Juvenile myasthenia gravis (MG; see this term) is a rare form of MG, an autoimmune disorder of the neuromuscular junction resulting in ocular manifestations or generalized weakness, with onset before 18 years of age.

Summary:
Epidemiology
The exact prevalence and incidence of juvenile MG are not known. Estimated incidence has been reported at 1/1,000,000 to 1/200,000. The disorder is uncommon in Europe and North America (10% to 15% of cases of myasthenia gravis; see this term). In the Asian population, a much higher proportion of cases (up to 50%) with mainly ocular manifestations occurs in children below 15 years of age.
Clinical description
Onset may be prepubertal (before 12 years of age) or postpubertal (over 12 years). The hallmark of MG is fatigable muscle weakness. Initial presentation may be acute or subacute, and the course is usually chronic with remission and relapses. Prepubertal children more commonly have the ocular presentation (fatigable ptosis, ophthalmoplegia, and diplopia) while postpubertal patients more often develop generalized weakness. The proportion of patients having only ocular symptoms is higher than in adult MG, particularly in the prepubertal group in which half of cases are purely ocular. In generalized cases, manifestations include facial weakness, dysarthria, and dysphagia. In severe cases (myasthenic crisis), respiratory muscle involvement may be life-threatening and require respiratory support. Thymoma (see this term) development is rare in juvenile MG.
Etiology
The exact pathogenesis is not known but MG is related to circulating antibodies to various muscle receptors, including, in most of patients, acetylcholine receptor (AChR) and, rarely, muscle-specific receptor tyrosine kinase (MuSK). The thymus is thought to trigger antibody production in the form with anti-AChR antibodies. In the prepubertal form, there is a high rate of the MG form with no antibodies detectable (30-50%). It is currently unknown whether anti-LRP4 antibodies could be found in these patients. The disorder can also be drug-induced.
Diagnostic methods
The diagnosis is primarily clinical and is suspected on the basis of fatigable muscle weakness. Specific serum antibody tests, including acetylcholine antibody test, are diagnostic. Other tests that support diagnosis include repetitive nerve stimulation and single-fiber electromyography. Edrophonium testing has been used and involves administration of this short-acting cholinesterase inhibitor intravenously. The test is positive if there is a rapid but transient improvement in a monitored clinical sign (usually ptosis). Computed tomography (CT) or magnetic resonance imaging (MRI) should be used to screen for thymoma.
Differential diagnosis
Congenital myasthenic syndrome (CMS; see this term) should be considered in case of seronegativity.
Management and treatment
Acetylcholinesterase inhibitors (pyridostigmine) are recommended as first-line treatment in juvenile MG and may be sufficient in ocular forms. Corticosteroids, azathioprine, mycophenolate mofetil, cyclosporine, and cyclophosphamide have been used in children with refractory MG, but adverse effects limit their usefulness. Plasmapheresis and intravenous immunoglobulin (IVIg) can also be used, mainly in severe exacerbation or myasthenic crisis, and pre- or postoperatively in the context of thymectomy. Thymectomy has been recommended for the treatment of generalized juvenile MG in patients not responding to anticholinesterase treatment, nor immunomodulatory or immunosuppressive treatments. Age at thymectomy is debated.
Prognosis
Severe cases may be life-threatening, but the prognosis is generally very good. In the prepuberal form, there is a higher rate of remission in patients with the ocular form.

                            Last update:
                            October 2014

                            - Expert reviewer(s):
                            Dr Sonia BERRIH-AKNIN  - Pr Bruno EYMARD


A rare myelodysplastic/myeloproliferative neoplasm characterized by a proliferation primarily of granulocytic and monocytic lineages with infiltration of the liver and spleen, among other organs. Blasts and promonocytes account for less than 20% of white blood cells in peripheral blood and bone marrow. Erythroid and megakaryocytic abnormalities are often present. BCR-ABL1 fusion is absent, while somatic mutations in genes of the RAS pathway or monosomy 7 may be found. The condition may also occur in the context of neurofibromatosis type 1 or Noonan syndrome-like disorder. Children of less than three years are predominantly affected, with a clear male preponderance. Most patients present with constitutional symptoms, signs of infection, and hepatosplenomegaly.


Juvenile myoclonic epilepsy is the most common hereditary idiopathic generalized epilepsy syndrome and is characterized by myoclonic jerks of the upper limbs on awakening, generalized tonic-clonic seizures manifesting during adolescence and triggered by sleep deprivation, alcohol intake, and cognitive activities, and typical absence seizures (30% of cases).


Juvenile nasopharyngeal angiofibroma (JNA) is a rare and benign but locally aggressive fibrovascular tumor arising from the posterolateral wall of the nasopharynx, which affects mainly young and adolescent males (onset usually occurring between 7-19 years of age) and that presents as a mass in the nasopharynx and nasal cavity, leading to manifestations such as nasal obstruction, epistaxis, profound facial swelling, proptosis or diplopia. Although slowly progressive, it has a high rate of recurrence and sometimes invades adjacent structures.


A subtype of cystinosis characterized by an accumulation of cystine in different organs and tissues, particularly in the kidneys and eyes, and that clinically manifests between childhood and adolescence with a slowly progressive proximal tubulopathy and/or proteinuria, and photophobia. Extra-renal manifestations (e.g. hypothyroidism, insulin-dependent diabetes, hepatosplenomegaly, muscular and cerebral involvement) are less severe than in the infantile form of the disease.


A rare juvenile idiopathic inflammatory myopathy characterized by the association of inflammatory myositis (manifesting with acral erythema, progressive weakness of the limbs, pain, general fatigue, moodiness or crankiness) with clinical and/or laboratory features of other autoimmune diseases (e.g. systemic lupus erythematosus, localized scleroderma, diabetes). Cardiac involvement has been reported in some patients.


Juvenile Paget disease is a very rare form of Paget disease of the bone characterized by a general increase in bone turnover with increased bone resorption and deposition, resulting in cortical and trabecular thickening, and clinically presenting as progressive skeletal deformities, growth impairment, fractures, vertebral collapse, skull enlargement and sensorineural hearing loss.


A rare type of juvenile idiopathic inflammatory myopathy (IIM) characterized by an onset before 18 years of age of chronic skeletal muscle inflammation, manifesting as progressive, proximal and distal muscle weakness and atrophy.


Juvenile polyposis of infancy (JPI) is the most severe form of juvenile gastrointestinal polyposis (see this term) and is characterized by pancolonic hamartomatous polyposis from stomach to rectum, diagnosed in the first two years of life.

Summary:
Epidemiology
Prevalence is unknown but only 11 cases have been described in the literature so far.
Clinical description
The digestive phenotype is severe and life-threatening, with gastrointestinal bleeding, diarrhea, inanition and exudative enteropathy. Early death has been reported and the risk of cancer in surviving children has not yet been clearly established. Signs of the Cowden or Bannayan-Riley-Ruvalcaba (BRRS) syndromes (see these terms) such as macrocephaly, lipomas, and hemangioblastomas can be observed. Dysmorphic signs, such as a large forehead, hypertelorism, down-slanting palpebral fissures, a flat nasal bridge, low-set ears, and a small mouth and chin, have also been described. Mild intellectual deficit has been reported in some cases. Recently, a less severe form of JPI has been described in several patients with early-onset gastrointestinal tract juvenile polyps but with a mild digestive phenotype.
Etiology
The majority of cases are caused by a large deletion in the chromosome 10q23 region, encompassing the PTEN and BMPR1A genes. The hypothesis is that the severe digestive phenotype results from a cooperative effect of the deletion of each gene. However, this hypothesis is under debate as the patients with the mild digestive phenotype were also found to harbor a deletion of the PTEN and BMPR1A genes.
Diagnostic methods
Diagnosis may be suspected on the basis of the clinical picture and digestive endoscopy investigation but is confirmed by detection of the 10q23 deletion. This deletion is rarely detected through karyotype analysis, and FISH or Array-CGH, followed by semiquantitative PCR methods (QMPSF, MLPA, MP/LC), are required to define the length and the location of the deletions.
Differential diagnosis
The differential diagnosis should include the allelic disorders Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome, which are caused by mutations in the PTEN gene, as well as familial adenomatous polyposis and Peutz-Jeghers syndrome (see these terms).
Genetic counseling
JPI appears to be sporadic.
Management and treatment
Management revolves around colonoscopy with endoscopic polypectomy. Early endoscopic polypectomy may reduce morbidity by reducing the risk of the cancer, bleeding, or intestinal obstruction.
Prognosis
However, as JPI is life-threatening and colectomy is generally necessary in infancy, the prognosis during infancy is severe and the survival rate is generally low. The prognosis for surviving children depends on the risk of gastrointestinal tract cancer.

                            Last update:
                            December 2008

                            - Expert reviewer(s):
                            Dr Capucine DELNATTE  - Pr Damien SANLAVILLE  - Pr Dominique STOPPA-LYONNET


A rare condition characterized by the presence of juvenile hamartomatous polyps in the gastrointestinal (GI) tract.

Summary:
Epidemiology
Annual incidence is estimated at between 1/100,000 and 1/15,000.
Clinical description
Polyps may develop at any age from infancy through to adulthood, with most affected individuals presenting polyps by adolescence/early adulthood. A diagnosis of JIP is made on the basis of one or several of the following findings: the presence of more than five juvenile polyps in the colon and/or rectum; the presence of juvenile polyposis throughout the digestive tract, including the stomach; the presence of any number of juvenile polyps in association with a family history of JIP. Several types of JIP have been described, including three forms that differ on the basis of the location of the polyps (generalized juvenile polyposis of the upper and lower GI tract, juvenile polyposis coli and juvenile polyposis of the stomach) and a more severe infantile form, juvenile polyposis of infancy (see this term). Regardless of the subtype, the clinical signs of JIP are isolated rectal bleeding, anemia, abdominal pain, intussusceptions and diarrhea. Rectal prolapse and spontaneous anal elimination of polyps have been noted in juvenile polyposis coli and generalized juvenile polyposis. Other associated signs may include growth delay and edema.
Etiology
JIP is transmitted in an autosomal dominant manner and mutations in the SMAD4 (18q21.1) and BMPR1A (10q22.3) genes have been associated with the disease. However, no genetic anomalies have been identified so far in around 60% of the cases. A few genotype-phenotype correlations have been established: the frequency of gastric polyposis is higher in SMAD4 carriers than in BMPR1A carriers and the association of JPS with hereditary hemorrhagic telangiectasia (juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome) is observed in just under a quarter of SMAD4 mutation carriers.
Diagnostic methods
Diagnosis is based on the clinical findings, family history, endoscopic findings and histological analysis of the polyps. Molecular genetic testing may also be useful for confirming the diagnosis in carriers of SMAD4 and BMPR1A gene mutations.
Differential diagnosis
The differential diagnosis should include other syndromes associated with polyposis including Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome, familial adenomatous polyposis and Peutz-Jeghers syndrome (see these terms).
Management and treatment
Management should involve routine colonoscopy and if the number of polyps remains low endoscopic polypectomy is the gold standard for treatment. Due to the risk of cancer and polyposis extension, surgical colectomy associated with protectomy and ileoanal anastomosis may also be proposed.
Prognosis
The prognosis of JIP is based on the risk of developing GI or pancreatic cancer after 20 years of age. The cumulative risk for developing cancer in patients with JIP is 20% at the age of 35 years and 68% after the age of 60 years. The risk of cancer is higher among individuals with generalized juvenile polyposis.

