A rare, genetic keratinization disorder which is classically characterized by keratotic papules, acral pits, and acral wart-like lesions that can be associated with a trigger, and may occur anywhere on the body (including mucosal surfaces). Extracutaneous manifestations may include, nail anomalies, blepharitis, dry eye, neuropsychiatric illness and, recurrent parotid gland obstruction and xerostomia.

Summary:
Epidemiology
The prevalence of Darier disease (DD) is estimated at around 1/30,000 in Europe.
Clinical description
Darier disease is a debilitating and chronic condition, with both cutaneous and extra-cutaneous manifestations, which can have a severe impact on patients' general health and quality of life. The cutaneous and extra-cutaneous manifestations have variable expression within and between families. Exacerbations may be triggered by summer, sweating, exposure to sunlight, mental distress, contact with wool and febrile illness. Classical lesions are characterized by keratotic papules (typically occurring on the trunk), acral pits (occurring on palms and soles) and acral wart-like lesions (typically occurring on the hands, particularly after soaking in water). Non-classical lesions may include acral keratoderma, leukodermic macules, giant comedones, vegetations and acral hemorrhagic blisters, and may co-exist with classical lesions. However, non-classical lesions are rare. Lesions can occur anywhere on the body with no specific location. Nail abnormalities include V-shaped notches at the free edge of nail, longitudinal red and white lines, ridging and splitting. Genital involvement, especially on female genitalia, is more frequent in patients with severe disease. Oral mucosal lesions may be found. Extra-cutaneous manifestations vary within and between families and may include, blepharitis, dry eye, neuropsychiatric illness, epilepsy (often only before age 20), learning disabilities, recurrent parotid gland obstruction and xerostomia. Staph aureus colonization in skin & nares is frequent and corresponds with extent of skin area affected and disease severity.
Etiology
DD is caused by mutations in the ATP2A2 gene (12q23-q24.1) encoding the sarco/endoplasmic reticulum Ca2+ ATPase isoform 2 (SERCA2), which has a central role in intracellular calcium signaling.
Diagnostic methods
The diagnosis is based on histological examination of skin lesion biopsies revealing hyperkeratosis, focal dyskeratosis and suprabasal acantholysis.
Differential diagnosis
Differential diagnoses include Hailey-Hailey disease, Grover disease (transient acantholytic dermatosis), seborrheic dermatitis, pemphigus, and warty dyskeratoma.
Antenatal diagnosis
The prenatal diagnostic tests and procedures are available for affected couples where the genetic variant has been identified.
Genetic counseling
The disorder is autosomal-dominant with complete and delayed penetrance, and variable expression. Genetic counselling is advised for affected patients to discuss identification of the mutation, the pattern of inheritance as well as the prenatal diagnostic tests and procedures available.
Management and treatment
Management and treatment are based on case reports and case series reported in the literature as well as clinical experience. The full extent of the disease should be assessed by a dermatologist and includes assessment of the skin involvement (including staph aureus colonization), the extracutaneous involvement (neuropsychiatric illness etc.), family history and triggering factors. Current treatment is symptomatic and includes topical and systemic therapy as well as minimizing exposure to triggers. For patients prone to secondary skin infections, a diluted bleach bath may be considered. Other therapies reported include injection of botulinum toxin to decrease sweating, surgical excision, electrosurgical excision, dermabrasion, laser ablation, photodynamic therapy and electron beam radiation. Extracutaneous manifestations should be treated according to standard protocols.
Prognosis
The disease is characterized by a chronic cycle with acute exacerbations and does not improve with age. In assessing the prognosis, it is very important to consider the extracutaneous manifestations of the disease. Secondary bacterial and viral infections were reported as causes of morbidity and mortality in a few cases.

                            Last update:
                            May 2022

                            - Expert reviewer(s):
                            Dr Roni DODIUK-GAD


DDOST-CDG is a form of congenital disorders of N-linked glycosylation characterized by failure to thrive, developmental delay, hypotonia, strabismus and hepatic dysfunction. The disease is caused by mutations in the gene  DDOST  (1p36.1).


DDX41-related hematologic malignancy predisposition syndrome

A rare inherited cancer-predisposing syndrome characterized by adult onset of hematologic malignancies mainly affecting the myeloid lineage (such as myelodysplastic syndrome and/or acute myeloid leukemia), less frequently lymphoid malignancies. Some patients have been reported to develop granulomatous or immune disorders (including sarcoidosis, systemic lupus erythematosus, asthma, eczema, or juvenile arthritis) before or in the absence of hematologic malignancies.


De Barsy syndrome (DBS) is characterized by facial dysmorphism (down-slanting palpebral fissures, a broad flat nasal bridge and a small mouth) with a progeroid appearance, large and late-closing fontanel, cutis laxa (CL), joint hyperlaxity, athetoid movements and hyperreflexia, pre- and postnatal growth retardation, intellectual deficit and developmental delay, and corneal clouding and cataract.

Summary:
Epidemiology
Prevalence is unknown but around 30 cases have been described in the literature so far.
Etiology
The etiology remains unknown in most cases, however, mutations in the PYCR1 gene (17q25.3) have recently been identified in patients with overlapping phenotypes (wrinkly skin, osteopenia and progeroid features) of DBS, autosomal recessive CL type 2 (ARCL2), wrinkly skin syndrome (WSS), and geroderma osteodysplastica (GO; see these terms).
Diagnostic methods
Histological examination of skin biopsies from DBS patients may reveal characteristic frayed and reduced elastic fibers but patients with normal skin biopsy results have also been reported.
Differential diagnosis
The eye anomalies, athetoid movements and hyperreflexia are distinguishing features of DBS that usually allow this syndrome to be differentiated from GO, ARCL2 and WSS.
Genetic counseling
The condition is transmitted in an autosomal recessive manner.
Management and treatment
Treatment is symptomatic, including early eye-surgery and physiotherapy to avoid contractures.
Prognosis
Patients with DBS have variable outcomes. Some patients die in childhood due to severe neurological dysfunction and intercurrent infections. Many patients diagnosed with PYCR1 mutations show a spontaneous improvement of the progerioid features, and in some children the movement disorder remain non-progressive.

                            Last update:
                            July 2010

                            - Expert reviewer(s):
                             M GUILLARD  - Pr D.J. [Dirk] LEFEBER  - Pr Eva MORAVA-KOZICZ  - Pr R.A. [Ron] WEVERS


De novo thrombotic microangiopathy after kidney transplantation

A rare renal disease characterized by thrombotic microangiopathy developing de novo in kidney transplant recipients with no evidence of occurrence of the disease prior to transplantation. Precipitating factors include antibody-mediated rejection, immunosuppressive medication, viral infections, and genetic abnormalities in the complement cascade, among others. The condition most commonly occurs within the first 3-6 months post-transplantation. Clinical presentation is highly variable and ranges from a limited form confined to the kidney with relatively good prognosis to a systemic variant consisting of the classic triad of thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury.


Deaf blind hypopigmentation syndrome, Yemenite type

Yemenite deaf-blind hypopigmentation syndrome is an exceedingly rare genetic disorder characterized by cutaneous pigmentation anomalies, ocular disorders and hearing loss.

Summary:
Epidemiology
The syndrome was described in 1990 in two patients from the same Yemenite family.
Clinical description
A brother and sister were described as having cutaneous patchy hypo- and hyperpigmentation on the trunk and extremities, gray hair, white brows and lashes. Ocular manifestations were microcornea, coloboma, and abnormalities of the anterior chamber of the eye. Both patients had severe hearing loss and dental abnormalities. Intelligence was reported to be normal. Their parents were unaffected and possibly consanguineous.
Etiology
The cause of this syndrome has not been determined.
Genetic counseling
The inheritance pattern appears to be autosomal recessive.

                            Last update:
                            March 2015

                            - Expert reviewer(s):
                            Dr Véronique PINGAULT


Deafness with labyrinthine aplasia, microtia, and microdontia (LAMM) is a genetic transmission deafness syndrome.

Summary:
Epidemiology
It has been described in 6 families to date.
Clinical description
The profound congenital deafness is associated with a complete absence of inner ear structures (Michel aplasia); microtia type I with small auricle and narrow external auditory canal; and microdontia with widely spaced teeth.
Etiology
Linkage analysis followed by sequencing of candidate genes led to identification of three different homozygous mutations in the FGF3 gene (11q13).
Genetic counseling
Transmission is autosomal recessive.

                            Last update:
                            November 2010


Deafness-craniofacial syndrome is characterised by the association of congenital hearing loss and facial dysmorphism (facial asymmetry, a broad nasal root and small nasal alae). It has been described in two members (father and daughter) of one Jewish family. Temporal alopecia was also noted. Transmission appeared to be autosomal dominant.


Deafness-ear malformation-facial palsy syndrome is characterized by profound conductive deafness due to stapedial abnormalities associated with variable malformations of the external ears and facial paralysis. It has been described in three sibs and their mother. Inheritance is autosomal dominant.


Deafness-enamel hypoplasia-nail defects syndrome

A rare genetic disease characterized by sensorineural hearing loss, abnormalities in the secondary dentition (such as enamel hypoplasia, taurodontism, or dental overcrowding), and nail abnormalities (including leukonychia and presence of transverse ridges). Association with macular dystrophy has also been reported.


Deafness-encephaloneuropathy-obesity-valvulopathy syndrome is a rare mitochondrial disease with marked clinical variability typically characterized by encephalomyopathy, kidney disease (nephrotic syndrome), optic atrophy, early-onset deafness, pancytopenia, obesity, and cardiac disease (valvulopathy). Additionally, macrocephaly, intellectual disability, hyperlactatemia, elevated lactate/pyruvate ratio, insulin-dependent diabetes, livedo reticularis, liver dysfunction and seizures have also been associated.


Deafness-epiphyseal dysplasia-short stature syndrome

A rare syndromic genetic deafness characterized by profound congenital bilateral sensorineural deafness, developmental delay, moderate intellectual disability, generalized delay in bone maturation, short stature, epiphyseal dysplasia particularly of the capital femoral epiphyses, and mild dysmorphic facial features such as prominent forehead and small, pointed chin. Bilateral obstruction of lacrimal ducts and inguinal and umbilical hernias have also been described.


Deafness-genital anomalies-metacarpal and metatarsal synostosis syndrome is characterised by sensorineural deafness, bilateral synostosis of the 4th and 5th metacarpals and metatarsals, genital anomalies (hypospadias in males), psychomotor delay and abnormal dermatoglyphics. So far, it has been described in two unrelated patients. Facial dysmorphism was noted in both patients (prominent forehead, ear anomalies, facial asymmetry and an open mouth appearance).


