.

Summary:
Epidemiology
Prevalence is unknown. Fewer than 50 cases have been reported to date, mostly in consanguineous families from the Punjabi region of Pakistan and India.
Clinical description
The condition is present at birth. Characteristic cutaneous findings are transient blisters leaving slowly healing erosions with exuberant granulation tissue formation, mainly localized to the head and neck, hands, feet, elbows and knees. Extracutaneous manifestations are always observed: the progressive laryngeal involvement frequently leads to fatal respiratory obstruction in infancy, and the chronic conjunctival lesions cause symblepharon formation, and also total palpebral occlusion and blindness. Enamel hypoplasia is also always present and nail dystrophies are common.
Etiology
The condition is associated with mutations in the alpha-3 chain of laminin-332 (LAMA3).
Genetic counseling
LOC syndrome follows an autosomal recessive pattern of inheritance.
Prognosis
Prognosis is poor.

                            Last update:
                            October 2012

                            - Expert reviewer(s):
                            Pr Giovanna ZAMBRUNO


A rare congenital laryngeal anomaly characterized by an abnormal dilation of the laryngeal saccule that is filled with air, maintains communication with the laryngeal lumen, and is either confined to the false vocal fold or extends upward, protruding through the thyrohyoid membrane to the neck. Symptoms may include cough, hoarseness, stridor, sore throat and uni- or bilateral swelling of the neck. Blockage of the laryngocele neck can result isn laryngomucocele, and forms laryngopyocele when infected.


Laryngo-tracheo-esophageal cleft (LC) type 0 is a congenital respiratory tract anomaly characterized by a submucosal laryngo-tracheo-esophageal cleft with minor symptoms or an asymptomatic course.

Summary:
Epidemiology
Prevalence of this form of LC is difficult to ascertain because of the mild or asymptomatic nature of the condition, but it is thought to be rare.
Clinical description
Subjects with type 0 LC may have no obvious symptoms or mild symptoms such as occasional aspirations. Syndromic associations may be present.
Etiology
The causes underlying development of this anomaly are unknown.
Diagnostic methods
The anomaly is often detected during endoscopy indicated for other reasons.
Management and treatment
No specific treatment is required.

                            Last update:
                            November 2011

                            - Expert reviewer(s):
                            Pr Noël GARABEDIAN  - Pr Nicolas LEBOULANGER


A congenital respiratory tract anomaly characterized by a supraglottic, interarytenoid cleft above the vocal folds with moderate respiratory symptoms.

Summary:
Epidemiology
Prevalence of this form of LC is difficult to ascertain because of the moderate nature of the condition, but it is thought to be rare.
Clinical description
Clinical signs include stridor, a toneless or hoarse cry, swallowing disorders such as aspirations, cough, dyspnea, cyanosis during feeding and gastro-esophageal reflux.
Etiology
The causes underlying development of this anomaly are unknown.
Management and treatment
In children with mildly symptomatic type 1 LC, management includes maintaining adequate ventilation, feeding with thickened food, treatment of gastro-esophageal reflux, and maintaining a postprandial upright position. Children with moderate symptoms may also benefit from nasogastric tube feeding. Treatment initially involves conservative measures such as anti-reflux therapy, thickened feeds, and maneuvers during feeding to prevent aspiration. In cases of failure of a conservative approach, surgical correction of the cleft, using an endoscopic treatment approach, is recommended.

                            Last update:
                            November 2011

                            - Expert reviewer(s):
                            Pr Noël GARABEDIAN  - Pr Nicolas LEBOULANGER


A congenital respiratory tract anomaly characterized by a cleft extending below the vocal folds into the cricoid cartilage, with swallowing disorders and lung infections.