                            Last update:
                            January 2009

                            - Expert reviewer(s):
                            Pr Frédérique SAUVAT


A very rare motor neuron disease characterized by progressive upper motor neuron dysfunction leading to loss of the ability to walk with wheelchair dependence, and subsequently, loss of motor speech production.

Summary:
Epidemiology
The prevalence and incidence of JPLS are not known. A very small number of cases have been reported to date with this condition. The disorder has been described in various ethnic groups.
Clinical description
Affected patients are usually normal at birth and have normal early development. During the second year of life, they lose the ability to walk (some patients never walk due to early severe spasticity) and then develop slowly progressive upper motor neuron disorders including pseudobulbar palsy and spastic quadriplegia. Other signs include clumsiness, muscle weakness and balance difficulties. Patients generally become wheelchair dependent by adolescence. Between 2 and 10 years of age, motor speech production is lost causing dysarthria, dysphagia and drooling. Cognitive function is generally not affected.
Etiology
Mutations in the ALS2 gene (2q33-q35) encoding alsin, a protein that is abundant in motor neurons, and less commonly mutations in the ERLIN2 gene (8p11.2) have been reported.
Diagnostic methods
Diagnosis is based on the characteristic clinical signs and can be confirmed by molecular genetic testing. Electromyography, nerve conduction velocities, visual evoked potentials, and brain stem auditory evoked potentials are all normal, while transcranial magnetic stimulation shows no motor evoked potentials. Computed tomography (CT) and magnetic resonance imaging (MRI) scans of the brain and spinal cord are normal.
Differential diagnosis
Differential diagnoses include the allelic disorders juvenile amyotrophic lateral sclerosis and infantile-onset ascending hereditary spastic paralysis (see these terms).
Antenatal diagnosis
Prenatal diagnosis for at-risk pregnancies is possible if the disease-causing mutations have been identified in the family.
Genetic counseling
JPLS is inherited in an autosomal recessive manner. The parents of an affected individual are obligate heterozygotes and are therefore asymptomatic carriers. Genetic counseling should be provided to affected families.
Management and treatment
Management primarily involves physical and occupational therapy to promote mobility and independence.
Prognosis
The prognosis is guarded, with the clinical signs having a major impact on quality of life.

                            Last update:
                            February 2014

                            - Expert reviewer(s):
                            Pr Enrico BERTINI


A rare vasculitis characterized by mostly unilateral inflammation of the temporal artery affecting patients up to fifty years of age. Patients typically present with a lump in the temporal region or a prominent temporal artery and often have headaches. Males are more frequently affected than females, and major systemic symptoms, ocular complications, and a biological inflammatory syndrome are usually absent, although peripheral blood eosinophilia may be seen. Histopathological analysis shows arteritis predominantly of the intima with possible extension to the perivascular tissue. The presence of granuloma, giant cells or fibrinoid necrosis is rare. Clinical relapses after one episode are uncommon.


Juvenile xanthogranuloma is the most common type of non-Langerhans cell histiocytosis (see this term) characterized by the occurrence of one or more reddish or yellowish self-limiting and benign papules or nodules of several millimeters in diameter, usually appearing on the head and neck (but sometimes on the extremities and trunk) during the first year of life (or rarely in adulthood) and usually regressing spontaneously. Extracutaneous involvement has also been reported, involving most commonly the eye (uveal tract) but with other locations including the central nervous system, lung, liver, bones and endocrine glands, and may be associated with considerable morbidity.


Juvenile-onset diabetes mellitus-central and peripheral neurodegeneration syndrome

A rare genetic disease characterized by juvenile-onset insulin-dependent diabetes mellitus associated with central and peripheral nervous system abnormalities with variable onset between infancy and adolescence. Neurological manifestations include combined cerebellar and afferent ataxia, sensorineural hearing loss, pyramidal tract signs, and demyelinating sensorimotor peripheral neuropathy. Hypothyroidism has been reported in some patients. Brain imaging may show generalized cerebral atrophy.


Juxtaposition of the atrial appendages is a rare atrial appendage anomaly when both appendages are located on the left or the right side of the great arteries. It is asymptomatic and is usually diagnosed incidentally, but is frequently associated with other congenital heart diseases.


A rare multiple congenital anomalies/neurodevelopmental disorder characterized by five major features: intellectual disability (typically mild to moderate), visceral malformations (frequently congenital heart defects), persistence of fetal fingertip pads, post-natal short stature, skeletal anomalies (brachymesophalangy, brachydactyly V, spinal column abnormalities and fifth digit clinodactyly) and specific facial features (arched and broad eyebrows, long palpebral fissures, eversion of the lower eyelid, large prominent, cupped ears, depressed nasal tip and short columella). Various additional features are frequently observed.

Summary:
Epidemiology
The prevalence of Kabuki syndrome (KS) is estimated at 1/32000 birth and seems a frequent etiology in malformed fetus.
Clinical description
Presentation is typically with neonatal/infantile hypotonia and feeding difficulties (affecting more than 70%). KS associates developmental delay and intellectual disability in 90% of patients. Intellectual disability is frequently mild to moderate; however, the spectrum ranges from normal intellect to severe disability. Verbal language acquisition and memory are usually better than visuospatial or processing speed. Individuals with KS usually achieve walking and language milestones. Heart malformations are observed in around 50% of patients. Kidney malformations, deafness, and seizures of different types are observed in 20%. Immune deficiency and recurrent infection are frequent. Autoimmune features increase with age affecting around 20% of the adults with KS. Scoliosis and patellar luxation require frequent screening and should be monitored carefully at puberty. Missing teeth are frequently observed. Obesity could arise from the age of 5 and requires monitoring. Growth hormone deficiency is observed in 25-30%. Premature thelarche occurs in 30% of females.
Etiology
KS is usually due to de novo pathogenic variants in about 70% of patients fulfilling the diagnostic criteria. For the majority of patients (56% to 75%), KS is due to mutations in KMT2D (12q13.12) and for the minority of patients (5%), KS is due to mutations in KDM6A (xp11.2).
Diagnostic methods
Diagnosis is evoked on clinical examination, and confirmed using genetic studies.
Differential diagnosis
Differential diagnosis includes CHARGE, 3MC, and Hardikar syndromes, KAT6B-related disorders, and other genetic disorders involving chromatin regulation.
Antenatal diagnosis
For parents of an index individual, detection of KS by amniocentesis in subsequent pregnancies should be discussed. KS could be identified using exome sequencing during pregnancy screening for malformative syndromes.
Genetic counseling
Transmission of KMT2D-related KS is autosomal dominant; however, in most situations, the pathogenic variants arise de novo and thus the risk of sibling recurrence is low. The estimated recurrence risk to siblings is 1% based on the possibility of parental germline mosaicism. Transmission of KDM6A-related KS is X-linked with males slightly more affected than females.
Management and treatment
Management requires a lifelong multidisciplinary approach. Regular follow-up by a clinical geneticist, pediatrician, psychologist/psychiatrist, speech therapist, physiotherapist and ophthalmologist will have a major impact. Feeding difficulties may require tube feeding (nasogastric or gastrostomy). Developmental assessments are required in order to tailor medical services to each individual's needs. Other specialists can be required, such as a cardiologist, gastroenterologist, nephrologist, immunologist, ENT (ear, nose and throat) or stomatologist. Special attention is need for fine graphomotor and visuals difficulties.
Prognosis
The prognosis is usually good. A specific survey is required for autoimmune and kidney problems. Autonomy may be limited and affected individuals will sometimes require life-long support from caregivers.

                            Last update:
                            September 2020

                            - Expert reviewer(s):
                            Pr David GENEVIEVE | ITHACA*

                                * European Reference Network


Kagami-Ogata syndrome is a rare genetic disease characterized by polyhydramnios (mostly due to placentomegaly), fetal macrosomia, abdominal wall defects, skeletal abnormalities (including bell-shaped thorax, coat-hanger appearance of the ribs and decreased mid to wide thorax diameter ratio in infancy), feeding difficulties and impaired swallowing, dysmorphic features (hairy forehead, full cheeks, protruding philtrum, micrognathia), developmental delay and intellectual disability. Additional features may include kyphoskoliosis, joint contractures, diastasis recti, muscular hypotonia. There is increased risk of hepatoblastoma.


Kallmann syndrome-heart disease syndrome

Kallmann syndrome with cardiopathy is characterised by hypogonadotropic hypogonadism associated with gonadotropin-releasing hormone (GnRH) deficiency, anosmia or hyposmia (with hypoplasia or aplasia of the olfactory bulbs) and complex congenital cardiac malformations (double-outlet right ventricle, dilated cardiomyopathy, right aortic arch). It represents a distinct clinical entity from Kallmann syndrome.

Summary:
Epidemiology
Less than 10 cases have been described so far.
Etiology
The aetiology is unknown but both autosomal recessive and dominant modes of inheritance, de novo mutations and a teratogenic origin have been suggested.

                            Last update:
                            September 2007


Kallmann syndrome (KS) is a developmental genetic disorder characterized by the association of congenital hypogonadotropic hypogonadism (CHH) due to gonadotropin-releasing hormone (GnRH) deficiency, and anosmia or hyposmia (with hypoplasia or aplasia of the olfactory bulbs).