A rare form of syndromic genetic deafness characterized by the association of congenital mixed hearing loss with perilymphatic gusher (Gusher syndrome or DFN3), hypogonadism and abnormal behavior.

Summary:
Epidemiology
It has been described in five related males.
Etiology
Inheritance appeared to be X-linked recessive and a microdeletion, encompassing the POU3F4 gene (DFN3 locus), was detected in one of the patients leading to the suggestion that deafness - hypogonadism is a contiguous gene deletion syndrome.

                            Last update:
                            May 2009


Deafness-infertility syndrome (DIS) is a very rare syndrome associating sensorineural deafness and male infertility.

Summary:
Epidemiology
It has been reported in fewer than 5 families.
Etiology
Male infertility is caused by abnormal spermatozoid morphology and motility. DIS is due to a contiguous gene deletion at chromosome 15q15.3 including 2 genes CATSPER2 and STRC, and is inherited in an autosomal recessive manner: affected males are homozygous for the deletion, parents are asymptomatic carriers and homozygous females are deaf but not infertile.

                            Last update:
                            September 2011


Deafness-intellectual disability syndrome, Martin-Probst type

A rare X-linked syndromic intellectual disability characterized by congenital sensorineural hearing loss, varying degrees of intellectual disability, short stature, and dysmorphic facial features (such as telecanthus, epicanthic folds, broad nasal root, malar hypoplasia, low-set ears, dental anomalies, and micrognathia). Additional reported manifestations include microcephaly, renal and genitourinary abnormalities, widely spaced, hypoplastic nipples, and adult onset of progressive pancytopenia.


Deafness-oligodontia syndrome is characterised by sensorineural hearing loss and oligodontia/hypodontia. It has been described in two pairs of siblings and in one isolated case. Dizziness was reported in one of the pairs of siblings. Transmission appears to be autosomal recessive.


Deafness-onychodystrophy syndrome is a group of rare, genetic, developmental defect during embryogenesis disorders characterized by the association of sensorineural deafness and onychodystrophy (e.g. absent/hypoplastic finger and toenails), as well as brachydactyly and finger-like thumbs. Additional features present in one of the diseases comprising this group include osteodystrophy, intellectual disability, seizures, developmental delay, and distinctive facies.


Deafness-small bowel diverticulosis-neuropathy syndrome

A rare neurologic disease characterized by progressive sensorineural deafness, progressive sensory neuropathy and gastrointestinal abnormalities, including progressive loss of gastric motility and small bowel diverticulosis and ulcerations, resulting in cachexia. Additonal neurological manifestations may include dysarthria and absent tendon reflexes, as well as ptosis and external ophthalmoplegia. There have been no further descriptions in the literature since 1985.


Deafness-vitiligo-achalasia syndrome is characterized by the association of deafness, short stature, vitiligo, muscle wasting, and achalasia.

Summary:
Epidemiology
It has been described in a brother and his sister born to first-cousin parents.
Genetic counseling
It is likely to be transmitted as an autosomal recessive trait.

                            Last update:
                            February 2007


Dedifferentiated liposarcoma (DDLS) is a high-grade subtype of liposarcoma (LS; see this term) that progresses from well-differentiated liposarcoma (WDLS; see this term), and most often occurs in the retroperitoneum. It is defined as a region of nonlipogenic sarcoma associated with WDLS. .

Summary:
Epidemiology
The incidence is approximately 1/ 330, 000 persons/year.
Clinical description
DDLS is a fast growing tumor with potential for distant metastasis but this occurs in less than 15% of patients. Like WDLS, it is usually a painless mass, though it can cause symptoms of obstruction, decrease in appetite and abdominal distention.
Etiology
The etiology is unknown. Like WDLS, DDLS usually has amplification of the chromosome region 12q and associated amplification and overexpression of the MDM2, HMGA2 and CDK4 genes.
Prognosis
The 5-year disease-specific survival rate for DDLS overall is 44% but this is location dependent with extremity lesions having a 5-year disease-specific survival rate of greater than 90%.

                            Last update:
                            January 2013

                            - Expert reviewer(s):
                            Dr Samuel SINGER


A rare mycosis characterized by severe, potentially life-threatening dermal and subcutaneous tissue invasion by dermatophytes. Dissemination to lymph nodes is frequent, but the infection may also occasionally spread to the central nervous system. Cutaneous signs and symptoms include erythema, desquamation, itching, nodules, plaques, or ulceration. The majority of deep dermatophytoses develop in immunocompromised patients.


Deficiency in anterior pituitary function-variable immunodeficiency syndrome

A rare, genetic endocrine disease characterized by the association of common variable immunodeficiency, manifesting with hypogammaglobulinemia and recurrent or severe childhood-onset sinopulmonary infections, followed, possibly many years later, by symptomatic adrenocorticotropic hormone (ACTH) deficiency resulting from anterior pituitary hormone deficiency.


Dehydrated hereditary stomatocytosis (DHS) is a rare hemolytic anemia characterized by a decreased red cell osmotic fragility due to a defect in cation permeability, resulting in red cell dehydration and mild to moderate compensated hemolysis. Pseudohyperkalemia (loss of potassium ions from red cells on storage at room temperature) is sometimes observed.

Summary:
Epidemiology
The prevalence of DHS is unknown but to date, about 20 families with DHS have been described in the literature.
Clinical description
The clinical presentation of the disease is very heterogeneous. Onset of DHS may occur during the perinatal period with occurrence of edema and ascites (most often not related to an underlying anemia) that usually resolve spontaneously during the first weeks of life but may rarely lead to hydrops fetalis (see this term). Most adult patients present a mild anemia or a totally compensated hemolysis, with fatigue, icterus, splenomegaly and risks of secondary complications including cholelithiasis. Patients can also be referred for unexplained hemochromatosis, since iron overload is frequently associated with the disease. Thrombotic complications (arterial and venous events, including portal vein thrombosis (see this term) and pulmonary hypertension) have been described at a high rate after splenectomy.
Etiology
Most reported DHS cases are caused by gain-of-function mutations in the gene PIEZO1 (16q24.3) which encodes part of a mechanosensitive ion channel. This results in increased red cell membrane permeability for cations that consequently leads to cation depletion, dehydration and shortened red cell survival. Rare atypical forms have been associated with mutations in SLC4A1 (17q21.31), coding for the Band 3 anion transport protein, or KCNN4 (19q13.2) which codes for the putative Gardos channel.
Diagnostic methods
Diagnosis relies on laboratory findings. The typical presentation includes normal hemoglobin level or mild anemia, normal mean cell volume (MCV) or mild macrocytosis, normal or elevated mean corpuscular hemoglobin concentration (MCHC), elevated reticulocytosis, and a small number of stomatocytes (<10% of red cells). A diagnosis of DHS must be evoked in patients with unexplained iron overload, even if hemoglobin levels are normal, as well as in patients with unexplained hemolysis (before splenectomy) or those presenting with thrombotic events, if already splenectomized. Osmolar gradient ektacytometry is the best phenotypic diagnosis method, showing a leftward shift of the bell-shaped curve with a normal maximum deformability index and a decreased hypo and hyper-osmotic point, reflecting decreased osmotic fragility and cell dehydration, respectively. In some cases, an increased serum potassium level is observed, which results from in vitro leakage and is clinically irrelevant. Measurement of ferritin level and liver magnetic resonance imaging (MRI) are performed to evaluate iron overload. Genetic screening of the causative genes can be performed after phenotypic investigations.
Differential diagnosis
Differential diagnoses include other causes of hemolysis, including hereditary spherocytosis, overhydrated hereditary stomatocytosis, hemoglobinopathy or red cell enzyme deficiencies such as hemolytic anemia due to red cell pyruvate kinase deficiency (see these terms).
Genetic counseling
Transmission is autosomal dominant and genetic counseling should be offered to affected families.
Management and treatment
Treatment is mainly symptomatic. Occurrence of cholelithiasis should be regularly monitored. Folic acid supplementation should be proposed in case of anemia. Pregnancy should be closely monitored. Iron status should be regularly monitored by serum ferritinemia and liver MRI. Iron depletion, most often by phlebotomy, is proposed when ferritinemia reaches the threshold of 1000 ng/ml or when iron liver overload is present. Splenectomy is contraindicated in DHS due to an elevated risk of life threatening arterial and venous thrombotic events.
Prognosis
Overall prognosis is favorable in well managed patients (not splenectomized and with regular monitoring of their iron status). Splenectomized patients are at risk of early or late thrombotic events.

                            Last update:
                            December 2015

                            - Expert reviewer(s):
                            Pr Loïc GARÇON  - Dr Véronique PICARD


A clinical entity that represents a severe phenotype of Charcot-Marie-Tooth disease characterized by onset occurring in infancy, severe motor weakness, delayed motor development, extremely slow nerve conduction (< 10-12 m/s), areflexia and foot deformity. Mutations in the genes PMP22 (17p12), MPZ (1q22), EGR2 (10q21.1) and PRX (19q13.2) have been implicated.


Delayed encephalopathy due to carbon monoxide poisoning

A rare neurologic disease characterized by delayed onset of encephalopathy typically within a few weeks after acute carbon monoxide poisoning. The most common symptoms are cognitive impairment, personality changes, and movement disorder including parkinsonism, among others. Prognosis is good with a high rate of spontaneous recovery within a year.


Delayed membranous cranial ossification is a rare, genetic primary bone dysplasia characterized by absent ossification of calvarial bones at birth and characteristic facial dysmorphisms (frontal bossing, hypertelorism, downward-slanting palpebral fissures, proptosis, flat nasal bridge, low-set ears, midface retrusion). Patients present a soft skull at birth which, over time, progressively ossifies and in adulthood typically results in a deformed skull (with brachycephaly and prominent occiput). No other skeletal abnormalities are associated and patients have normal cognitive and motor development.


Delayed speech-facial asymmetry-strabismus-ear lobe creases syndrome

This syndrome is extremely rare and is characterized by delayed speech development, mild facial asymmetry, strabismus and transverse ear lobe creases.

Summary:
Epidemiology
To date, six cases have been reported in five families.
Clinical description
Dysmorphic features include asymmetrical face, unilateral narrow palpebral fissure, divergent strabismus, long philtrum, high-arched palate, apparently low-set ears and transverse ear lobe creases on both sides. Delayed language development is constant but intellectual development can be normal.
Genetic counseling
In one family, the transmission was compatible with either autosomal dominant or X-linked dominant inheritance.