Summary:
Epidemiology
Prevalence of this form of LC is unknown, but it is thought to be rare.
Clinical description
Patients most often have aspirations and severe respiratory and swallowing disorders. Dyspnea and stridor are also possible.
Etiology
The causes underlying development of this anomaly are unknown.
Management and treatment
Management includes anti-reflux treatment and nasogastric tube feeding. Treatment involves surgical correction of the cleft, often using an endoscopic treatment approach.

                            Last update:
                            November 2011

                            - Expert reviewer(s):
                            Pr Noël GARABEDIAN  - Pr Nicolas LEBOULANGER


A congenital respiratory tract anomaly characterized by a cleft extending through the cricoid cartilage, sometimes into the cervical trachea, with severe swallowing disorders, lung infections and pulmonary damage.

Summary:
Epidemiology
Prevalence of this form of LC is unknown, but it is thought to be very rare. To date, about 30 cases have been reported in the literature. .
Clinical description
Patients have constant aspirations and severe respiratory and swallowing disorders with a high risk of pulmonary infection.
Etiology
The causes underlying development of this anomaly are unknown.
Management and treatment
Parenteral nutrition may be required temporarily in patients with high-grade LCs due to the high risk of aspirations. High-grade LCs often require a mid- to long-term gastrostomy, often with fundoplication. Treatment involves surgical correction of the cleft, often requiring an external approach.
Prognosis
The prognosis in this type of LC is poor.

                            Last update:
                            November 2011

                            - Expert reviewer(s):
                            Pr Noël GARABEDIAN  - Pr Nicolas LEBOULANGER


A serious congenital respiratory tract anomaly characterized by a cleft extending into the thoracic trachea and possibly down to the carina, with respiratory distress.

Summary:
Epidemiology
Prevalence of this form of LC is difficult to ascertain because of the extremely poor prognosis and death before diagnosis, but it is thought to be very rare. Fewer than 20 cases have been reported in the literature to date.
Clinical description
Patients have constant aspirations and serious life-threatening respiratory and swallowing disorders, often associated with other severe cardiopulmonary malformations.
Etiology
The causes underlying development of this anomaly are unknown.
Management and treatment
Parenteral nutrition may be required temporarily in patients with high-grade LCs due to the high risk of aspirations. High-grade LCs often require a mid- to long-term gastrostomy, often with fundoplication. Gastric division with a proximal drainage tube and distal gastrotomy have also been proposed. Treatment involves surgical correction of the cleft, often requiring an external cervical and/or thoracic approach, sometimes with cardiopulmonary bypass.
Prognosis
The prognosis in this type of LC is very poor.

                            Last update:
                            November 2011

                            - Expert reviewer(s):
                            Pr Noël GARABEDIAN  - Pr Nicolas LEBOULANGER


A laryngo-tracheo-esophageal cleft (LC) is a congenital malformation characterized by an abnormal, posterior, sagittal communication between the larynx and the pharynx, possibly extending downward between the trachea and the esophagus.