Summary:
Epidemiology
The prevalence is estimated at 1/8,000 males and 1/40,000 females, but is probably underestimated.
Clinical description
Most cases are diagnosed at the time of puberty due to lack of sexual development, but KS may also be suspected in infancy in males with cryptorchidism, micropenis or associated non reproductive signs. The main clinical features consist of the absence of complete spontaneous puberty and a partial or total impairment of the sense of smell (anosmia) in both sexes. Untreated adult males usually have decreased bone density and muscle mass, decreased testicular volume (< 4 mL), erectile dysfunction, diminished libido and infertility. Untreated adult females almost always experience primary amenorrhea with absent, little or normal breast development. Rare presentations include unilateral (occasionally bilateral and lethal at birth) renal agenesis, hearing impairment, cleft lip or palate, dental agenesis or bimanual synkinesis persisting beyond childhood.
Etiology
KS is caused by impaired development of the olfactory system and disrupted embryonic migration of the GnRH-synthesizing neurons from the olfactory epithelium to the hypothalamic region of the brain. The majority of reported cases are sporadic but familial forms have been described. Causative genes include: KAL1 (Xp22.32), in the X-linked recessive form, FGFR1 (8p12), FGF8 (10q25-q26), CHD7 (8q12.2) and SOX10 (22q13.1) in the AD form, and PROKR2 (20p12.3) and PROK2 (3p21.1), in both the AR and oligogenic forms. More evidence is needed to determine if other genes (ex: SEMA3A), presumably involved in KS, are indeed causal.
Diagnostic methods
Diagnostic methods consist of hormone evaluation (sex steroids, gonadal peptides and pituitary gonadotropin dosage), as well as evaluation of the sense of smell (olfactometry). Morphological analysis of the olfactory bulbs by MRI can be useful, especially in young children. Genetic testing can identify a disease causing mutation, and is mandatory before starting infertility treatment.
Differential diagnosis
Differential diagnoses include isolated congenital gonadotropin deficiency and CHARGE syndrome (see these terms).
Antenatal diagnosis
In a familial context of FGFR1, FGF8, KAL1, or CHD7 mutations, bone abnormalities, cleft lip/palate, renal agenesis, or multiple developmental defects can be found in the fetus by ultrasonography.
Genetic counseling
Genetic counseling should be adapted to each family, taking into account the potential mode of inheritance (AD/AR, X-linked, or presumably oligogenic) and the great variability in clinical expression, even within the same family, as well as the risk, in sporadic cases, of neomutations.
Management and treatment
Hormonal replacement therapy is used to induce puberty, and later, fertility. Testosterone esters are usually used and sometimes human chorionic gonadotropin (hCG) injections in combination with follicle-stimulating hormone (FSH) or in monotherapy are given to males to achieve normal virilization and increased testicular volume. In adults combined gonadotropin therapy is mandatory to stimulate spermatogenesis. In females, estrogen is administered to induce breast development and genital development along with progestin to establish endometrial cyclicity. Pulsatile GnRH administration or exogenous gonadotropins are used to induce folliculogenesis and ovulation and therefore to restore fertility. There is currently no treatment for anosmia.
Prognosis
KS is not a life threatening disease. With hormonal treatment, pubertal feminization or virilization occurs in all patients. Fertility, when desired, is achieved in most cases but cryptorchidism has a poor prognosis in males.

                            Last update:
                            June 2013

                            - Expert reviewer(s):
                            Dr Jean-Pierre HARDELIN  - Pr Jacques YOUNG


Kandori fleck retina is a rare, genetic retinal dystrophy disorder characterized by irregular, sharply defined, yellowish-white lesions of variable size that are distributed mainly in the nasal equatorial region of the retina, with a tendency to confluence, that are not associated with any vascular or optic nerve abnormalities. They frequently manifest as mild and stationary night blindness.


A rare vascular tumor that is characterized by human herpes virus 8 (HHV-8)-induced endothelial inflammatory neoplasm that develops with various clinically distinct settings, manifesting mostly as cutaneous lesions, or mucosal or visceral involvement.

Summary:
Epidemiology
More than 100 million people worldwide are infected with HHV-8, with a heterogeneous geographic distribution (high in Africa and the Mediterranean). Only a very small proportion of those infected with HHV-8 develop KS. Incidence in Europe is reported to be about 1/300,000.
Clinical description
HHV-8 infection is asymptomatic in the vast majority of cases. In some clinical contexts, the risk of developing Kaposi sarcoma (KS) is much higher, giving rise to four subtypes: Classic KS, African endemic KS, iatrogenic immunodepression KS, and AIDS-related KS. Cases affecting otherwise healthy people with no manifest immunological deficit except ''immunosenescence'' are known as classic KS (mostly reported in the Mediterranean basin) and African endemic KS (reported in sub-Saharan Africa) which affects primarily children and middle-aged men. Iatrogenic KS is mostly found in recipients of solid organs. Lastly, AIDS-related KS affects mainly homosexual men. A fifth subtype has been recently identified affecting non HIV infected homosexual men. Skin lesions manifest as solitary, localized or disseminated patches, or macular/papular eruptions, which progress to nodular plaques or lesions on any area of the skin. Progression is highly variable with lesions at different stages possibly occurring in the same individual. Lymph node and visceral involvement may be found in some forms especially iatrogenic and AIDS-KS. The oral cavity and the gastrointestinal tract (GI) are frequently affected. Pulmonary involvement is less common but may be life-threatening. Lymphedema of the face, genitalia and lower extremities may be found especially in classic and endemic KS. Some rare patients do not present skin lesions.
Etiology
All known forms of KS are caused by HHV-8 infection. The exact routes of HHV-8 transmission are currently unknown but both sexual and non-sexual modes are suspected. The highest levels of HHV-8 shedding are found in saliva.
Diagnostic methods
KS is usually diagnosed on the basis of disseminated skin lesions, sometimes with lymph node and visceral involvement. Skin biopsy reveals neoangiogenesis and proliferating spindle-shaped cells, admixed with a variable chronic inflammatory infiltrate. Immunohistochemistry using monoclonal antibody against latent protein of HHV-8 is useful to differentiate KS from other angioproliferative tumors. Imaging techniques may be required to identify systemic disease but there is no consensus on systematic explorations.
Differential diagnosis
The differential diagnosis may include bacillary angiomatosis, hemosiderotic hemangioma, fibrous histiocytoma, interstitial granuloma annulare, arteriovenous malformations, and pyogenic granuloma.
Management and treatment
No specific treatment recommendations have been established. Treatment depends on the KS type and presence of localized or systemic involvement. The main aim of treatment is to restore immunity. Rapamycin or everolimus can be used in organ transplant recipients, and discontinuation or reduction of immunosuppressive therapy is recommended. Antiretroviral therapy should be systematically prescribed in KS-AIDS to prevent or reduce lesions. For localized lesions, radiotherapy, topical gels (alitretinoin), intralesional injections (vinblastine or bleomycin), surgery, or cryotherapy can be used. Visceral involvement generally requires systemic therapy with antiproliferative agents (taxanes and liposomal anthracyclins or interferon alpha 2b). Use of steroids should be avoided in patients with KS.
Prognosis
KS ranges from an indolent disorder to an aggressive disease with significant morbidity and mortality. It is generally not life-threatening in most forms, but may have major psychosocial implications and significant impact on quality of life.

                            Last update:
                            May 2019

                            - Expert reviewer(s):
                            Pr Nicolas DUPIN


A rare low-grade malignant cutaneous or visceral vascular tumour that may be associated with severe thrombopaenia with consumption coagulopathy (Kasabach-Merritt syndrome) in pediatric patients.

Summary:
Epidemiology
The prevalence is unknown.
Clinical description
Kaposiform haemangioendothelioma may develop at any age, but is most common during infancy. Congenital forms have also been described. Depending on the initial site of development, the vascular tumours present as sensitive blue-purple infiltrated plaques, palpable masses or as a tumour compression syndrome (retroperitoneal, severe cervical or mediastinal forms). The majority of reported cases concern the complicated visceral forms. Superficial forms appear to be less common. Cutaneous forms show clinical similarities to tufted angiomas, or graft on to diffuse lymphatic malformations (lymphangiomas). Osseous and regional lymph node involvement has been reported but metastasis does not appear to be a feature of this disease.
Etiology
The etiology is unknown.
Diagnostic methods
The diagnosis is based on the results of histological studies (after definition of the boundaries by magnetic resonance imaging, MRI), which reveal nodules and dense nests of fusiform cells with slight cellular atypia and mitotic activity, frequent slit-like vascular spaces and positive immunostaining for the D2-40 lymphatic marker.
Differential diagnosis
The differential diagnoses include Kaposi's sarcoma and tufted angioma. The clinical similarities with tufted angioma, the association of both conditions with Kasabach-Merritt syndrome and the histological features of these syndromes have led to the suggestion that kaposiform haemangioendothelioma and tufted angioma are part of the same clinical spectrum of vascular tumours.
Antenatal diagnosis
Prenatal diagnosis is possible for voluminous forms of kaposiform haemangioendothelioma through detection of highly vascularised masses on foetal ultrasound, followed by foetal MRI. However, precise diagnosis of the tumour type can only be made by biopsy after the birth.
Management and treatment
Treatment depends of the form of disease present: treatment of non-complicated cutaneous forms differs from that for forms associated with Kasabach-Merritt syndrome. Non-complicated cutaneous forms presenting as relatively small lesions may be treated by local corticotherapy, whereas diffuse invalidating forms may require alpha 2b-interferon therapy or vincristine administration. Therapeutic options for forms associated with Kasabach-Merritt syndrome include pharmacological treatment (systemic corticotherapy, vincristine, alpha 2b-interferon, polychemotherapy and a combination of ticlopidine, asprin and pentoxyphilline), embolisation, surgical excision and radiotherapy.
Prognosis
The prognosis depends on the chronicity of the lesions and extent of the complications (severity of the form present and association with Kasabach-Merritt syndrome).

                            Last update:
                            September 2006

                            - Expert reviewer(s):
                            Dr Odile ENJOLRAS


A rare vascular anomaly or angioma characterized by multifocal malformed lymphatic channels lined by clusters or sheets of spindled lymphatic endothelial cells with a predilection for the thoracic cavity, but also involving extra-thoracic locations, especially bones and spleen. Typical clinical signs and symptoms are pericardial and pleural effusions, cough, dyspnea, bleeding, and fractures secondary to bone involvement. Prognosis is generally poor due to the progressive nature of the condition.


Kapur-Toriello syndrome is an extremely rare syndrome characterized by facial dysmorphism, severe intellectual deficiency, cardiac and intestinal anomalies, and growth retardation.

Summary:
Epidemiology
Only four cases have been reported in the literature, in three unrelated families.
Clinical description
Dysmorphic features include bilateral cleft lip and palate, bulbous nasal tip and eye anomalies.
Genetic counseling
The condition seems to be inherited as an autosomal recessive trait.

                            Last update:
                            February 2010


Karsch-Neugebauer syndrome is a rare syndrome characterized by split-hand and split-foot deformity and ocular abnormalities, mainly a congenital nystagmus.