                            Last update:
                            June 2010


Deletion 5q35 refers to the different congenital malformation syndromes resulting from deletions of variable extent of the terminal part of the long arm of chromosome 5 (5q), spanning the region from 5q35.1 to 5q35.3 . The most significant anomaly is a recurring deletion in 5q35.2 comprising the NSD1 gene that causes Sotos syndrome that is characterized by cardinal features including excessive growth during childhood, macrocephaly, distinctive facial gestalt and various degrees of learning difficulty. Subtelomeric deletions of the terminal 3.5 Mb region on 5q35.3 are very rare, characterized by prenatal lymphedema with increased nuchal translucency, pronounced muscular hypotonia in infancy, borderline intelligence, postnatal short stature due to growth hormone deficiency, and a variety of minor anomalies such as mildly bell-shaped chest, minor congenital heart defects and a distinct facial gestalt. Larger deletions including bands 5q35.1, 5q35.2 and 5q35.3 cause a more severe phenotype that associates severe developmental delay with microcephaly, and significant cardiac defects (e.g. atrial septal defect with/without atrioventricular conduction defects, Ebstein anomaly, tetralogy of Fallot) linked to haploinsufficiency of NKX2.5 (5q35.1). Various combinations of signs may result from deletions of variable extent depending on the genes comprised in the deleted segment.


Delta-beta-thalassemia is a form of beta-thalassemia (see this term) characterized by decreased or absent synthesis of the delta- and beta-globin chains with a compensatory increase in expression of fetal gamma-chain synthesis.

Summary:
Epidemiology
Prevalence of this form is not known. The condition is found in many ethnic groups but is most common in Greece and Italy.
Clinical description
The heterozygous form of the condition is clinically asymptomatic with mild microcytosis and no elevation of HbA2 whereas the few homozygous patients have a mild clinical presentation. When inherited with heterozygous classical beta-thalassemia, patients usually have the thalassemia intermedia phenotype, but the thalassemia major phenotype has been described in some cases.
Etiology
Delta-beta-thalassemia is commonly caused by deletions of the entire delta and beta gene sequences with production of only gamma-globin and formation of HbF. Rarely, non-deletional forms have been reported.
Diagnostic methods
Diagnosis is based on hypochromic microcytic red cell indices with significant elevation of HbF, ranging from 5-15% in heterozygotes. HbF is heterogeneously distributed among the erythrocytes. The alpha/beta-globin synthesis ratio is >1.
Differential diagnosis
Hereditary persistence of fetal Hb and beta-thalassemia (see this term) is the main differential diagnosis. The distinction between these two conditions cannot always be made from routine hematologic analyses and alpha-beta-globin chain synthesis ratio and DNA analysis may be necessary.
Genetic counseling
Transmission is autosomal recessive.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Pr Renzo GALANELLO  - Dr Raffaella ORIGA


Delta-sarcoglycan-related limb-girdle muscular dystrophy R6

A subtype of autosomal recessive limb-girdle muscular dystrophy characterized by a variable age of onset of progressive weakness and wasting of the proximal skeletal muscles of the shoulder and pelvic girdles, frequently associated with progressive respiratory muscle impairment and cardiomyopathy. Calf hypertrophy, muscle cramps and elevated serum creatine kinase levels are also observed. Neuropsychomotor development is usually normal.


A rare neurologic disease characterized by progressive neurodegeneration secondary to repetitive mild traumatic brain injuries. The clinical picture is highly variable and includes behavioral or psychiatric symptoms (such as aggression, depression, delusions, and suicidality), cognitive impairment (including diminished attention, memory deficits, executive functioning deficits, and dementia), and motor deficits (including parkinsonism, ataxia, and dysarthria). Neuropathological hallmark is the accumulation of phosphorylated tau-protein in sulci and perivascular regions.


Demodicidosis is a rare parasitic cutaneous disease due to Demodex mite infestation characterized by variable degrees of spinulosis, erythema, papules, and pustules, usually accompanied by a burning or pruritic sensation. Face (incl. eyelids) is most frequently affected, but ear canal, scalp, neck, back, chest, nipples, buttocks, penis, and extremity (legs and arms) involvement have also been observed. Dermoscopic examination reveals Demodex tails and follicular openings.


A rare form of neonatal diabetes mellitus characterized by a triad of Developmental delay, Epilepsy, and Neonatal Diabetes (DEND syndrome), with a generally severe course. This form of neonatal diabetes is not associated with abnormal pancreatic development.

Summary:
Epidemiology
Fewer than 60 cases have been reported to date.
Clinical description
DEND syndrome represents the most severe end of the neonatal diabetes mellitus spectrum. Birth-weight is below the 10th percentile in approximately half of the cases. Patients have hyperglycemia requiring insulin therapy that presents within 12 months of birth. The onset is usually before 6 months of age and before 1 month of age in about 1/3rd of the patients. Remission from the hyperglycemia happens in about half of the patients (median age 39 weeks, but may not occur until 5 years old), however, relapse frequently occurs during puberty. The associated neurologic features range from mild to severe developmental delay (psychomotor and cognitive). Attention deficit or language disorder (dyslexia) is found in 100% of cases. Patients also present with intractable epilepsy and muscle hypotonia. A less severe, intermediate form has been described and is known as intermediate DEND syndrome.
Etiology
DEND syndrome is caused in most cases by gain of channel function mutations in the KCNJ11 gene (11p15.1), encoding a subunit of the ATP-sensitive potassium (KATP) channel. Mutations in this gene also cause permanent neonatal diabetes mellitus (PNDM). Only 20% of individuals with mutations in this gene develop DEND or the intermediate DEND form. Rare reports of specific mutations in the ABCC8 gene (11p15.1) have also been associated with DEND.
Diagnostic methods
DEND syndrome should be suspected when there is onset of diabetes mellitus before 6 months, or before 1 year of age with no pancreatic involvement or no evidence of autoimmune disorder, or with unusual family history and associated neurological complications. The diagnosis is confirmed by genetic testing which should be performed as soon as possible in order to prescribe the appropriate treatment and follow up. Diagnosis should be established before the onset of complications and should not wait for a potential remission of the hypoglycemia.
Differential diagnosis
The differential diagnosis includes the less severe intermediate DEND syndrome and other forms of neonatal diabetes mellitus, permanent and/or transient.
Antenatal diagnosis
Non-invasive prenatal testing of fetal genotype can be performed for monogenic diabetes and give highly accurate results before the third semester.
Genetic counseling
The mode of inheritance of DEND syndrome is usually dominant (50% of transmitting the disease by an affected couple) and rarely recessive (25% chance of transmitting the disease by an affected couple), however, most diagnosed cases occur from a de novo mutation, in which case chances of recurrence in siblings are close to zero.
Management and treatment
Treatment must begin as soon as the diagnosis is established using hypoglycemic sulfonylureas, which act by binding to the regulator SUR1 subunit of the potassium channel, and provide a better metabolic equilibrium than insulin. The clinician should aim to optimize the treatment to the maximum possible dose without causing hypoglycemia (preprandial target: 70-120 mg/dL - postprandial target: 100-145 mg/dL) in order to optimize the drug's beneficial effect on the central nervous system. Calorie and carbohydrate intake must be carefully balanced (15-18 g/kg/d of carbohydrates) to allow for weight gain while avoiding the risk of future insulin resistance. Restriction below the nutritional recommendations for children with low birth weight isn't recommended. Blood glucose must be monitored with as little amount of blood as possible (0.3 microliter) either with an appropriate blood glucose meter or a continuous glucose monitor.
Prognosis
In the neonatal period, the prognosis of the disease is linked to the severity of the symptoms. Rapid diagnosis and treatment with hypoglycemic sulfonylureas after metabolic control has been restored with insulin are critical to improve the prognosis and reduce neurological complications. Later in life, the prognosis depends on the metabolic control which determines the timing of appearance of the long-standing diabetes complications.

                            Last update:
                            July 2024

                            - Expert reviewer(s):
                            Pr Michel POLAK | Endo-ERN*

                                * European Reference Network


Dendritic cell sarcoma not otherwise specified

A rare dendritic cell tumor characterized by a neoplasm composed of spindled to ovoid cells with phenotypic features similar to those of normal indeterminate cells. The tumor cells consistently express S100 protein and CD1a, while langerin, specific B- and T-cell markers, CD30, the histiocytic marker CD163, and the follicular dendritic cell markers CD21, CD23, and CD35 are negative. Birbeck granules are absent on ultrastructural examination. Patients typically present with multiple papules, nodules, or plaques of the skin. Primary lymph node or splenic involvement is less common. Systemic symptoms are usually absent. The clinical course is highly variable.


Dengue fever (DF), caused by dengue virus, is an arboviral disease characterized by an initial non-specific febrile illness that can sometimes progress to more severe forms manifesting capillary leakage and hemorrhage (dengue hemorrhagic fever, or DHF) and shock (dengue shock syndrome, or DSS).

Summary:
Epidemiology
DF is found in the tropics worldwide, especially in Southeast Asia, the Pacific region, and the Americas, with 40% of the global population at risk. An estimated 50 to 100 million cases of DF, 500,000 hospitalizations, and 20,000 deaths occur yearly worldwide.
Clinical description
The vast majority of dengue virus infections result in DF, which is characterized by sudden onset of fever, malaise, headache (classically retro-orbital), and myalgia/arthralgia, often followed soon after by a petechial rash, which may be pruritic. In most cases, symptoms will resolve within 7 days without further complications. However, in a small minority of patients, a brief period of deffervescence is followed by worsening abdominal symptoms (pain, nausea, vomiting, diarrhea), thrombocytopenia, hemorrhage (DHF: epistaxis, bleeding gums, gastrointestinal bleeding) and a capillary leak syndrome (DSS: hemoconcentration, hypoalbuminemia, pleural effusion, shock). DHF/DSS are seen most often in children under the age of 15 years. Risk is greater with secondary heterologous infection by one of the four dengue virus serotypes, but severe disease may be seen with first infections.
Etiology
Over 25 different viruses cause viral hemorrhagic fever. Dengue virus belongs to the Flaviviridae family, genus Flavivirus. Four distinct serotypes, with significant strain variation, are recognized. Dengue viruses are maintained in humans and transmitted between them by the bite of infected mosquitoes, most commonly Aedes aegypti but also Aedes albopictus). Person-to-person transmission has not been reported.
Diagnostic methods
Common diagnostic modalities include serologic testing by enzyme linked immunosorbent assay (ELISA) and reverse transcription polymerase chain reaction (RT-PCR). Virus isolation may also be performed in specialized laboratories. The viremic phase of DF/DHF is usually brief (first 3-5 days of illness), after which time detection of anti-dengue IgM antibodies, which appear as early as 2-4 days after disease onset, is the mainstay. Numerous commercial ELISA assays are available with varying degrees of sensitivity and specificity.
Differential diagnosis
DF is difficult to distinguish from a host of other febrile illnesses such as malaria and typhoid fever (see these terms), especially early in the course of disease before the rash appears. For DHF/DSS, other viral hemorrhagic fevers, leptospirosis, rickettsial infection (see these terms) and meningococcemia need to be excluded.
Management and treatment
As there is presently no antiviral drug available for DF/DHF, treatment is supportive, following the guidelines for treatment of severe septicemia. Insecticide-treated bed nets, room screens and elimination of larval development sites should be used in open-air settings to prevent further transmission.
Prognosis
Case-fatality rates for DF are less than 1% but may rise to as high as 40% in DHF/DSS, largely dependent upon whether access to advanced medical care exists. Children and persons with underlying chronic diseases such as diabetes, heart disease, and asthma are at increased risk. The most severe phase of disease usually lasts only a few days and survivors generally have no lasting sequelae.