Summary:
Epidemiology
The estimated annual incidence of LC is 1/10,000 to 1/20,000 live births, accounting for 0.2% to 1.5% of congenital malformations of the larynx. These incidence rates may however be underestimated due to difficulty in diagnosing minor forms and a high mortality rate in severe forms. A slightly higher incidence has been reported in boys than in girls. No specific geographic distribution has been found.
Clinical description
Depending on the severity of the malformation, patients may present with stridor, hoarse cry, swallowing difficulties, aspirations, cough, dyspnea and cyanosis through to early respiratory distress. Five types of laryngo-tracheo-esophageal cleft have been described based on the downward extension of the cleft, which typically correlates with the severity of symptoms: Type 0 laryngo-tracheo-esophageal cleft to Type 4 laryngo-tracheo-esophageal cleft (see these terms). LC is often associated with other congenital abnormalities/anomalies (16% to 68%), mainly involving the gastro-intestinal tract, which include laryngomalacia, tracheo-bronchial dyskinesia, tracheo-bronchomalacia (mostly in types 3 and 4), and gastro-esophageal reflux disease (GERD). The syndromes most frequently associated with an LC are Opitz/BBB syndrome, Pallister Hall syndrome, VACTERL/VATER association, and CHARGE syndrome (see these terms).
Etiology
Laryngeal clefts result from failure of fusion of the posterior cricoid lamina and abnormal development of the tracheo-esophageal septum. The causes of the embryological developmental anomalies leading to LC are not known but are thought to be multifactorial.
Diagnostic methods
The age of diagnosis depends mainly on the severity of the clinical symptoms and therefore on the extent of the LC. Diagnosis is made either based on clinical manifestations or on investigations, such as endoscopy, X-ray, CT scan, performed for other conditions.
Differential diagnosis
Differential diagnoses include tracheo-bronchial fistula, gastro-esophageal reflux disease and neurological swallowing disorders, as well as laryngomalacia and laryngeal palsy.
Antenatal diagnosis
Prenatal diagnosis of LC has never been reported, although associated anomalies may be detected on fetal ultrasonography.
Genetic counseling
LC appears to be mostly sporadic although some familial cases with suspected autosomal dominant transmission have been reported.
Management and treatment
Once the cleft is diagnosed, it is essential to determine its length to orient the management and treatment approach. Management involves maintenance of satisfactory ventilation, prevention of secondary pulmonary complications as a result of repeated aspirations, and adequate feeding. Endotracheal intubation may be required for respiratory distress in severe cases. Treatment requires endoscopic or external surgery to close the cleft. Surgery should be performed as early as possible to avoid complications related to aspiration and gastric reflux, except in type 0 and type 1 cases in which conservative measures must first be attempted.
Prognosis
The prognosis is variable depending on the severity of the LC and associated malformations. Early diagnosis and appropriate treatment and management help to reduce mortality and morbidity.

                            Last update:
                            November 2011

                            - Expert reviewer(s):
                            Pr Noël GARABEDIAN  - Pr Nicolas LEBOULANGER


A rare larynx anomaly characterized by complete absence of the laryngeal lumen resulting in congenital upper airway obstruction syndrome which, without fetal or neonatal intervention, is incompatible with life. Fetal sonography shows a dilated trachea, hyperechoic lungs, pleural effusion, minimal fetal abdominal ascites or hydrops, and amniotic fluid abnormalities.


Lassa fever (LF) is a potentially severe viral hemorrhagic disease caused by Lassa virus and characterized by initial fever and malaise followed by gastrointestinal symptoms and, in severe cases, bleeding, shock and multi-organ system failure.

Summary:
Epidemiology
LF is endemic in West Africa. Lack of surveillance prohibits accurate estimates of incidence, but estimates range up to 300,000-500,000 infections and 5,000-10,000 cases of LF per year. Up to 80% of infections are thought to be asymptomatic or mild.
Clinical description
After an incubation period of 1-3 weeks (range 3-21 days), patients typically present with the insidious onset of non-specific signs and symptoms including fever, sore throat, malaise, headache, chest pain and myalgia/arthralgia, followed rapidly by gastrointestinal manifestations (vomiting, diarrhea, abdominal pain) and, in some cases, rash. In the second week, severe cases develop neck and facial swelling, bleeding (usually from the nose and mouth), neurologic involvement, shock and multi-organ system failure. Mild-to-moderate leukopenia and thrombocytopenia are often present. Deafness is a sequelae in up to 30% of survivors.
Etiology
Over 25 different viruses cause viral hemorrhagic fever. LF is caused by Lassa virus, a member of the virus family Arenaviridae. Lassa virus is maintained in nature in the multimammate rat (Mastomys natalensis) and humans are infected through exposure to this rodent's excreta. Human-to-human transmission occurs through direct contact with blood or bodily fluids of infected persons.
Diagnostic methods
Common diagnostic modalities include cell culture (restricted to biosafety level-4 laboratories), serologic testing by enzyme linked immunosorbent assay (ELISA) or indirect fluorescent antibody (IFA), and reverse transcription polymerase chain reaction (RT-PCR). Because no commercial assays are presently available, these tests are typically performed only in a few specialized laboratories.
Differential diagnosis
LF is difficult to distinguish from a host of other febrile illnesses, at least during its onset. Other viral hemorrhagic fevers need to be excluded, as well as malaria, typhoid fever, leptospirosis, rickettsial infection (see these terms), and meningococcemia.
Management and treatment
Patients should be isolated and viral hemorrhagic fever precautions (face shields, surgical masks, double gloves, surgical gowns, and aprons) should be used to prevent nosocomial transmission. The nucleoside analogue drug ribavirin should be administered intravenously. Oral ribavirin may also be effective but is less so than the IV form. Otherwise, treatment generally follows the guidelines for severe septicemia. Anti-malarials and broad spectrum antibiotics should be considered until the diagnosis of LF can be confirmed. Persons who had unprotected contact with someone with LF should be monitored and post-exposure treatment with oral ribavirin considered.
Prognosis
The case-fatality rate in hospitalized patients is typically 15-20%. Shock, bleeding, neurological manifestations, high viremia, aspartate aminotransferase (AST > 150 IU/L) and pregnancy confer a poor prognosis.