Summary:
Epidemiology
Ten cases from four families have been reported in the literature.
Clinical description
In some cases the hands are monodactylous. The affected patients have normal mental development.
Genetic counseling
The condition seems to be autosomal dominant with a relatively high proportion of gonadal mosaicism.

                            Last update:
                            September 2010


A rare, genetic renal disease characterized by slowly progressive, chronic, tubulointerstitial nephritis, leading to end-stage renal disease before the age of 50 years, manifesting with mild proteinuria, glucosuria and, occasionally, urinary sediment abnormalities (mainly hematuria). Mild extrarenal manifestations, such as recurrent upper respiratory tract infections and abnormal liver function tests, may be associated. Renal biopsy reveals severe, chronic, interstitial fibrosis and tubular changes, as well as hallmark karyomegalic tubular epithelial cells which line the proximal and distal tubules and have enlarged, hyperchromatic nuclei.


A rare hemorrhagic disorder characterized by potentially life-threatening thrombocytopenia, microangiopathic hemolytic anemia, and consumptive coagulopathy in the context of kaposiform hemangioendothelioma or tufted angioma.


A rare inflammatory disease characterized by an acute febrile, systemic, self-limiting, medium-vessel vasculitis primarily affecting children. It often causes acute coronary arteritis which is associated with coronary arterial aneurysms (CAA) that may be life threatening when untreated.

Summary:
Epidemiology
Although it has been reported worldwide, Kawasaki disease (KD) is over-expressed among Asian populations. In Europe, the annual incidence for children under 5 years of age ranges between 1/6,500-20,500. The disease is the most common cause of acquired heart disease in children in developed countries.
Clinical description
Median age of onset is 2 years (with 75% of patients being under 5 years old). Fever (greater than 39 degrees C) that persists for greater than 5 days when untreated is a constant feature. Children are usually very irritable. Additional typical manifestations of KD include extremity changes (erythema and edema of palms and soles that desquamate after 2-3 weeks, usually seen in the subacute phase), polymorphic skin rash (maculopapular, urticarial, or scarlatiniform rash), lymphadenopathy (cervical, often unilateral, greater than 1.5 cm diameter), non-exudative bilateral conjunctivitis, and involvement of lips and oral mucosa (erythema, strawberry tongue, lip fissures). CAA is a life threatening complication that usually occurs in the subacute phase (6 to 8 weeks after onset) in 20-35% of untreated children. The regression of giant CAA (greater than 8 mm) is very unlikely, while minor dilations are usually transient. Atypical manifestations include myocarditis pericarditis, valvular regurgitation, hepatitis, diarrhea, abdominal pains, hydrops of gallbladder, arthralgia, arthritis, myalgia, aseptic meningitis, sensorineural hearing loss, urethritis and sterile pyuria. KD is a risk factor for ischemic heart disease in adulthood.
Etiology
Etiology is unknown but several pathogenic theories have been proposed (e.g. infection by a toxin-secreting microorganism and a superantigen-driven process). Genetics appear to play a major role, and the disease is much more common in Asian populations. Genome-wide studies have identified single nucleotide polymorphisms which would confer increased susceptibility to the disease and to its complications.
Diagnostic methods
Diagnosis is clinical. Complete KD is defined by fever and 4/5 of the standard clinical criteria (extremity changes, polymorphous rash, conjunctival injection, changes in lips and oral cavity, and cervical lymphadenopathy greater than 1.5 cm diameter). Incomplete KD can be diagnosed in case of prolonged fever, 2-3/5 standard criteria, and specific signs of coronary disease, particularly CAA when other causes of coronary vasculitis are excluded. Laboratory findings (elevated inflammatory markers and liver enzymes, neutrophilia and thrombocytosis), though non-specific, are supportive. At diagnosis, patients must be investigated for coronary involvement via transthoracic echocardiography.
Differential diagnosis
Differential diagnosis includes autoimmune and autoinflammatory diseases (e.g. systemic-onset JIA), bacterial infections (i.e. bacterial toxic shock syndrome, leptospirosis, adenophlegmon), viral infections (i.e. measles, enterovirus, Epstein-Barr virus), and toxin or drug reactions.
Management and treatment
Early administration of intravenous immunoglobulin (IVIg) reduces the rate of coronary abnormalities to less than 5% of patients. IVIg is administrated at a single dose of 2 g/kg before the 10th day of onset, or even later if persistent inflammation. In case of treatment failure, IVIg readministration, corticosteroids, anakinra and infliximab may be considered as second line treatments. Aspirin (30-50 mg/kg/day) are usually given in the febrile phase, followed by low (antiplatelet) doses (3-5 mg/day) for 6-8 weeks. Following diagnosis, coronary involvement is monitored at 2 weeks and 6-8 weeks by transthoracic echocardiography.
Prognosis
Non-complicated cases resolve without sequelae, while patients with persistent CAA are at risk for major cardiovascular events and their long-term outcome may be complicated by premature ischemic heart disease.

                            Last update:
                            February 2020

                            - Expert reviewer(s):
                            Pr Rolando CIMAZ  - Dr Caroline GALEOTTI  - Dr Teresa GIANI  - Pr Isabelle KONE-PAUT


A rare congenital malformation syndrome characterized by a typical facial dysmorphism, macrodontia of the permanent upper central incisors, short stature, skeletal anomalies, developmental delay and behavioral abnormalities.

Summary:
Epidemiology
The prevalence is unknown. More than 150 cases have been reported to date. ANKRD11 is one of the most frequently muted gene in patients with neurodevelopmental disorders diagnosed by whole exome sequencing.
Clinical description
KBG syndrome (KBGS) manifests in childhood with global developmental delay with short stature, mild-to-moderate intellectual disability, characteristic facies, macrodontia of the permanent upper central incisors and skeletal anomalies. Behavioral disturbances including hyperactivity, aggressiveness, attention deficit and autism spectrum disorders are recognized as constant clinical features. Developmental delay includes delayed motor milestones and markedly delayed speech and is almost always present in all patients. Characteristic facial dysmorphism is prominent in about half of the patients, consisting of triangular face, wide eyebrows with mild synophrys, hypertelorism, prominent ears and nasal bridge with bulbous nasal tip, long flat philtrum and thin upper lip. The hallmark feature, macrodontia, is observed in about 80% of cases; additional dental findings include oligo- or hypodontia, premature teeth loss in adults and enamel hypoplasia. Height below the 10th centile is observed in about two-thirds of cases. The most frequent skeletal anomalies are brachydactyly and fifth finger clinodactyly. Seizures, feeding difficulties, recurrent otitis media/hearing loss, palatal abnormalities and precocious puberty are notable additional features associated with KBGS.
Etiology
KBGS is caused by loss-of function alterations (pathogenic variants and copy number variations) affecting the ANKRD11 gene (16q24.3) which encodes ankyrin repeat domain-containing protein 11. The extent of ANKRD11 functions is yet to be determined, but it has been shown to be a crucial chromatin regulator that controls histone acetylation and gene expression during neural development.
Diagnostic methods
Diagnosis is based on clinical evaluation; there is no consensus on diagnostic criteria. The diagnosis is established by cytogenetic and molecular studies including a-CGH (array-comparative genome hybridization), targeted sequencing, gene panel, whole exome or genome sequencing.
Differential diagnosis
Differential diagnosis includes Cornelia de Lange syndrome, cleidocranial dysplasia, Robinow syndrome and 22q11.2 deletion syndrome.
Genetic counseling
The pattern of inheritance is autosomal dominant. Most cases occur sporadically due to de novo mutations. Intra-familial variability of the phenotype has been noted in familial cases.
Management and treatment
Management is symptom-based and requires a multidisciplinary approach. At diagnosis, systematic echocardiogram, palatal assessment, vision, hearing and dental assessment, pediatric assessment for developmental delay, autism spectrum disorders and behavioral anomalies are recommended. Additional investigations depends on the clinical presentation. Management and follow-up include educational support, surveillance of growth and puberty, screening for hearing loss (otitis media), educational and speech therapy, and treatment of seizures when needed.
Prognosis
Despite the history of developmental delay, many patients grow into autonomous adults.

                            Last update:
                            September 2020

                            - Expert reviewer(s):
                            Pr Nicole PHILIP | ITHACA* - Dr Florence RICCARDI | ITHACA*

                                * European Reference Network


KCNQ2-related epileptic encephalopathy is a severe form of neonatal epilepsy that usually manifests in newborns during the first week of life with seizures (that affect alternatively both sides of the body), often accompanied by clonic jerking or more complex motor behavior, as well as signs of encephalopathy such as diffuse hypotonia, limb spasticity, lack of visual fixation and tracking and mild to moderate intellectual deficiency. The severity can range from controlled to intractable seizures and mild/moderate to severe intellectual disability.


KDM5C-related syndromic X-linked intellectual disability

A rare multiple congenital anomalies/dysmorphic syndrome characterized by mild to severe intellectual deficit associated with variable clinical manifestations including spasticity, cryptorchidism, maxillary hypoplasia, alopecia areata, epilepsy, short stature, impaired speech, and behavioral problems.


A rare inborn error of metabolism that is characterized by progressive external ophthalmoplegia (PEO), pigmentary retinitis and an onset before the age of 20 years. Common additional features include deafness, cerebellar ataxia and heart block.