                            Last update:
                            December 2012

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


A histological subtype of C3 glomerulopathy characterized by C3 deposition in renal tissue in the absence or near-absence of immunoglobulin deposits, in a patient with the classic clinical features of glomerulonephritis and electron microscopic findings of highly electron-dense intra-membranous, osmiophilic deposits.


A rare X-linked monogenic renal tubular disease, characterized by manifestations of complex proximal tubule dysfunction with low-molecular-weight (LMW) proteinuria, hypercalciuria, nephrolithiasis, nephrocalcinosis, and progressive renal failure. Extra-renal involvement is absent.

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
The disease is generally found in males only, who may have manifestations of the disease from early childhood. It is characterized by proximal tubule (PT) dysfunction and LMW proteinuria (100% of cases), associated with hypercalciuria (90-95%), nephrolithiasis (30-50%), nephrocalcinosis (40-50%), and progressive renal failure. PT dysfunction may be severe, resulting in complete Fanconi syndrome, i.e. aminoaciduria, phosphaturia, glycosuria, uricosuria, kaliuresis, and impaired urinary acidification, and can be complicated by rickets or osteomalacia. If tested, nearly all patients have a urinary concentration defect. Patients may present symptoms related to renal stones (abdominal pain, hematuria), Fanconi syndrome (polyuria, poor growth, rickets), or chronic kidney failure. Patients are also frequently referred after fortuitous discovery of nephrocalcinosis, renal stones, proteinuria or other biological signs of PT dysfunction, or after family screening. Some patients present with LMW proteinuria associated with significant albuminuria and glomerulosclerosis, in the absence of nephrotic syndrome and with mild tubular involvement that may be overlooked. There is considerable inter- and intra-familial variability. Most females carriers have low-degree of LMW proteinuria and may develop mild kidney failure later in life.
Etiology
Dent disease type 1 is caused by inactivating mutations in the CLCN5 gene (Xp11.22) that encodes a 746 amino acid electrogenic Cl-/H+ exchanger (ClC-5). Close to 250 CLCN5 mutations have been reported. Of these 9% are de novo mutations. Approximately 40% of patients with a phenotype compatible with Dent disease do not have CLCN5 mutations. Of these, approximately half have mutations in the OCRL1 gene and are considered to have Dent disease type 2.
Diagnostic methods
The diagnosis is based on the presence of LMW proteinuria, which is associated in the majority of cases with hypercalciuria and other biological, radiological and clinical symptoms of the disease. Molecular genetics confirms the diagnosis.
Differential diagnosis
Differential diagnosis includes other causes of low molecular weight proteinuria and Fanconi syndrome.
Antenatal diagnosis
Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Genetic counseling
Transmission is X-linked. Genetic counseling should be offered to at-risk couples informing them that there is a 50% risk of having an affected boy or a carrier girl at each pregnancy, if the mother carries the mutation.
Management and treatment
Care is supportive, focusing on the prevention of nephrolithiasis, maintaining appropriate hydration and treatment of chronic kidney disease, if present. Long-term treatment with a high citrate diet or supplementation might delay progression of renal disease, even in the absence of stone formation. Thiazide diuretics have been used to treat hypercalciuria, but can cause significant adverse effects; in addition, their benefit on kidney function has not been demonstrated, and they may aggravate hypovolemia and hypokalemia, if present. Similarly, treatment of rickets with vitamin D must be cautious since it may increase hypercalciuria and aggravate nephrocalcinosis.
Prognosis
Progression to end-stage renal failure occurs between the third and fifth decades of life in the majority of affected males. Frequency of kidney failure increases with age: approximately 35-40% in patients between 30-50 years, and 75% in between 50 and 60 years. The disease does not recur in the transplanted kidney.

                            Last update:
                            August 2021

                            - Expert reviewer(s):
                            Pr Gema ARICETA | ERKNet* - Pr Francesco EMMA | ERKNet*

                                * European Reference Network


A rare genetic renal tubular disease, characterized by manifestations of proximal tubule dysfunction with low-molecular-weight (LMW) proteinuria, hypercalciuria, nephrolithiasis, nephrocalcinosis, and progressive renal failure. Extra-renal involvement is frequent, but may be mild and not recognized.

Summary:
Epidemiology
The exact prevalence is unknown. Compared to Dent disease type 1, Dent disease type 2 is approximately 4 times less frequent.
Clinical description
The disease is generally found in males only, who may have manifestations of the disease from early childhood. It is characterized by proximal tubule (PT) dysfunction and low-molecular-weight (LMW) proteinuria (100% of cases), associated with hypercalciuria (>95%), nephrolithiasis (20-30%), nephrocalcinosis (10-20%), and progressive renal failure. PT dysfunction may be severe, resulting in complete Fanconi syndrome, i.e. aminoaciduria, phosphaturia, uricosuria, kaliuresis, and impaired urinary acidification, and can be complicated by rickets or osteomalacia. Unlike Dent disease type 1, glycosuria is rarely observed. Patients may present symptoms related to renal stones (abdominal pain, hematuria), Fanconi syndrome (polyuria, poor growth, rickets), or chronic kidney failure. Patients are also frequently referred after fortuitous discovery of nephrocalcinosis, renal stones, proteinuria or other biological signs of PT dysfunction. Extra-renal symptoms include variable degrees of intellectual impairment in approximately one-quarter of patients, partial cataract in approximately 10% of patients, and growth retardation (mean height Z-score: -2.1). Nearly all patients have creatine phosphokinase (CPK) and/or lactate dehydrogenase (LDH) levels above the normal range.
Etiology
The disease is due to variants on the OCRL1 gene (Xq26.1) and is allelic with oculocerebrorenal syndrome of Lowe (Lowe syndrome). Unlike Lowe syndrome, severe pathogenic variants causing Dent disease type 2 (nonsense, frameshift, and splice site mutations) are clustered in exons 4-7; variants that are located in other regions of the OCRL1 gene are nearly always missense mutations.
Diagnostic methods
The diagnosis is based on the presence of LMW proteinuria, which is associated in the majority of cases with hypercalciuria and other biological, radiological and clinical symptoms of the disease. Elevated CPK and LDH help distinguishing Dent disease type 1 from type 2. When present, lens abnormalities and intellectual impairment also favor the diagnosis of Dent disease type 2. Molecular genetics confirms the diagnosis.
Differential diagnosis
The differential diagnosis includes other causes of low molecular weight proteinuria and Fanconi syndrome. There is a continuum in the clinical manifestations of Dent disease type 2 and Lowe syndrome, which are both caused by OCRL1 pathogenic variants. In some patients, the distinction between these two phenotypes can be difficult.
Antenatal diagnosis
Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Genetic counseling
Transmission is X-linked. Genetic counseling should be offered to at-risk couples informing them that there is a 50% risk of having an affected boy or a carrier girl at each pregnancy, if the mother carries the mutation.
Management and treatment
Care is supportive. From the renal perspective, the focus is on the prevention of nephrolithiasis, maintaining appropriate hydration and treatment of chronic kidney disease, if present. Experimental data in Dent 1 disease suggest that long-term treatment with a high citrate diet or supplementation with citrate might delay progression of renal disease, but data are not available for Dent 2 disease. Treatment of rickets with vitamin D must be cautious in patients with hypercalciuria and/or nephrocalcinosis. Patients with intellectual impairment require neuropsychological and educational support.
Prognosis
Progression to end-stage renal failure occurs between the second and fifth decades of life in the majority of affected males. The disease does not recur in the transplanted kidney.

                            Last update:
                            August 2021

                            - Expert reviewer(s):
                            Pr Gema ARICETA | ERKNet* - Pr Francesco EMMA | ERKNet*

                                * European Reference Network


A rare X-linked renal tubular diseases characterized by a primary proximal tubule dysfunction with low-molecular-weight proteinuria. Other renal features often include hypercalciuria, nephrolithiasis/nephrocalcinosis, and progressive renal failure, among others. There are two subtypes: Dent disease type 1 characterized by an isolated renal phenotype in association with CLCN5 variants, and Dent disease type 2, often characterized by the addition of extra renal manifestations in association with OCRL1 variants.


A rare odontologic disorder characterized by the loss of the periodontal ligament space and orthodontic mobility.

Summary:
Epidemiology
The prevalence is unknown.
Clinical description
In dental ankyloses, the tooth is in contact with the alveolar bone with obliteration of the periodontal ligament and can lead to submergence. It can affect both primary and permanent teeth and may occur at any time during eruption. Permanent molars are less frequently affected than deciduous molars. Varying numbers of teeth may be affected. After eruption, it halts any adaptive changes. In a growing child, an ankylosed tooth appears to 'submerge' as adjacent unaffected teeth and alveolar bone continue their normal pattern of growth occlusally. The disorder may result in loss of the retained molar and neighboring teeth due to caries and periodontal disease, and, in severe cases, deformation of the facial skeleton (reduction in the height of the lower face, relative mandibular prognathism, posterior open bite). Occasionally, dental ankylosis may be associated with fifth finger clinodactyly. Dental ankylosis exists in isolation or associated with other abnormalities as part of a syndrome.
Etiology
Etiology remains uncertain but a genetic predisposition, trauma, inflammation or infection may play a causative role.
Diagnostic methods
Clinical examination and X-ray are the main diagnostic methods for detecting ankylosis.
Differential diagnosis
Differential diagnosis includes mechanical obstruction, primary failure of eruption, and malocclusion.
Genetic counseling
Familial occurrence has been shown in several families, with autosomal dominance inheritance suggested.
Management and treatment
The recommended management includes removing the ankylosed tooth to ensure development and eruption of the permanent teeth, and surgery to expose, protect, or reposition the emerging tooth. Dental composites reestablish occlusion and improves esthetics. Decoronation is recommended in the incisal sector before vertical bone development is complete and the crown reaches a certain degree of infraocclusion. This permits preservation of the alveolar bone for eventual implants after completion of growth. Where primary teeth ankylosed, removal of the affected tooth is recommended to ensure development and eruption of the permanent teeth.
Prognosis
Ankylosed teeth have an unfavorable prognosis with risk of progression to replacement resorption.