                            Last update:
                            December 2012

                            - Expert reviewer(s):
                            Dr Daniel BAUSCH  -  Andrew BENNETT


A form of citrullinemia type I characterized clinically by adult onset of symptoms including variable hyperammonemia and less striking neurological findings which may include intense headache, scotomas, migraine-like episodes, ataxia, slurred speech, lethargy and drowsiness. Serious increased intracranial pressure may occur.


Late-onset distal myopathy, Markesbery-Griggs type

A rare, genetic, non-dystrophic myofibrillar myopathy disorder characterized by late-adult onset of distal and/or proximal limb muscle weakness with initial involvement of posterior lower leg muscles, medial gastrocnemius and soleus. Patients present with ankle weakness followed by weakness of finger and wrist extensors and later on of proximal muscles. Ambulation is usually preserved. Late-onset associated cardiomyopathy and/or neuropathy has been reported in a minority of cases.


A rare form of familial hypoaldosteronism characterized by adult onset of subnormal plasma aldosterone with elevated plasma renin activity, hyperkalemia, metabolic acidosis, and hypotension. Signs and symptoms are typically mild, and affected individuals may be clinically asymptomatic and diagnosed only after biochemical screening.


Late-onset focal dermal elastosis is a rare, acquired, dermis elastic tissue disorder characterized by a pseudoxanthoma elasticum-like papular eruption consisting of multiple, slowly progressive, asymptomatic, 2-5 mm, white to yellowish, non-follicular papules (that tend to form cobblestone plaques) predominantly distributed over the neck, axillae and flexural areas, with no systemic involvement. Skin biopsy reveals a focal increase of normal-appearing elastic tissue in the reticular dermis with no calcium deposits.


Late-onset isolated ACTH deficiency is a rare, acquired, pituitary hormone deficiency characterized by secondary adrenal insufficiency, with normal secretion of anterior pituitary hormones, except for ACTH. Patients present with weakness, fatigue, weight loss, anorexia, vomiting/nausea, hypoglycemia, and abnormally low serum ACTH and cortisol levels. Association with autoimmune disease such as Hashimoto's thyroiditis has been described.


Late-onset junctional epidermolysis bullosa

A form of junctional epidermolysis bullosa characterized by onset in childhood or young adulthood of blistering that first occurs around nails, accompanied by nail dystrophy and shedding, and then affects the hands and feet and, to a lesser extent, the elbows, and knees. Lesions heal with atrophic scarring. Other manifestations include disappearance of dermatoglyphs and palmoplantar hyperhidrosis. Extracutaneous involvement is restricted to soft tissue abnormalities of the oral cavity and enamel defects with development of caries.