Summary:
Epidemiology
Kearns-Sayre syndrome (KSS) exact prevalence is unknown, but has been estimated at 1/125,000.
Clinical description
The disease often presents in childhood with the hallmark ocular symptoms of ptosis, pigmentary retinopathy and PEO, followed by the progressive occurrence of several other signs, depending on the tissue distribution of the molecular anomaly. The most frequently associated features include bilateral sensorineural deafness, heart involvement (cardiomyopathy, cardiac conduction defect), central nervous system involvement (cerebellar ataxia, dysarthria, bilateral facial weakness, intellectual deficit), skeletal muscle myopathy, intestinal disorders, endocrine disorders (delayed puberty, hypoparathyroidism, diabetes), and renal failure. The disease progresses slowly, over decades, with new symptoms appearing and previous symptoms slowly worsening. A very few cases of Pearson syndrome have progressed into KSS.
Etiology
KSS is caused by deletions of large portions of mitochondrial DNA (mtDNA), resulting in the loss of genes involved in the oxidative phosphorylation pathway. Deletions are heteroplasmic (i.e. a single cell can harbor both deleted and normal DNA molecules). Symptoms only appear if the proportion of abnormal DNA is high. The abnormal DNA threshold depends on the organ (e.g. about 60% for the skeletal striated muscle). Exceptional cases of KSS may be observed in the absence of a typical single large mtDNA deletion. They may be due either to point mutations located in the mtDNA encompassing tRNA genes or in nuclear genes involved in mtDNA maintenance (i.e. RRM2B).
Diagnostic methods
Clinical diagnostic criteria of the disorder include the triad of progressive external ophthalmoplegia, pigmentary retinopathy, and onset before 20 years of age, plus at least one of the followings: heart block, cerebellar symptoms, or cerebrospinal fluid protein levels above 100 mg/dl. Apart from clinical features, muscle pathology and molecular genetic analysis can play a great role in the diagnostic workup. Muscle pathology showed ragged-red fibers (RRF), ragged-blue fibers (RBF), or cytochrome c-oxidase (COX)-negative fibers in almost all patients. Diagnosis can be confirmed by the detection of a large deletion of mtDNA (1.3-10 kb) in a clinically or morphologically affected tissue (usually skeletal muscle).
Differential diagnosis
Differential diagnoses include any disease caused by large mtDNA deletions or with an overlapping clinical picture, such as Pearson syndrome or maternally-inherited progressive external ophthalmoplegia.
Antenatal diagnosis
Prenatal diagnosis is usually not performed.
Genetic counseling
Most cases of KSS are sporadic. Deletions of mtDNA are only exceptionally transmitted from one generation to the next. Men do not transmit their mtDNA to their offspring. The risk of a woman, carrying a large size mtDNA deletion, transmitting the deletion to her child has been estimated to be less than 4%. The exceptional cases of KSS due to causes other than a large size mtDNA deletion follow the transmission associated with the gene involved (maternal transmission in the case of mtDNA point mutations or autosomal recessive in the case of nuclear gene mutations).
Management and treatment
Treatment of KSS is supportive. Regular follow-up with a cardiologist is recommended. In those with high-grade heart block, a permanent pacemaker/implantable cardioverter-defibrillator device may be suggested and improves the prognosis. Hearing aids may be given to those with sensorineural deafness. Supplementation with coenzyme Q10 has been beneficial in some cases. Ophthalmologic manifestations may be treated by surgery but there is a high risk of recurrence and possible ocular complications.
Prognosis
The prognosis essentially depends on the number of organs involved and, in each of them, on the proportion of the abnormal mtDNA. In the majority of cases, life expectancy can be normal with appropriate support.

                            Last update:
                            October 2019

                            - Expert reviewer(s):
                            Pr Josef FINSTERER


A rare multiple congenital anomalies syndrome characterized by facial dysmorphism (hypertelorism, broad and high nasal bridge, depressed nasal ridge, short columella, underdeveloped maxilla, and prominent cupid-bow upper lip vermillion), mild to severe congenital sensorineural hearing loss, and skeletal abnormalities consisting of brachytelephalangy and broad thumbs and halluces with large, rounded epiphyses. Additional manifestations that have been reported include pulmonary valve stenosis, voice hoarseness and renal agenesis.


Kennedy's disease, also known as bulbospinal muscular atrophy (BSMA), is a rare X-linked recessive motor neuron disease characterized by proximal and bulbar muscle wasting.

Summary:
Epidemiology
The prevalence of BSMA is 1/30,000 male births. The incidence is 1/526,315 males/year.
Clinical description
Disease onset occurs between 30-60 years of age. Initial clinical manifestations include tremor, muscle cramps, muscle twitching, fatigue and slurred speech. With disease progression patients additionally develop weakness and wasting of the limb and bulbar muscles, manifesting as dysarthria, dysphonia, hanging jaw, tongue wasting, chewing difficulty and impaired mobility. Intellectual decline is minimal to none. In the terminal stages of the disease some patients may be unable to swallow or breathe. Non-neurological manifestations include gynecomastia, hypogonadism (leading to infertility and impotence) and in rare cases Dupuytren's contracture, or groin hernia.
Etiology
BSMA is caused by an unstable expansion of a CAG triplet repeat (40-62 repeats) in exon 1 of the androgen receptor (AR) gene on chromosome Xq11-12. The abnormally increased repetition of this CAG triplet leads to an expanded stretch of glutamines within the androgen-receptor (AR). Polyglutamine-expansion results in misfolding and proteolysis of the mutated AR, rendering it insensitive to androgen hormones. In the nucleus AR fragments are produced, which aggregate and these aggregates are believed to cause dysregulation of the transcription of various other proteins and consecutively lead to motor neuron degeneration. Without a sufficient number of motor neurons, initiation and maintenance of muscle contractions can no longer occur, leading to progressive muscle wasting. Recently, a BSMA phenotype with distal predominance of limb weakness and wasting has been reported, caused by mutations in a subunit of the dynactin 1 DCTN1 gene.
Diagnostic methods
Diagnosis is established upon medical history, clinical examination, elevated creatine-kinase, testosterone, progesterone, follicle-stimulating hormone, luteinizing hormone, reduced nerve conduction velocities or reduced nerve action potential amplitudes, acute or chronic denervation and re-innervation on electromyography and documentation of the mutation.
Differential diagnosis
Differential diagnoses include hereditary spastic paraplegia, spinocerebellar ataxia (see these terms), other motor neuron diseases, myopathies, neuropathies, lead or aluminum poisoning, and cervical spondylosis.
Antenatal diagnosis
Antenatal diagnosis is possible for mothers carrying the mutation.
Genetic counseling
Female mutation carriers usually do not manifest clinically but have a 50% risk to transmit the mutation to their male and female offspring. Affected males do not transmit the disease but 100% of their daughters become mutation carriers.
Management and treatment
Symptomatic treatment includes physiotherapy and rehabilitation, agents against tremor and muscle cramps and hormone therapy or surgical treatment of gynecomastia. Recently, treatment of patients with the anti-testosterone leuprorelin was found to be beneficial. In advanced stages of the disease, tube feeding or ventilatory support may be indicated.
Prognosis
Disease progression is slow with only one third of patients requiring a wheelchair 20 years after diagnosis. Prognosis of BSMA is usually fair with only a small decrease in life expectancy.

                            Last update:
                            July 2011

                            - Expert reviewer(s):
                            Pr Josef FINSTERER


A rare primary bone dysplasia syndrome characterized by growth retardation with proportionate short stature, cortical thickening and medullary stenosis of the long bones, delayed anterior fontanelle closure, hypocalcemia due to congenital hypoparathyroidism and facial dysmorphism, including prominent forehead, microphthalmia, and micrognathia. Additional manifestations include ocular and dental anomalies (e.g. corneal opacity, hyperopia, optic atrophy, tortuous retinal vessels, dental caries, enamel defects) and, occasionally, hypoplastic nails and neonatal liver disease. Inheritance may be autosomal dominant or autosomal recessive, with more severe growth retardation, small hands and feet, intellectual disability, microcephaly and recurrent bacterial infections being observed in the latter.


A rare, genetic, primary lipodystrophy syndrome characterized by severe developmental delay and intellectual disability, hypertonia, hyperreflexia, microcephaly, tightly adherent skin, an aged appearance, severe generalized lipodystrophy, and distinct facial dysmorphism which includes large prominent eyes, narrow nasal bridge, tented upper lip vermilion, an open mouth, and high-arched palate. Laboratory analysis of serum and urine are normal.


A group of rare inherited non-syndromic ichthyoses characterized by mutations in keratin genes. Mutations in KRT1 and KRT10 cause most cases of epidermolytic ichthyosis (EI), as well as congenital reticular ichthyosiform erythroderma (CRIE). EI manifests at birth with generalized blistering, which later transforms into hyperkeratosis. Severe palmoplantar involvement is suggestive of the presence of a KRT1 mutation. CRIE patients present at birth with erythroderma and scaling, often with a collodion membrane, and gradually develop confetti-like clear areas of normal skin. KRT2 mutations are associated with superficial epidermolytic ichthyosis (SEI), which is clinically similar to EI, but generally milder and more localized.


A rare odontogenic tumor characterized by an unilocular or multilocular cyst most commonly located in the posterior body and lower ramus of the mandible, often surrounding the crown of the third molar. Histopathologically, the lesion shows a lining of parakeratinized stratified squamous epithelium with palisading hyperchromatic basal cells. Patients may be asymptomatic or present with local infection and/or signs and symptoms of mass effect. Recurrence is rare after complete surgical removal. Some patients have multiple cysts (metachronous or synchronous), especially in the context of nevoid basal cell carcinoma syndrome (Gorlin syndrome).


Keratoderma hereditarium mutilans with ichthyosis

A rare diffuse, mutilating, hereditary palmoplantar keratoderma characterized by severe, honeycomb-pattern palmoplantar keratosis and pseudoainhum of the digits leading to autoamputation, associated with mild to moderate congenital sensorineural hearing loss. Additional features include stellate keratosis on the extensor surfaces of the fingers, feet, elbows and knees. Alopecia, onychogryphosis, nail dystrophy or clubbing, spastic paraplegia and myopathy may also be associated.


Keratoderma hereditarium mutilans is a rare, diffuse, mutilating, hereditary palmoplantar keratoderma disorder characterized by severe, honeycomb-pattern palmoplantar keratosis and pseudoainhum of the digits leading to autoamputation, associated with mild to moderate congenital sensorineural hearing loss. Additional features include stellate keratosis on the extensor surfaces of the fingers, feet, elbows and knees. Alopecia, onychogryphosis, nail dystrophy or clubbing, spastic paraplegia and myopathy may also be associated.


Keratolytic winter erythema is a rare epidermal disease, characterized by recurrent centrifugal palmoplantar peeling and erythema presenting seasonal variation (cold weather). Skin lesions may spread to the dorsum of hands and feet and to the interdigital spaces. Lower legs, knees and thighs may also be involved. Episodes may be preceded by itch and hyperhidrosis. Skin biopsy reveals an epidermal spongiosis with clefting in the stratum corneum, followed by regrowth. Keratolytic winter erythema follows an autosomal dominant mode of transmission.


Keratosis follicularis spinulosa decalvans is a rare genodermatosis occurring during infancy or childhood, predominantly affecting males, and characterized by diffuse follicular hyperkeratosis associated with progressive cicatricial alopecia of the scalp, eyebrows and eyelashes. Additional findings can include photophobia, corneal dystrophy, facial erythema, and/or palmoplantar keratoderma.


Keratosis follicularis-dwarfism-cerebral atrophy syndrome

A rare, genetic, developmental defect during embryogenesis syndrome characterized by generalized keratosis follicularis, severe proportionate dwarfism and cerebral atrophy. Alopecia (of scalp, eyebrows and eyelashes) and microcephaly are additionally observed features. Intellectual disability, inguinal hernia and epilepsy may also be associated. There have been no further descriptions in the literature since 1974.