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Dr Marion STRUB


A rare subtype of autosomal dominant cerebellar ataxia type I characterized by involuntary movements, ataxia, epilepsy, mental disorders, cognitive decline and prominent anticipation.

Summary:
Epidemiology
Worldwide prevalence is unknown. However, the disease is found most commonly in Japan where the prevalence is estimated to be 1/208,000.
Clinical description
Age of onset ranges from 1 to 60 years (mean age = 28.8 years). Patients with earlier onset (below 20 years of age) tend to show myoclonus epilepsy and intellectual deficit. Patients with late onset (over 40 years of age) tend to present with cerebellar ataxia, choreoathetosis and dementia. Clinical features and the age of onset are significantly correlated with the size of CAG repeats. Head magnetic resonance imaging (MRI) shows atrophy of cerebellum, brainstem, cerebrum and high signal has been shown in periventricular white matter.
Etiology
Unstable expansion of CAG repeats in the ATN1 gene (12p13.31) has been demonstrated.
Prognosis
Prognosis is poor. DRPLA progresses rather rapidly. The mean disease duration is about 13 years. Recurrent seizures and dysphagia with frequent fluid and food aspiration lead to bronchopneumonia and subsequent death. However, some patients can reach 60 years of age or more.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK


Dentin dysplasia type I (DD-I) is a rare form of dentin dysplasia (DD, see this term) characterized by sharp conical short roots or rootless teeth.

Summary:
Epidemiology
Prevalence of DD-I is reported to be 1/100,000.
Clinical description
The condition affects both primary and permanent dentition. Signs of the condition are variable. In patients with DD-I, the teeth are generally unremarkable clinically with a normal shape and color. However, the roots appear sharp with conical, apical constrictions on radiography. The teeth are generally mobile, with frequent abscess formation and can be lost prematurely. Aberrant dentin formation can lead to partial or total pulp obliteration.
Etiology
DD-I is caused by mutations in the DSPP gene (4q21.3) coding for dentin sialophosphoprotein, a precursor for dentin sialoprotein and dentin phosphoprotein which are involved in dentinogenesis.
Diagnostic methods
Since teeth in DD-I appear clinically normal, diagnosis is based on radiographic features (abnormal roots, pulp obliteration, partially obliterated crescent shaped pulp chamber and occasionally pulp stones). Molecular genetic testing can be used to confirm the diagnosis.
Differential diagnosis
Differential diagnoses include conditions that have overlapping clinical or radiographic features with DD such as those leading to early tooth loss: Kostmann syndrome, cyclic neutropenia, Chediak-Hegashi syndrome, Langerhans cell histiocytosis, Papillon-Lefèvre syndrome, hypophosphatasia, and vitamin D-resistant rickets (see these terms).
Genetic counseling
DD-I follows an autosomal dominant pattern of inheritance. There is therefore a 50% risk that a child born to an affected parent will have the condition.
Management and treatment
Appropriate care makes it possible to achieve good esthetic appearance and functional performance.
Prognosis
Prognosis depends primarily on the age of diagnosis and the quality of management.

                            Last update:
                            September 2012

                            - Expert reviewer(s):
                            Pr Agnès BLOCH-ZUPAN


Dentin dysplasia type II (DD-II) is a rare mild form of dentin dysplasia (DD, see this term) characterized by normal tooth roots but abnormal primary dentition.

Summary:
Epidemiology
Prevalence of DD-II is not known.
Clinical description
In DD-II, features of primary dentition resemble those observed in dentinogenesis imperfecta type 2 (DGI-2, see this term) and include amber translucent coloration, bulbous crowns, cervical constriction, tooth attrition, and short constricted roots. Pulp obliteration is also observed. The permanent dentition seems either unaffected (normal teeth morphology and color) or mild radiographic abnormalities are found (thistle tube-shaped pulp chambers and multiple pulp calcifications).
Etiology
DD-II is caused by mutations in the DSPP gene (4q21.3) coding for dentin sialophosphoprotein, a precursor for dentin sialoprotein and dentin phosphoprotein which are involved in dentinogenesis.
Diagnostic methods
Diagnosis is based on history, clinical examination and radiographic features. Molecular genetic testing can be used to confirm the diagnosis.
Differential diagnosis
Differential diagnoses include conditions that have similar clinical or radiographic features to DD such as osteogenesis imperfecta or dentinogenesis imperfecta (see these terms).
Genetic counseling
DD-2 follows an autosomal dominant pattern of inheritance. There is therefore a 50% risk that a child born to an affected parent will have the condition.
Management and treatment
In the primary dentition, preformed stainless steel crowns on molars may be used to prevent tooth wear and maintain the occlusal vertical dimension. Appropriate care makes it possible to achieve good esthetic appearance and functional performance.
Prognosis
Prognosis depends primarily on the age of diagnosis and the quality of management.

                            Last update:
                            September 2012

                            - Expert reviewer(s):
                            Pr Agnès BLOCH-ZUPAN


Dentin dysplasia-sclerotic bones syndrome is a rare, genetic odontologic disease characterized by the clinical, radiographic, and histologic features of dentine dysplasia and osteosclerosis of all long bones, with heavy cortical bone and narrowed or occluded marrow spaces. There have been no further descriptions in the literature since 1977.


Dentin dysplasia (DD) is a rare disorder belonging to the group of hereditary dentin defects (see this term) and is characterized by abnormal dentin structure and root development resulting in abnormal tooth development. It encompasses two subtypes: DD type I and DD type II (see these terms).

Summary:
Epidemiology
Prevalence of DD type I is 1/100,000, and that of DD type II is unknown.
Clinical description
There is significant overlap between different types of DD and dentinogenesis imperfecta (DGI, see this term). Two clinical subtypes of DD have been identified. Dentin dysplasia type I (DD-1, see this term) involves sharp conical short roots or rootless teeth and is associated with premature loss of teeth. Dentin dysplasia type II (DD-2, see this term) involves normal tooth roots but abnormal amber color primary dentition, permanent teeth of normal morphology and color with pulp chamber shape anomalies and multiple intrapulpal calcifications.
Etiology
DD is caused by mutations in the DSPP gene (4q21.3) coding for dentin sialophosphoprotein, a precursor for dentin sialoprotein and dentin phosphoprotein.
Genetic counseling
Transmission is autosomal dominant.

                            Last update:
                            September 2012

                            - Expert reviewer(s):
                            Pr Agnès BLOCH-ZUPAN


Dentinogenesis imperfecta type 2 (DGI-2) is a rare, severe form of dentinogenesis imperfecta (DGI, see this term) and is characterized by weakness and discoloration of all teeth.

Summary:
Epidemiology
Prevalence of DGI-2 is reported to be 1/6,000 to 1/8,000.
Clinical description
The dental features of DGI-2 are typically bulbous crowns with marked cervical constriction along with amber translucent discoloration and tooth attrition. Roots are generally short and constricted. Both primary and permanent teeth present pulp obliteration. Patients with this form of DGI have no normal teeth. Sensorineural hearing loss has also been found in some patients.
Etiology
DGI-2 is caused by mutations in the DSPP gene (4q21.3) coding for dentin sialophosphoprotein, a precursor for dentin sialoprotein and dentin phosphoprotein which are involved in dentinogenesis.
Diagnostic methods
Diagnosis is based on history, clinical examination and radiographic features. Molecular genetic testing can be used to confirm the diagnosis.
Differential diagnosis
Differential diagnoses include conditions that may have similar clinical or radiographic features to DGI such as osteogenesis imperfecta and dentin dysplasia (see this term). The clinical symptoms may be mistaken for hypocalcified amelogenesis imperfecta, congenital erythropoietic porphyria, conditions leading to early tooth loss (Kostmann syndrome, cyclic neutropenia, Chediak-Hegashi syndrome, Langerhans cell histiocytosis, Papillon-Lefèvre syndrome), vitamin D-resistant rickets (see these terms), as well as permanent teeth discoloration due to tetracyclines, and vitamin D-dependent rickets. It is important to investigate for a history of bone fractures with minimal trauma, hearing loss and to check for blue sclerae to rule out osteogenesis imperfecta (see this term).
Genetic counseling
DGI-2 follows an autosomal dominant pattern of inheritance. There is therefore a 50% risk that a child born to an affected parent will have the condition.
Management and treatment
Protection of primary and then permanent teeth with preformed pediatric crowns, cast occlusal onlays on first permanent molars and eventually premolars, may help to minimize tooth wear and maintain the occlusal vertical dimension. Obliteration of pulp spaces in teeth that develop abscesses makes endodontic treatment extremely difficult if not impossible. Appropriate care makes it possible to achieve good esthetic appearance and functional performance. The replacement of teeth might be considered with dentures or implants.
Prognosis
Prognosis depends primarily on the age of diagnosis and the quality of management. Early diagnosis and regular dental care cannot always prevent premature tooth loss.

                            Last update:
                            September 2012

                            - Expert reviewer(s):
                            Pr Agnès BLOCH-ZUPAN


Dentinogenesis imperfecta type 3 (DGI-3) is a rare, severe form of dentinogenesis imperfecta (DGI, see this term) characterized by opalescent primary and permanent teeth, marked attrition, large pulp chambers, multiple pulp exposure and shell teeth radiographically (i.e. teeth which appear hollow due to dentin hypotrophy).