Keratosis linearis-ichthyosis congenita-sclerosing keratoderma syndrome is an inherited epidermal disorder characterized by palmoplantar keratoderma, linear hyperkeratotic papules on the flexural side of large joints (cord-like distribution around wrists, in antecubital and popliteal folds), hyperkeratotic plaques (on neck, axillae, elbows, wrists, and knees), mild ichthyosiform scaling, and sclerotic constrictions around fingers that present flexural deformities.


Keratosis palmaris et plantaris-clinodactyly syndrome is characterised by the association of palmoplantar keratosis with clinodactyly of the fifth finger. Less than 20 cases have been described in the literature so far, and the majority of reported patients were of Mexican origin. Transmission is autosomal dominant.


A rare inflammatory and suppurating type of tinea capitis, a skin infection caused by Trichophyton or Microsporum fungi, that predominantly affects the scalp and that is characterized by the development of painful crusty lesions covered with follicular pustules and surrounded by erythematous alopecic areas, that can later evolve into abscesses and leave permanent cicatricial alopecia. Lesions can be associated with regional lymphadenopathy.


Ketamine-induced biliary dilatation is an acquired biliary tract disease caused by the abusive consumption of ketamine, which results in the fusiform dilatation of the common bile ducts (CBD) without obstructive lesions or dilatation of the intrahepatic biliary ducts. Possible manifestations of the underlying cholangiopathy include epigastric pain and impaired liver function. Severity of CBD dilatation appears to correlate with the duration of ketamine consumption and the condition has been reported to be reversible in abstinent patients.


Ketoacidosis due to monocarboxylate transporter-1 deficiency

A rare disorder of ketone body transport characterized by recurrent episodes of ketoacidosis provoked by fasting or infections in the first years of life. The episodes are typically preceded by poor feeding and vomiting and are associated with dehydration, in severe cases also with decreased consciousness and insufficient respiratory drive. Hypoglycemia is observed only infrequently. Patients with homozygous mutations tend to present at a younger age, have more profound ketoacidosis, and may show mild to moderate developmental delay in addition.


A rare multiple congenital anomalies/dysmorphic syndrome characterized by diffuse cartilage calcification, brachytelephalangism, peripheral pulmonary artery stenoses and facial dysmorphism. Vascular calcification has been reported in some cases.

Summary:
Epidemiology
More than 40 cases have been reported in the literature so far, with the majority of patients being diagnosed during childhood or earlier.
Clinical description
The abnormal calcification principally involves the cartilage of the ears, nose, larynx and the tracheobronchial tree. Epiphyseal stippling of the long bones and calcification of the spinal column vertebrae have also been reported. The facial dysmorphism is characterized by maxillary and midface hypoplasia (broad and depressed nasal bridge with small alae nasi). Other associated features may include hearing loss and recurrent otitis and/or sinusitis, mild intellectual deficit, seizures/epilepsy, frequent respiratory infections, nasal speech and short stature. Patients may show vascular calcification, cerebral calcification, moyamoya and arterial stenosis. Additional findings of white matter anomalies, encephalomalacia, optic nerve atrophy, and lax and doughy skin with prominent skin folds were reported in one affected family.
Etiology
The syndrome is caused by mutations in the gene encoding the matrix Gla protein (MGP, located at 12p13.1-p12.3).
Diagnostic methods
Diagnosis is usually suspected on the basis of the clinical presentation and radiographic examination, with abnormal cartilage calcification and brachytelephalangism being the cardinal signs of the syndrome. The diagnosis can be confirmed by gene mutation analysis.
Differential diagnosis
The principle differential diagnosis is X-linked recessive chondrodysplasia punctata, but abnormal calcification has also been observed in children with warfarin embryopathy and in those with combined vitamin K-dependent coagulation factor deficiency.
Antenatal diagnosis
Antenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Treatment is symptomatic and may involve angiographic dilatation for peripheral pulmonary artery stenosis and bronchodilating agents to relieve dyspnea and wheezing.
Prognosis
The prognosis for most patients is good, but life expectancy depends on the extent of the pulmonary involvement.

                            Last update:
                            March 2024

                            - Expert reviewer(s):
                             Kyoungmi BAK  - Pr Monzur MURSHED


A rare congenital ectodermal disorder characterized by vascularizing keratitis, hyperkeratotic skin lesions and hearing loss.

Summary:
Epidemiology
Less than 100 cases have been described so far.
Clinical description
Patients usually present at birth with generalized erythema and ichthyosiform scaling. The skin manifestations are progressive with erythrokeratoderma characterized by well-demarcated erythematous and keratotic plaques with a verrucous appearance predominantly located on the face, scalp, ears, elbows and knees. Other skin changes include deep furrows around the mouth, palmoplantar hyperkeratosis (PPHK) with leather grain-like keratoderma, follicular HK on the trunk, and spiky HK (hystrix-like ichthyosis) in some cases. The skin lesions are prone to infection and rare fatal cases of severe recurrent infections with septicemia have been reported. Nail dystrophy, alopecia, and sparse or absent eyebrows and eyelashes are also frequent. KID/HID patients have an increased susceptibility for squamous cell and tongue carcinomas. Hearing loss is congenital, usually sensorineural and is often profound. Ocular findings may be absent in some patients but when present onset usually occurs during childhood or adolescence with photophobia, punctate keratitis and progressive corneal vascularization leading to vision loss. The combined vision and hearing loss may lead to severe developmental delay. Cerebellar and neuromuscular defects have been reported in a few cases.
Etiology
KID/HID syndrome is caused by mutations involving the N-terminus and first extracellular loop of the GJB2 gene (13q11-q12), encoding connexin-26. One patient with KID and atrichia had a mutation in the GJB6 gene (13q12) encoding connexin-30.
Diagnostic methods
Diagnosis is suspected on the basis of dermatological, ophthalmological and hearing evaluation. Histological findings are nonspecific, revealing acanthosis and orthokeratotic HK. MRI may also be indicated to detect cerebellar anomalies. The diagnosis may be confirmed by molecular analysis.
Differential diagnosis
Differential diagnoses should include diseases belonging to the erythrokeratoderma group, as well as Clouston syndrome and keratosis follicularis spinulosa decalvans (see these terms).
Antenatal diagnosis
Prenatal diagnosis may be offered to families of an index case (generalized form or mosaicism) in which the disease-causing mutation has been identified.
Genetic counseling
Most of the reported cases were sporadic, but familial cases with autosomal dominant inheritance have been reported. A few cases of KID syndrome caused by parental germline mosaicism for the GJB2 gene have also been described. Genetic counseling should be proposed to affected families as the risk of transmission from an affected parent is 50%. Segmental skin lesions may correspond to somatic and germline mosaicism, and should be considered as a risk factor for transmission of a generalized form.
Management and treatment
Management is symptomatic only. The use of systemic retinoids is controversial in patients with KID/HID and several authors have recommended limiting the treatment of the skin manifestations to application of topical therapies (bland emollients and topical keratolytics). KID/HID patients should undergo regular surveillance for mucosal carcinomas. Careful ophthalmological and ORL follow-up should be recommended and patients should be included in developmental programs for combined hearing and vision loss. Cochlear implants have been shown to be beneficial in some cases.
Prognosis
The prognosis for patients with KID/HID syndrome is variable and, although cases with a fatal outcome are rare, the cutaneous manifestations persist and are generally severe with recurrent infections and an increased risk of mucosal carcinomas. The combined hearing and vision loss may lead to significant developmental delay.

                            Last update:
                            April 2009

                            - Expert reviewer(s):
                            Pr Alain HOVNANIAN


Kidney tubulopathy-dilated cardiomyopathy syndrome

A rare renal disease characterised by hypokalaemic metabolic alkalosis secondary to a tubulopathy, hypomagnesaemia with hypermagnesuria, severe hypercalciuria and dilated cardiomyopathy.


Kienbock disease is a rare bone disorder of unknown etiology characterized clinically by osteonecrosis of the carpal lunate, eventually leading to collapse of the lunate bone impacting wrist function.


A rare systemic disease characterized by subacute, necrotizing, regional lymphadenopathy with tenderness, usually accompanied with mild fever, night sweats, myalgia, leukopenia and anemia. Less frequent symptoms include weight loss, nausea, vomiting and sore throat. It is a self-limiting benign disease that usually recedes within six months, even without drug treatment.

Summary:
Epidemiology
Kikuchi-Fujimoto disease is an extremely rare disease known to have a worldwide distribution, with higher prevalence among Japanese and other Asian populations. It is found in both sexes, with female predominance, albeit sex ratio has been found close to 1:1 in some reports and male predominance was observed in Asian pediatric populations.
Clinical description
Kikuchi-Fujimoto disease is self-limiting, with acute to subacute course evolving during several weeks. It usually affects young adults (< 40 years old), but can occur in any age group. Patients most commonly present with posterior cervical lymphadenopathy, frequently with concomitant involvement of axillary and/or supraclavicular lymph nodes. Affected lymph nodes are tender and painful. Lymphadenopathy is most commonly associated with fever; other infrequent symptoms include weight loss, nausea and vomiting, weakness, headache, arthralgia, night sweats, upper respiratory symptoms, and sore throat. Hepatomegaly and splenomegaly rarely occur.
Etiology
Two competing theories exist to explain the etiology of this disease: infectious or autoimmune origin. The prevailing explanation for Kikuchi-Fujimoto disease is that a viral, bacterial or other infectious agent triggers an inflammatory process in susceptible individuals. The co-occurrence of different autoimmune diseases, including systemic lupus erythematosus (most commonly), relapsing polychondritis, Sjögren-Larsson syndrome, systemic sclerosis or antiphospholipid syndrome, is suggestive of an alteration of the immune system in these patients. The chronology of co-occurrence was found to be variable; autoimmune disease may appear before, during, or after the course of Kikuchi-Fujimoto disease.
Diagnostic methods
Diagnosis is based on the histological analysis and immunohistochemistry of biopsies from affected lymph nodes, essential for the exclusion of other clinically similar entities (i.e. lymphoma, metastasis or tuberculous adenitis). Histological landmarks include follicular hyperplasia with paracortical infiltration of histiocytes and lymphocytes, absence of neutrophils and eosinophils (in the proliferative stage), and necrotic foci with a high degree of karyorrhexis (in the necrotizing stage).
Differential diagnosis
The differential diagnosis includes infectious lymphadenitis of different etiologies, autoimmune lymphadenopathy (primarily systemic lupus erythematosus) and non-Hodgkin lymphoma.
Management and treatment
Treatment is symptomatic and includes antipyretics, analgesics, nonsteroidal anti-inflammatory drugs and, rarely, corticosteroids. Patients with Kikuchi-Fujimoto disease should be followed up for several years to monitor the possible development of systemic lupus erythematosus and other autoimmune diseases.
Prognosis
Spontaneous recovery occurs in 1 to 6 months, but recurrences (3-4%) and fatal cases have been reported.

                            Last update:
                            June 2023

                            - Expert reviewer(s):
                            Dr Massimo FUSCONI  - Dr Fabiana ZACCARELLI


Kimura disease is a benign and chronic inflammatory disorder of unknown etiology, occurring mainly in Asian countries (very rarely in Western countries) and predominantly affecting young men, that usually presents with solitary or multiple non-tender subcutaneous masses in the head and neck region (in particular the preauricular and submandibular area) and/or generalized painless lymphadenopathy, often with salivary gland involvement. Characteristic laboratory findings include blood eosinophilia and markedly elevated serum immunoglobulin E (IgE) levels. It is often associated with autoinflammatory disorders (i.e. ulcerative colitis, bronchial asthma) and a co-existing renal disease.


A rare inherited epidermolysis bullosa (EB) characterized by skin fragility and blistering at birth followed by development of photosensitivity and progressive poikilodermatous skin changes.

Summary:
Epidemiology
Kindler epidermolysis bullosa (KEB) is the fourth major type of EB, after EB simplex, junctional EB and dystrophic EB. The exact prevalence is unknown. More than 250 cases have been reported to date.
Clinical description
The disease usually manifests at birth with trauma-induced skin blistering that is more prominent on extremities and tends to regress with age, becoming rare in adulthood. Healing of blisters occurs with minimal scarring. With age, additional skin findings are observed: (i) in most patients, photosensitivity with erythema and photo-induced blisters is obvious since early childhood and often diminishes after adolescence, (ii) progressive skin poikiloderma (atrophy, telangiectases, and reticular pigmentation) manifests from childhood and is predominantly localized to the face and neck, and (iii) skin atrophy is localized to hands and feet in the first years of life but becomes generalized by adolescence. Blisters also affect the mucosae. In the oral cavity, chronic gingivitis and periodontitis are frequent and prominent features in adulthood. Esophageal strictures, causing dysphagia and requiring repeated dilatations, frequently develop in adulthood. Anal (bleeding, stenosis), urogenital (urethral bleeding, meatal stenosis), and ocular (ectropion) involvement has also been described. The frequency of these manifestations increases with age. An additional frequent feature is digit webbing/partial pseudosyndactyly. Laryngeal and intestinal involvement, the latter manifesting with severe colitis, are rare. Other features may include: skin xerosis and fine scaling, palmoplantar hyperkeratosis, milia formation, nail dystrophy, constricting bands of pseudoainhum type, and orogenital leukokeratosis. Finally, KEB patients present an increased susceptibility to the development of squamous cell carcinomas (SCC).
Etiology
Kindler epidermolysis bullosa is caused by loss-of-function mutations in the kindlin-1 gene (FERMT1; 20p12.3) causing the defective expression of the fermitin family homologue 1 (kindlin-1), a component of cell adhesive focal contacts.
Diagnostic methods
Diagnosis is based on clinical examination and determination by biopsy of the level within which blisters develop following minor traction. Immunofluorescence antigen mapping and transmission electron microscopy of blistered skin samples show single or multiple cleavage planes at the level of the cutaneous basement membrane zone as well as an extensive reduplication of the lamina densa. Blister formation can occur below the lamina densa, within the lamina lucida or within basal keratinocytes. The diagnosis is confirmed by molecular genetic testing, particularly during the first years of life.
Differential diagnosis
The differential diagnosis includes all forms of inherited EB, in particular dystrophic EB and EB simplex with mottled pigmentation, as well as congenital diseases with photosensitivity and poikiloderma, such as Rothmund-Thomson syndrome, Bloom syndrome, dyskeratosis congenita, poikiloderma with neutropenia or xeroderma pigmentosum.
Antenatal diagnosis
Antenatal diagnosis can be performed in families at risk of having a child with KEB where the disease-causing genetic variant has been previously identified in an affected family member.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.
Management and treatment
Management is based on the avoidance of blistering by protective padding of the skin. Skin moisturizers should be applied to reduce xerosis and skin fissures. Preventive measures should also be adopted for photosensitivity. Careful and early care of the oral mucosa is mandatory to preserve dentition. Esophageal strictures can be treated by balloon dilatation with fluoroscopic guidance. Early diagnosis of SCC (skin and mucosal membranes) requires a rigorous and regular follow-up from young adulthood onwards.
Prognosis
In the majority of cases, life expectancy is normal. However, there are reports of patients with fatal aggressive SCC and, in a case series, skin cancer affected 70% of the patients older than 45 years.

                            Last update:
                            May 2021

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

                                * European Reference Network


King-Denborough syndrome is a rare genetic non-dystrophic myopathy characterized by the triad of congenital myopathy, dysmorphic features and susceptibility to malignant hyperthermia. Patients present with a wide phenotypic range, including delayed motor development, muscle weakness and fatigability, ptosis and facies myopathica (with or without creatine kinase elevations), skeletal abnormalities (e.g. short stature, scoliosis, kyphosis, lumbar lordosis and pectus carinatum/excavatum), mild dysmorphic facial features (e.g. hypertelorism, down-slanting palpebral fissures, epicanthic folds, low set ears, micrognathia), webbing of the neck, cryptorchidism, and a susceptibility to malignant hyperthermia and/or rhabdomyolysis due to intensive physical strain, viral infection or statin use.


Klatskin tumor is an extra-hepatic cholangiocarcinoma (CCA, see this term) arising in the junction of the main right or left hepatic ducts to form the common hepatic duct.

Summary:
Epidemiology
The prevalence is unknown.
Clinical description
Klatskin tumors occur in the hepatic duct bifurcation, usually presenting in the 5th to 7th decade of life and are seen slightly more frequently in males (1.3:1 male to female ratio). Patients are usually asymptomatic until advanced stages of the disease where jaundice is the principle manifestation. Abdominal pain, weight loss and malaise are other manifestations experienced by some patients. Metastasis to regional lymph nodes is frequent. It can spread from the pericholedochal nodes in the hepatoduodenal ligament to the posteriorsuperior area around the pancreatic head, common hepatic artery and portal vein.
Etiology
In 90% of cases Klatskin tumors occur sporadically but certain risk factors have been associated with the disease. Risk factors include primary sclerosing cholangitis (see this term), secondary sclerosing cholangitis, chronic typhoid carriage, parasitic infections (with Opisthochis viverrini and Clonorchis sinensis), exposure to thorotrast (x-ray contrast medium) and choledochal cysts, all of which cause chronic biliary inflammation.
Diagnostic methods
Diagnosis is suspected on clinical and laboratory findings. Serum carbohydrate antigen (CA) 19-9 is a glycoprotein tumor marker found to be elevated in most cases of Klatskin tumors. Increased levels of alkaline phosphate (ALP), conjugated bilirubin and gamma-glutamyl transpeptidase (GGT) are also noted. Abdominal imaging, visualization of the biliary tree and biopsies of the lesion are necessary to make the diagnosis. Endosonography (EUS) guided fine needle aspiration (FNA) of hilar lymph nodes is the most useful tool in the diagnosis and staging of Klatskin tumors. Brush cytology and percutaneous biopsies have a low sensitivity for diagnosis. Ultrasound, and contrast enhanced helical computerized computed tomography (CT) can be used in visualizing the extent of disease.
Differential diagnosis
Autoimmune cholangitis and primary biliary non-Hodgkin's lymphoma are differential diagnoses of Klatskin tumors.
Management and treatment
Relief of biliary blockage and resection of disease are the main goals of treatment. As Klatskin tumors are typically resistant to chemotherapy and radiotherapy, surgical resection of the tumor is the only curative treatment but it is not always an option in those patients with widespread metastasis. Surgical resection involves a liver resection with caudate lobectomy in order to achieve a higher chance of negative resection margins. Palliative treatment involves the placement of plastic or metallic biliary stents. Percutaneous transhepatic catheters provide the best access for palliation of inoperable Klatskin tumors. Unresectable Klatskin tumors are treated with radiotherapy and/or chemotherapy. Gemcitabine combined with cisplatin therapy has been recognized as a standard treatment for unresectable biliary tract cancers including Klatskin tumors.
Prognosis
As Klatskin tumors are often only discovered at an advanced stage, the prognosis is quite poor with five year survival rates after surgery ranging from 25-30% and 0% in unresectable tumors.

                            Last update:
                            September 2012

                            - Expert reviewer(s):
                            Dr Junji FURUSE


A rare genetic, intellectual disability syndrome characterized by intellectual disability, childhood hypotonia, severe expressive speech delay, autism spectrum disorder, and a distinctive facial appearance with a spectrum of additional clinical features.

Summary:
Epidemiology
The prevalence is unknown. However, based on genomic wide studies, it is estimated to be around 1 in 500 individuals with a neurodevelopmental disorder.
Clinical description
Patients with Kleefstra syndrome (KS) have a distinctive facial appearance comprised of brachy-microcephaly, midface hypoplasia, unusual eyebrow shape, synophrys, cupid bow upper lip, full-everted lower lip, protruding tongue and prognathism. With age, facial features become more coarse. Dental anomalies, like retention of primary dentition, are observed. Birth weight is normal but half of children go on to suffer from obesity. Childhood hypotonia causes motor delay, but most children walk independently by age 2 or 3 years. Most patients have moderate to severe intellectual disability with expressive speech delay and little speech development (nonverbal communication is possible). Additional features include congenital heart malformations (interauricular communication, ventricular septal defects, bicuspid aortic valve, pulmonary valve stenosis), genital defects in males (hypospadias, cryptorchidism, micropenis), renal defects (hydronephrosis, chronic renal insufficiency, renal cysts, vesico-ureteral reflux), epilepsy, recurrent infections, severe constipation and hearing problems. In adolescence/adulthood behavioral problems (aggressive/emotional outbursts, attention deficit problems, self-mutilation and severe sleep disturbances) can occur, these often coincide with regression. Autistic-like behavior can be noted earlier in some children.
Etiology
The majority of the clinical features in KS can be attributed to loss of function of EHMT1, either due to a point mutation or a microdeletion in the chromosome region 9q34.3, leading to the loss of the entire gene. This gene encodes an enzyme that modifies histone function and is essential for normal development. Whilst there is not a clear gene-phenotype, correlation, individuals with an intragenic EHMT1 pathogenic variant or a small (<1Mb) 9q34.3 deletion have similar clinical findings whereas the phenotype of individuals with a relatively larger 9q34.3 deletion (i.e. ≥1Mb) appears to be more severe with a more pronounced intellectual disability and more comorbidities. Pulmonary infections and aspiration difficulties in particular appear to be more severe in individuals with a larger 9q34.3 defect. A similar phenotype is reported in patients with a loss of function mutation in the gene KMT2C (7q36.1).
Diagnostic methods
Diagnosis of KS is determined by the presence of the characteristic clinical features and molecular genetic testing. Most cases will be identified by unbiased genetic testing, including chromosomal microarray, intellectual disability gene panels, whole exome or whole genome sequencing. Targeted genetic testing is possible.
Differential diagnosis
Differential diagnoses include Down, Pitt-Hopkins, Smith-Magenis, Angelman, Rett and 2q23.1 microdeletion syndromes.
Antenatal diagnosis
Antenatal diagnosis is offered to unaffected parents of a child with KS, especially in case of parental mosaicism of the pathogenic variant or in case of balanced chromosomal rearrangements in one of the parents.
Genetic counseling
Most reported cases have been de novo but familial recurrence has been observed. KS has a theoretical autosomal dominant transmission, but the majority of patients do not reproduce.
Management and treatment
Treatment requires a multidisciplinary team, specializing in patients with intellectual deficiencies. Special education and vocational training along with speech therapy, physical and occupational therapy and sensory integration therapy are recommended from an early age. Standard treatment is necessary for those with renal, cardiac and urologic issues and for hearing loss. Psychiatric care along with behavioral intervention therapy may be needed. Cardiac screening (for the presence of arrhythmias) as well as intestinal and renal/urologic monitoring is recommended. Medical follow-up is life-long.
Prognosis
The prognosis of KS is variable but in most cases it is not a life-threatening disease. Prognosis is mainly based on the incidence and severity of comorbidities that can occur with KS.