Summary:
Epidemiology
Prevalence of DGI-3 is not known. The disease was identified in the Brandywine isolate in southern Maryland, USA.
Clinical description
In DGI-3, both primary and permanent dentition are affected and teeth are often opalescent. Enamel loss and excessive wear have been reported, as well as marked tooth attrition. DGI-3 is associated with multiple periapical radiolucencies in noncarious teeth.
Etiology
The disorder is caused by mutations in the DSPP gene (4q21.3) coding for dentin sialophosphoprotein, a precursor for dentin sialoprotein and dentin phosphoprotein which are involved in dentinogenesis.
Genetic counseling
Transmission is autosomal dominant.

                            Last update:
                            September 2012

                            - Expert reviewer(s):
                            Pr Agnès BLOCH-ZUPAN


Dentinogenesis imperfecta-short stature-hearing loss-intellectual disability syndrome

A rare malformative syndrome with dentinogenesis imperfecta, characterized by dentin dysplasia with opalescent discoloration and severe attrition of primary and permanent teeth, and delayed eruption, bulbous crowns, long and tapered roots, and progressive root canal obliteration of the permanent dentition, associated with proportionate short stature, sensorineural hearing loss, mild intellectual disability, and dysmorphic facial features. The latter include a prominent nose with high nasal bridge and short philtrum. Osteoporosis, mild platyspondyly, and cone-shaped epiphyses have also been reported.


Dentinogenesis imperfecta (DGI) is a hereditary dentin defect (see this term) characterized by abnormal dentin structure resulting in abnormal tooth development.

Summary:
Epidemiology
Prevalence of DGI is reported to be 1/6,000 to 1/8,000.
Clinical description
Signs of the condition are variable and there is significant overlap between different types of dentin dysplasia (DD, see this term) and dentinogenesis imperfecta. Three different types of DGI were originally described in the Shield's classification: DGI type 1, type 2 and type 3. The condition formerly known as DGI-1 is now considered to be a syndromic form of DGI associated with osteogenesis imperfecta types 1b,c, 2, 3, 4b, 9, and 10. In dentinogenesis imperfecta type 2 (DGI-2, see this term), osteogenesis imperfecta is not a feature and the condition is usually characterized by abnormal amber or opalescent dentin, worn teeth, bulbous crowns with cervical constriction, short roots, obliterated pulp chambers and root canals (visible on X-rays). Dentinogenesis imperfecta type 3 (DGI-3, see this term) is characterized by opalescent primary and permanent teeth, marked attrition, and large pulp chambers.
Etiology
DGI is a hereditary condition caused by missense and nonsense mutations in the DSPP gene (4q21.3) encoding the major proteins involved in dentin formation.
Genetic counseling
DGI follows an autosomal dominant pattern of inheritance.

                            Last update:
                            September 2012

                            - Expert reviewer(s):
                            Pr Agnès BLOCH-ZUPAN


A rare genetic, syndromic glomerular disorder characterized by the association of nephropathy presenting as persistent proteinuria or overt nephrotic syndrome, Wilms tumor and genitourinary structural defects. In addition, disorders of testicular development are common in subjects with 46,XY karyotype.

Summary:
Epidemiology
The prevalence is not known. Fewer than 300 cases have been reported in the literature to date.
Clinical description
Presentation is typically of infantile nephrotic syndrome progressing to end-stage renal disease (ESRD) within 1 to 15 years. Alternatively, initial clinical presentation may be with ambiguous external genitalia (e.g. hypospadias, cryptorchidism) in 46,XY individuals or uni- or bilateral Wilms tumor (WT). Affected individuals with 46,XY karyotype may have a wide range of disorders of testicular development ranging from undervirilized male to complete sex reversal, and carry a risk of developing gonadoblastoma in dysgenic gonads. Congenital anomalies of kidney and urinary tract (CAKUT) including duplex or horseshoe kidney, urogenital sinus and vesico-ureteric reflux, are present in ~10% of individuals. Genotype-phenotype correlations have been described; in particular, missense pathogenic variants affecting DNA-binding are associated with severe nephropathy and progression to ESRD within 1-3 years, and truncating variants are associated with a high risk (>85%) of developing WT and having a CAKUT (25%) while proteinuria is typically diagnosed in the second decade of life .
Etiology
Constitutional pathogenic variants in the Wilms tumor predisposing genes, WT1 (11p13), most of which are located in exons 8 and 9, have been described in the majority of individuals. WT1 encodes for a protein that serves as regulatory transcription factor important both for renal and gonadal development.
Diagnostic methods
Diagnosis is suspected on infantile presentation of glomerulopathy with either urogenital abnormalities and/or WT. Careful renal ultrasonography (US) for WT should be performed in any subject found to have early onset nephrotic syndrome. Diffuse mesangial sclerosis is the classic finding on renal biopsy, although other types of nephropathy are common. Imaging is used to assess internal genitalia. Identification of WT1 pathogenic variant confirms diagnosis. Karyotype testing is recommended for all individuals with ambiguous genitalia or gonadal dysgenesis.
Differential diagnosis
The differential diagnosis includes WAGR syndrome, Frasier syndrome, Meacham syndrome, congenital nephrotic syndrome of the Finnish type, idiopathic nephrotic syndrome, and isolated diffuse mesangial sclerosis
Antenatal diagnosis
Undervirilized / ambiguous genitalia in 46,XY individuals may sometimes be noted on prenatal US. Prenatal genetic testing is possible if the pathogenic variant has been previously identified in a family.
Genetic counseling
The pattern of inheritance is autosomal dominant with non-full penetrance and variable expressivity. Most of the patients have a de novo mutation. Precise evaluation of the risk of reoccurrence requires genetic testing of the index case and his/her biological parents. Where karyotyping is indicated, pre-test genetic counseling on the possibility of detecting sex reversal is recommended.
Management and treatment
Multidisciplinary management should involve a nephrologist, urologist, endocrinologist, oncologist and surgeons. The nephrotic syndrome is resistant to corticosteroids and immunosuppressive drugs. Chronic renal failure is managed initially with nephroprotective medical therapy, followed by renal replacement therapies or transplantation when ESRD occurs. Patients with ESRD are recommended to undergo bilateral nephrectomy at the time of placement of a peritoneal dialysis catheter or renal transplantation to prevent WT development/relapse. Early gonadectomy should be considered in 46,XY with complete gonadal dysgenesis in order to prevent tumorigenesis. WT is treated by nephrectomy with or without chemotherapy.
Prognosis
The prognosis varies widely with most of the subjects living into adulthood. The primary cause of death is renal failure and disseminated WT but respiratory and heart failure have also been reported. Nephrotic syndrome does not recur after kidney transplantation. 46, XY individuals with complete gonadal dysgenesis are infertile.

                            Last update:
                            December 2019

                            - Expert reviewer(s):
                            Pr Beata LIPSKA-ZIETKIEWICZ | ERKNet*

                                * European Reference Network


A chronic autoimmune subepidermal bullous disease characterized by grouped pruritic lesions such as papules, urticarial plaques, erythema, and herpetiform vesiculae, with a predominantly symmetrical distribution on extensor surfaces of the elbows (90%), knees (30%), shoulders, buttocks, sacral region, and face of children and adults. Erosions, excoriations and hyperpigmentation usually follow. It may also appear as a consequence of gluten intolerance.


Dermatofibrosarcoma protuberans (DFSP) is a rare infiltrating soft tissue sarcoma, generally of low grade malignancy, arising from the dermis of the skin and characteristically associated with a specific chromosomal translocation t(17;22).

Summary:
Epidemiology
Prevalence is estimated at 1 in 10,000 and annual incidence is estimated at around 1 in 200,000.
Clinical description
DFSP can present at any age, including infancy and childhood, but usually presents in the 2nd to 5th decade of life. Between 85 and 90% of tumors are low grade lesions, with the remainder classified as the high grade fibrosarcomatous (FS) type. The lesions typically present as an indurated pink or violet-red plaque or nodular mass on the trunk, proximal extremities, or head and neck region. Growth tends to be slow with local infiltration into deeper tissues and a propensity for local recurrence after excision. However, metastases are rare. Occurrence is sporadic.
Etiology
DFSP is most likely fibroblastic in origin: over 90% of cases are associated with dysregulated platelet-derived growth factor (PDGF) production resulting from chromosomal translocation or a supernumerary ring chromosome derived from t(17;22). The translocation breakpoint most often involves the second exon of the PDGFB gene on chromosome 22 (22q13.1), with fusion to the collagen, type I, alpha 1 gene (COL1A1) on chromosome 17 (17q21.33). This chromosomal translocation results in the upregulation of the PDGFB gene in the form of a fused proto-oncogene COL1A1/PDGFB.
Diagnostic methods
Diagnosis may be suspected on the basis of histological findings on biopsy samples showing features of a well-differentiated fibroblastic tumor with the characteristic microscopic appearance of interwoven fascicles of cells forming a swirling pattern and positive staining for CD34. Cytogenetic analysis identifying the characteristic t(17;22) chromosomal translocation or interphase FISH using split-apart probes for chromosome 22 can be used to confirm the diagnosis. Imaging modalities suchas MRI or CT scans are most useful for assessing the depth of tumor invasion or identifying metastatic sites.
Differential diagnosis
The differential diagnosis should include fibrosarcoma (see this term), dermatofibroma, neurofibroma, and other soft tissue tumors.
Management and treatment
Complete surgical resection with clear margins is the standard treatment for primary and recurrent DFSP. Mohs microscopic surgery (MMS) using sequential horizontal sectioning with immediate microscopic examination may reduce the amount of tissue resected and is associated with a low risk of recurrence. Post-operative radiotherapy can be used when resection is incomplete. Imatinib, an oral PDGF receptor tyrosine kinase inhibitor may be beneficial for patients with an unresectable, locally advanced lesion or with metastatic disease. Cytotoxic therapy is of little proven value.
Prognosis
The prognosis is excellent for low grade lesions but a poorer prognosis is associated with the FS variant due to a higher risk of recurrence and metastases. Overall, the rate of mortality is low (< 3% at 10 years).

                            Last update:
                            October 2008

                            - Expert reviewer(s):
                            Dr D HANDOLIAS  - Pr Grant MCARTHUR


A rare leukodystrophy characterized by congenital thickened, wrinkled skin showing loss of elasticity, in combination with childhood onset of rapidly progressive generalized cognitive and motor impairment quickly resulting in a vegetative state and early death. Neuropathologic examination reveals neuroaxonal leukodystrophy with numerous neuroaxonal spheroids and diffuse loss of axons and myelin sheaths.


A rare idiopathic inflammatory myopathy (IIM) characterized by evocative skin lesions, muscle involvement with symmetrical proximal muscle weakness, and specific histological features. The clinical subtypes are defined by the presence of myositis-specific antibodies (anti-Mi2, anti-NXP2, anti-TIF1-γ, anti-MDA5, or anti-SAE antibodies) and are associated with specific clinical phenotypes and prognosis.

Summary:
Epidemiology
Annual incidence is estimated between 1/125,000-1,000,000, and prevalence between 1/10,000-50,000. Dermatomyositis (DM) is more common in women than in men (2:1).
Clinical description
Onset is generally in adulthood, in some cases earlier (Juvenile DM). The classical skin findings are of periorbital heliotrope rash and Gottron's papules, photodistributed violaceous erythema and poikiloderma, and periungual telangiectasias. Symmetrical proximal muscle weakness subsequently develops over weeks or months, with severity depending on antibody type. Anti-Mi2 DM (5-20% of DM patients) and anti-TIF1-gamma DM (15-25%) present a moderate to severe proximal muscle weakness with classical skin lesions. Anti-NXP2 DM (15-25%) presents specifically subcutaneous edema and calcinosis. Anti- SAE DM (5%) presents classical skin lesions with mild or no muscle involvement. Anti-MDA5 DM (5-20%) present with classical skin lesions, ulcerations, mechanic's hands, arthritis, pulmonary involvement, and no or mild muscle involvement. Pulmonary manifestations ranges from aspiration pneumonia to a severe life-threatening rapidly progressive interstitial lung disease (ILD). DM may involve other systems (cardiac, articular, gastro-intestinal). About one third of DM patients develop malignancy, often within 0 to 3 years before or after disease onset (breast and ovarian cancers in women, and lung and prostate cancer in men).
Etiology
Although the etiology is not fully understood, it is suggested to be associated with certain HLA regions, genes implicated in other autoimmune diseases, and triggers such as infections or cancer. The interferon (IFN) pathways play a key role in DM physiopathology, especially type I IFNs, and an IFN signature has been detected in blood sample, muscle and skin tissues.
Diagnostic methods
Diagnosis is based on the characteristic clinical and laboratory (elevated serum creatine kinase and presence of myositis-specific antibody) findings, as well as myopathic findings on electromyography (EMG). It is generally confirmed by muscle biopsy showing inflammatory infiltrates around blood vessels and perifascicular atrophy.
Differential diagnosis
The differential diagnoses include other inflammatory myopathies, muscular dystrophies of late onset, as well as adult-onset nemaline myopathy, proximal myotonic myopathies, systemic lupus erythematosus, pityriasis rubra pilaris, lichen planus, and polymorphous light eruption.
Management and treatment
Treatment aims to eliminate inflammation and restore muscle performance. Initial treatment includes high-dose corticosteroids, followed by tapering to an appropriate maintenance dose. Immunosuppressive agents (methotrexate, azathioprine, and mycophenolate mofetil) are frequently used in combination. Intravenous immunoglobulin or intravenous methylprednisolone may be used in severe cases. For patients with rapidly progressive ILD a specific approach must be discussed (cyclophosphamide, calcineurin inhibitors). Physical therapy is also recommended. Topical corticosteroid, tacrolimus, and hydroxychloroquine have been used to treat skin manifestations. Patients should avoid direct UV light and use high-factor sunscreen. There is no validated treatment for calcinosis. Pulmonary involvement should be evaluated with high resolution computed tomography and pulmonary function tests, and suspected cardiac involvement with echocardiography. Skin lesion severity should be evaluated with the CDASI (Cutaneous Dermatomyositis Disease Area and Severity Index). Age-appropriate cancer screening is recommended at diagnosis and in cases of relapse within 3 years or refractory disease.
Prognosis
Prognosis is sometimes poor and depends on patient response to treatment, severity of disease manifestations and comorbidities (notably, cancer and pulmonary involvement). Increased cancer risk is associated with age > 50 years, male sex, and presence of specific DM autoantibodies: anti-TIF1-y > anti-NXP2 > anti-Mi2. The anti-MDA5 subgroup is associated with 20% mortality due to rapidly progressive ILD.

                            Last update:
                            February 2021

                            - Expert reviewer(s):
                            Dr Céline ANQUETIL  - Pr Olivier BENVENISTE


A rare genetic disease characterized by infantile onset of recurrent skin ulcerations, arthralgias, fever, peri-articular fistulous osteolysis, oligodontia, nail dystrophy, and keratitis. The disease takes a self-limiting course in childhood but results in severe cicatrization, chronic arthroses, pseudoacromegalic appearance of hands and feet, secondary scoliosis, and visual impairment. There have been no further descriptions in the literature since 1983.


A rare, genetic, ectodermal dysplasia characterized by a widespread, early-onset, reticulate hyperpigmentation that persists throughout life, mild, diffuse non-cicatricial alopecia, and onychodystrophy. There are no dental anomalies. Patients may also present with adermatoglyphia, palmoplantar hyperkeratosis, acral dorsal blistering, and hypohidrosis or hyperhidrosis.


A form of Ehlers-Danlos syndrome (EDS) characterized by extreme skin fragility and laxity, a prominent facial gestalt, excessive bruising and, sometimes, major complications due to visceral and vascular fragility.


Dermochondrocorneal dystrophy is characterised by osteochondrodystrophy of the hands and feet, corneal dystrophy and the presence of skin nodules clustered around the metacarpophalangeal and interphalangeal joints, around the nose and ears and on the posterior surface of the elbow. Gingival lesions may also be present. It has been described in less than 20 patients. Transmission is autosomal recessive.


Dermoid or epidermoid cyst of the central nervous system

A rare congenital tumor characterized by a benign cyst with epithelial and epidermoid components, originating from embryologic displacement and ectopic growth of ectodermal tissue in the central nervous system. In contrast to epidermoid cysts, dermoid cysts also contain dermis and skin appendages. Most common location is the lumbosacral region, as well as the cerebellopontine angle and parasellar area for intracranial lesions. Clinical presentation depends on the location and size of the tumor and includes pain, muscle weakness, motor and sensory disturbances, and incontinence for intraspinal lesions, and intracranial hypertension, gait disturbances, cranial nerve dysfunction, and visual deficits for intracranial tumors. The cysts may rupture and cause chemical meningitis.


A rare ectodermal dysplasia syndrome characterized by a variably severe clinical picture comprising dry, thin skin, onychodysplasia, trichodysplasia, and dental abnormalities (such as hypodontia, microdontia, and persistence of deciduous teeth). There have been no further descriptions in the literature since 1990.


A rare, genetic, ectodermal dysplasia syndrome characterized by skin, hair and nail anomalies (i.e. generalized ichthyosis, congenital alopecia universalis, dystrophic, convex nails), associated with hypohidrosis without hyperthermia, intellectual disability, seizures, and skeletal (e.g. proportionate short stature, platyspondyly) and intestinal (e.g. congenital aganglionic megacolon) anomalies. Facial dysmorphism includes frontal bossing, blepharophimosis, large ears, low nasal bridge and small nose. There have been no further descriptions in the literature since 1992.


Desbuquois syndrome (DBQD) is an osteochondrodysplasia characterized by severe micromelic dwarfism, facial dysmorphism, joint laxity with multiple dislocations, vertebral and metaphyseal abnormalities and advanced carpotarsal ossification. Two forms have been distinguished on the basis of the presence (type 1) or the absence (type 2) of characteristic hand anomalies. A variant form of DBQD, Kim variant (see these terms), has also been described and is characterized by short stature and articular, minor facial and significant hand anomalies.

Summary:
Epidemiology
To date, less than 50 cases have been described in the literature.
Clinical description
DBQD is characterized by severe micromelic dwarfism, facial dysmorphism (round flat face, prominent eyes, midface hypoplasia, short nose, microstomia, long upper lip with flat philtrum, microretrognathia, often resulting in isolated Pierre Robin syndrome (see this term)), thoracic hypoplasia, kyphoscoliosis, severe joint laxity with dislocation, and osteopenia. Additional features include glaucoma, cardiac septal defects, lung hypoplasia, obesity and clubbed feet with rocker bottom appearance. Two forms have been distinguished on the basis of the presence (type 1) or the absence (type 2) of characteristic hand anomalies (accessory ossification center distal to the second metacarpal, bifid distal phalanx, or thumb with delta-shaped phalanx). A variant form of DBQD, Kim variant, has been described in 7 patients originating from Korea and Japan, and is characterized by short stature, articular and minor facial anomalies, together with significant hand anomalies including short metacarpals and elongated phalanges with advanced carpal bone age.
Etiology
DBQD type 1 and Kim variant are caused by mutation in the gene CANT1 (17q25.3). However, the function of CANT1 is still unknown. Mutations in the gene XYLT1 (16p12) has been reported to cause DBQD type 2. XYLT1 encodes xylosyltransferase 1 which is involved in proteoglycan synthesis. However not all DBQD type 2 have XYLT1 mutations supporting the involvement of other disease causing genes.
Diagnostic methods
'Diagnosis relies upon recognition of clinical and radiological features which include an advanced carpal and tarsal bone age; broad femoral neck with a spur-like projection and prominent lesser trochanter, producing characteristic ''monkey wrench'' (Swedish key) appearance; narrow thorax; coronal or sagittal clefting of the vertebrae and typical hand changes for DBQD type 1 that consist of small delta-shaped extraphalangeal bone, distal to the second metacarpal, leading to radial deviation of the index fingers (delta phalanx or bifid thumb),and horizontal acetabular roofs with dislocation of femoral heads. Diagnosis is confirmed by the genetic screening of CANT1 in type 1 and XYLT1 in type 2DBQD.'
Differential diagnosis
Differential diagnosis includes autosomal dominant or recessive Larsen syndrome, Reunion island's Larsen syndrome, Catel-Manzke syndrome, chondrodysplasia with joint dislocations, gPAPP type, CHST3-related skeletal dysplasia, spondyloepiphyseal dysplasia, Omani type, diastrophic dwarfism and humerospinal dysostosis (see these terms).
Antenatal diagnosis
Antenatal diagnosis is achieved by ultrasound during the second trimester of pregnancy, by the detection of hydramnios, hydrops fetalis (see this term), intrauterine growth retardation, vertebral abnormalities and characteristic dysmorphic features.
Genetic counseling
Transmission is autosomal recessive and genetic counseling is recommended.
Management and treatment
Management includes regular orthopedic survey with often a need for multiple surgeries (scoliosis, hip and knee dislocation), and eye and ear follow up.
Prognosis
Type 1 DBQD displays a high lethality rate of >33% due to respiratory failure. Survivors may have intellectual disability, developmental delay, generalized and progressive joint laxity with dislocated knees. Orthopedic complications often limit the ambulation in DBQD.