                            Last update:
                            January 2021

                            - Expert reviewer(s):
                            Pr T. [Tjitske] KLEEFSTRA | ITHACA*

                                * European Reference Network


Kleine-Levin syndrome (KLS) is a rare neurological disorder of unknown origin characterised by relapsing-remitting episodes of hypersomnia in association with cognitive and behavioural disturbances.

Summary:
Epidemiology
It affects around 1/500 000 individuals. Patients are mostly male (68-78% of cases) and adolescents (81% of patients), with a mean age of onset of 15 years (range 4-82 years).
Clinical description
The first episode is triggered by an infection in 72% of patients. Patients experience 7-19 neurological episodes with a duration of 10-13 days/episode and relapses every 3.5 months. One third of patients have episodes lasting longer than one month. Episodes recur more quickly in patients with childhood onset. During episodes, all patients have hypersomnia (with sleep periods lasting 15-21 hours per day), cognitive impairment (apathy, confusion, slowness and amnesia) and a specific feeling of derealization (a dream-like state with altered perception). Less frequently, patients experience hyperphagia (66% of patients), hypersexuality (53% of patients, principally men), anxiety, compulsive or mood disorders and depression (53% of patients, predominantly women). Sleep, vigilance, mood, and eating habits are similar to those of controls between episodes. The median disease course is 8-14 years, but tends to be longer in men, in patients with hypersexuality, and when onset occurs after 20 years of age.
Etiology
Susceptibility factors include perinatal and developmental problems. Familial clustering occurs in 5% of cases with multiplex families and similar symptoms. An association of KLS with HLA-DQ2 positivity was found in a small series but not replicated in larger independent sample groups. There is no family history of neuropsychiatric disorders. In 10% of cases, KLS arises secondary to various genetic, inflammatory, vascular or paraneoplastic conditions. In these cases the patients are older and have more frequent and longer episodes, but clinical symptoms, disease course and treatment response are similar to those of primary cases.
Diagnostic methods
Structural brain imaging, cerebrospinal fluid and serological inflammatory markers are unremarkable. EEG slowing is noted in 70% of cases during episodes, without epileptic activity. Sleep structure varies from harmonious hypersomnia to hypoarousal with low sleep efficiency. Functional brain imaging (brain scintigraphy or TEP scan) frequently show hypoperfusion/hypometabolism, mainly focused in the thalamic, hypothalamic and frontotemporal associative areas, especially when compared to images obtained between episodes. Reduced metabolism at the parietotemporal junction is marked during episodes, correlates with the intensity of derealization and persists during asymptomatic periods.
Differential diagnosis
The disorder should mainly be differentiated from epilepsy, migraine with aura, and bipolar disorder.
Management and treatment
The prevention of episodes is mainly based on lithium therapy, combined with regular sleep-wake habits, as well as avoidance of alcohol intake and infections. Lithium therapy stops episodes in 37% patients (vs. 3.4% if no treatment is given) and reduces the frequency/duration of episodes in 46% of other patients. The treatment is usually given to patients with frequent, prolonged or very severe episodes. Patients with rare (e.g., 1/y) episodes may not need any treatment. Antiepileptics (valproate, carbamazepine, lamotrigine) have marginal benefits. During episodes, patients feel better resting at home under parental supervision, unless psychotic or depressive symptoms require hospitalization. Stimulants are not effective. Trials of IV steroids may help terminate long episodes in around 40% of patients.
Prognosis
The prognosis is generally good, with most patients presenting less frequent and less severe episodes with advancing age and disappearance of the syndrome around 30-35 y old. During asymptomatic periods, around 20-30% of patients have mild difficulties focusing or remembering. Persistent psychiatric disorders occur in a minority of patients.

                            Last update:
                            September 2018

                            - Expert reviewer(s):
                            Pr Isabelle ARNULF


KLHL9-related early-onset distal myopathy is a rare, genetic distal myopathy characterized by slowly progressive distal limb muscle weakness and atrophy (beginning with anterior tibial muscle involvement followed by the intrinsic hand muscles) in association with reduced sensation in a stocking-glove distribution. Patients present with high stepping gait, ankle areflexia and contractures in the first to second decade of life, associated with marked ankle extensor muscle atrophy; later proximal muscle involvement is moderate and ambulation is preserved throughout the life.


Klippel-Feil anomaly-myopathy-facial dysmorphism syndrome

A rare genetic disease characterized by the association of Klippel-Feil anomaly (fusion of the cervical spine), myopathy, hypotonia, short stature, microcephaly, and facial dysmorphism (including low-set ears, bulbous nose, long philtrum, high-arched palate, and low posterior hairline, among others). Cardiac abnormalities and various skeletal anomalies (such as pectus excavatum or clinodactyly) have also been reported.


A rare congenital complex vascular malformation syndrome characterized by capillary malformations manifesting as wine stains and venous varicosities typically prominent along the lateral aspect of the lower extremities, associated with overgrowth of a limb (most commonly a leg, less frequently other regions of the body), involving bone and/or soft tissues. The diagnosis is usually made in presence of at least two of these three features. Lymphatic malformations are also observed, while arteriovenous fistulas are absent. Patients present recurrent painful thrombophlebitis, venous thrombosis, and sudden venous hemorrhage.

Summary:
Epidemiology
The prevalence of Klippel-Trénaunay syndrome (KTS) is unknown. KTS is one of the overgrowth syndromes associated with a PIK3CA variant, also known as PROS (for PIK3CA-related overgrowth spectrum), which affects over 500 patients in France.
Clinical description
Clinical diagnosis is based on a clinical triad combining: planar angioma(s), truncal venous/lymphatic-venous slow-flow malformation, and soft tissues and bone hypertrophy in the area affected by vascular dysplasia. The existence of an incontinence of marginal venous system with very slow or even stagnant flow, leading to a risk of thrombosis (mostly superficial, less frequent in deep veins) with embolic potential and pain, coexisting with a deep venous system that may be dysplasic, are characteristic features. Blood stagnation can lead to coagulation activation and even chronic localized intravascular coagulation. Lymphatic malformations can be macro- or microcystic, the latter being at risk of inflammation.
Etiology
The syndrome is due to heterozygous post-zygotic mosaic variation in the PIK3CA gene, occurring in early embryogenesis. It has to be noted that not all KTS appear to result from PIK3CA mosaic variation.
Diagnostic methods
Diagnosis must be confirmed by identification of a PIK3CA mosaic variation on affected tissue (most often skin) without culture, using high-depth high-throughput sequencing.
Differential diagnosis
The differential diagnosis includes: Parkes-Weber syndrome which is due to variants of the RASA1 and EPHB4 genes, and characterized by high-flow vascular malformations with arteriovenous fistula; CLOVES syndrome; other PROS syndromes and PTEN-related overgrowth disorders.
Antenatal diagnosis
The diagnosis may be suspected during pregnancy in the presence of segmental hypertrophy. Prognosis will be based on the extent of vascular malformations. A negative amniocentesis does not exclude the diagnosis.
Genetic counseling
The risk for siblings of a proband with a PIK3CA mosaic variant is the same as in the general population if the parents are not variant carriers. Prenatal diagnosis is therefore not particularly recommended.
Management and treatment
Because of the multisystemic involvement, patient management requires multi-disciplinary care by expert teams, with at least one annual physical examination, and further investigations may be needed based on clinical presentation. Screening for Wilms tumor is not needed when the risk is less than 5%. Therapeutic management consists of preventing and treating complications: medical management of inflammatory or painful flare-ups, thromboembolic complications, superficial or non-disabling vascular malformations, correction of lower limb length discrepancy, and of a possibly associated scoliosis. Acute painful episodes due to the presence of phleboliths in venous malformations are relieved by anti-inflammatory drugs or even heparin rather than analgesics. Compression of vascular deformities of the limbs is often unavoidable. Some vascular malformations can be managed by interventional radiology, thus avoiding the need for surgery. Laser treatment may be required for superficial vascular malformations. Alpelisib, a PI3K pathway inhibitor, is currently proposed in therapeutic trials or on a compassionate basis, according to a therapeutic protocol. This treatment improves quality of life, reduces hypertrophy and vascular symptoms, and avoids the need for surgery.
Prognosis
The clinical presentation of the disease can be highly variable. Treatment with alpelisib changes the prognosis when a PIK3CA variant was identified.

                            Last update:
                            January 2024

                            - Expert reviewer(s):
                            Pr Laurent GUIBAUD | ERN CRANIO* - Pr Laurence OLIVIER-FAIVRE | ITHACA*

                                * European Reference Network


A rare neurologic disease characterized by visual agnosia, hyperorality (strong tendency to examine objects orally), hypermetamorphosis (described as the irresistible impulse to notice and react to everything within sight), hypersexuality, changes in dietary habits and hyperphagia, placidity, and amnesia, due to bilateral lesions of the temporal lobe including the hippocampus and amygdala.