                            Last update:
                            January 2015

                            - Expert reviewer(s):
                            Pr Valérie CORMIER-DAIRE


Desmin-related myopathy with Mallory body-like inclusions

A rare inclusion myopathy characterized by hypotonia and axial muscle weakness leading to spinal rigidity and development of scoliosis and other deformities which can result in respiratory failure. The symptoms are apparent from birth or early childhood. The muscle weakness is not progressive, and most patients remain ambulatory. Muscle biopsies show variable myopathic changes.


A rare genetic skeletal muscle disease characterized by abnormal chimeric aggregates of desmin and other cytoskeletal proteins and granulofilamentous material at the ultrastructural level in muscle biopsies and variable clinical myopathological features, age of disease onset and rate of disease progression. Patients present with bilateral skeletal muscle weakness that starts in distal leg muscles and spreads proximally, sometimes involving trunk, neck flexors and facial muscles and often cardiomyopathy manifested by conduction blocks, arrhythmias, chronic heart failure, and sometimes tachyarrhythmia. Weakness eventually leads to wheelchair dependence. Respiratory insufficiency can be a major cause of disability and death, beginning with nocturnal hypoventilation with oxygen desaturation and progressing to daytime respiratory failure.


A desmoid tumor (DT) is a benign, locally invasive soft tissue tumor associated with a high recurrence rate but with no metastatic potential.

Summary:
Epidemiology
DTs account for < 3% of soft tissue tumors. Their annual incidence is estimated to range between 1/250,000-1/500,000. They predominantly affect women and can occur between the ages of 15-60 years, but frequently during early adolescence and with a peak age of about 30 years.
Clinical description
In principle, DTs can occur in any part of the body: extra-abdominally (neck, shoulders, upper limbs, gluteal region), abdominally (originating from muscle fascia or the abdominal/chest wall), and more rarely intra-abdominally in the mesentery or retroperitoneum. Usually, they are firm and smooth palpable masses upon discovery. Depending on the location of the tumor, symptoms may include pain, fever, and functional impairment or loss of function of the organ involved. DTs may appear after surgical resections, typically after caesarian section. Intra-abdominal DTs are often observed in patients with an association of familial adenomatous polyposis (FAP) or Gardner syndrome (see these terms).
Etiology
DTs result from the proliferation of well-differentiated myofibroblasts. The exact etiopathogenetic mechanism is still unknown, but they seem to have a multi-factorial origin with hormonal and genetic factors being involved. Somatic mutations in the CTNNB1 gene (3q21) encoding beta-catenin have been found in about 85 % of sporadic cases. In cases with FAP, DTs have been associated with mutations in the tumor suppressor gene APC (5q21-q22) encoding the adenomatous polyposis coli protein.
Diagnostic methods
Initial diagnosis is based on imaging techniques (computed tomography and magnetic resonance imaging) revealing the presence of an infiltrative growing mass. Diagnosis is confirmed by tumor biopsy showing abundant collagen surrounding elongated spindle-shaped cells containing small and regular nuclei and pale cytoplasm. Immunohistological examination shows expression of muscle cell markers (e.g. actin, desmin, vimentine) and absence of CD34. Moreover, diagnosis can be confirmed by screening for mutations of CTNNB1.
Differential diagnosis
The differential diagnosis is broad with fibrosarcomas on the one extreme and myofibroblastic processes such as nodular fasciitis and even hypertrophic scars and keloids on the other. The differential diagnosis of intra-abdominal DTs includes gastrointestinal stromal tumors, solitary fibrous tumors, inflammatory myofibroblastic tumors, sclerosing mesenteritis and retroperitoneal fibrosis (see these terms).
Genetic counseling
Most cases are sporadic. Familial cases (5-10 %) are associated with FAP.
Management and treatment
Complete surgical resection remains the therapeutic mainstay of DTs. For unresectable tumors or those not amenable to surgical resection with R0 (microscopic tumor clearance) intent or accompanied by an unacceptable function loss, non-surgical treatments comprise radiotherapy, anti-estrogen therapy, non-steroidal anti-inflammatory agents, chemotherapy (e.g. methotrexate, vinblastine/vinorelbine, pegylated liposomal doxorubicin) and/or tyrosine kinase inhibitors (e.g. imatinib, sorafenib). As DTs have a variable and often unpredictable clinical course, a period of watchful waiting is advisable for asymptomatic patients. As DTs often recur, a surveillance strategy every 3-6 months is essential.
Prognosis
Local recurrence occurs in around 70 % of cases. Prognosis depends on the type of tumor. Life expectancy is normal for abdominal and extra-abdominal tumors. However, it is lower in cases of intra-abdominal DTs due to complications such as intestinal obstruction, hydronephrosis or sepsis. Repeated surgical resections are associated with a greater risk of morbidity.

                            Last update:
                            September 2013

                            - Expert reviewer(s):
                            Pr Bernd KASPER


Desmoplastic infantile astrocytoma/ganglioglioma are mixed neuronal-glial tumors representing a histological spectrum of the same tumor. They are usually supratentorially located, large, cystic masses with a peripheral solid component, characterized by prominent desmoplastic stroma and pleomorphic populations of neoplastic cells with either astrocytic or ganglionic differentiation and poorly differentiated cells in variable proportions. They usually present in the first 18 months of age with rapid head growth, bulging anterior fontanel and bone structures over the tumor, signs of raised intracranial pressure (headache, vomiting, papilledema), focal neurological signs and sometimes seizures.


An aggressive soft tissue cancer that typically arises in serous lined surfaces of the abdominal or pelvic peritoneum, and spreads to the omentum, lymph nodes and hematogenously disseminates especially to the liver. Extraserous primary location has been reported in exceptional cases.

Summary:
Epidemiology
DSRCT is extremely rare. Only a few hundred cases have been reported worldwide since the first description in 1989. It usually affects males, during adolescence or young adulthood, with a male-to-female ratio of 4:1.
Clinical description
Clinical signs and symptoms of DSRCT are non-specific. DSRCT presents with abdominal pain, enlarged abdomen, dyspepsia, and/or vomiting and weight loss depending on the stage of the disease. Other signs can be observed such as a palpable abdominal mass, gastrointestinal occlusion, ascites, and hepatomegaly. Sometimes, DSRCT can arise from other primary sites such as the brain, thorax, lung, paratesticular region, ovaries and nasal cavity, without characteristic clinical signs.
Etiology
DSRCT seems to originate from the mesothelium. In almost all cases, a specific translocation t(11;22)(p13;q12) is found that juxtaposes the EWSR1 gene to the WT1 tumor suppressor gene. However, the underlying molecular mechanism remains unknown. Several other associated chromosomal translocations have been described (t(5;19), t(X;16) and t(4;10)).
Diagnostic methods
The diagnosis is difficult due to the rarity of the tumor and its similarities with other small round cell tumors. Diagnosis is based on clinical signs, endoscopic examination (laparoscopy) and/or imaging techniques (radiography, chest-abdominal-pelvic computed tomography (CAP-CT)). Biopsy of the mass shows nests of poorly differentiated small round cells with little cytoplasm and hyperchromatic nuclei that are surrounded by desmoplastic stroma. Cells can present an epithelial, mesenchymal, or neuronal differentiation. The diagnosis is confirmed by the presence of a polyphenotypic immunoprofile (tumor cells express several cytokeratins (KL1, AE1/AE3), desmin, and neuron-specific enolase), and by molecular identification (FISH, RT-PCR) of the EWSR1/WT1 translocation.
Differential diagnosis
Differential diagnoses include all the small round cells tumors: Ewing sarcoma and other peripheral neuroectodermal tumors (PNET), Wilms tumor, rhabdomyosarcoma and undifferentiated carcinoma (see these terms).
Management and treatment
Management is multidisciplinary and must be discussed by a panel of physicians in a specialized center. Up to 30% of DSRCT cases are misdiagnosed leading to incorrect management. There are currently no validated recommendations on clinical management and no cytotoxic agents have been granted a European Marketing Authorization (MA) in this indication. Some teams have proposed treatment based on aggressive multiagent chemotherapy (off-label use), followed by optimal cytoreductive surgery and abdominal radiotherapy. Prospective studies are underway to evaluate the effect of hyperthermic intraperitoneal chemotherapy (HIPEC), maintenance chemotherapy and targeted therapy.
Prognosis
Prognosis is poor. Median overall survival is 17 months and less than 20% of patients live more than 5 years after diagnosis.

                            Last update:
                            March 2011

                            - Expert reviewer(s):
                            Dr Gwenaël FERRON  - Pr François-Noël GILLY


Desmoplastic/nodular medulloblastoma is a histological variant of medulloblastoma (see this term), an embryonic malignancy, often located in one of the cerebellar hemispheres, occurring most frequently in adults and manifesting with symptoms such as vomiting and headache.


Desmosterolosis is a very rare sterol biosynthesis disorder characterized by multiple congenital anomalies, failure to thrive, and intellectual disability, with elevated levels of desmosterol.

Summary:
Epidemiology
Only 9 cases have been reported in the literature to date.
Clinical description
Desmosterolosis presents at birth with growth restriction, spasticity with variable degrees of hand contractures, either microcephaly or relative macrocephaly, and microretrognathia. Transient neonatal seizures, nystagmus, strabismus and failure to thrive are also seen in most cases. Intellectual disability occurs in all patients and is first noted by delayed milestones for speech and adaptive, fine and gross motor development. Less common manifestations reported include hirsutism, facial dysmorphism (downslanting palpebral fissures, bilateral epicanthal folds, submucous cleft palate, and thick alveolar ridges), sensorineural hearing loss, patent arterial duct, ambiguous genitalia, bilateral clubfeet, muscle wasting, and cutis aplasia. Optic atrophy, corpus callosum agenesis and loss of white matter are also noted.
Etiology
Desmosterolosis is due to mutations in the DHCR24 gene (1p32.3) encoding 3-beta-hydroxysterol delta-24-reductase. This enzyme catalyzes the conversion of desmosterol (the cholesterol precursor) to cholesterol, which is highly involved in embryonic development and morphogenesis. Reduced enzyme activity leads to the accumulation of desmosterol and a lack of cholesterol, disrupting antenatal and postnatal development.
Genetic counseling
Desmosterolosis is inherited in an autosomal recessive manner and genetic counseling is possible.

                            Last update:
                            December 2014

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


A rare idiopathic interstitial pneumonia characterized by extensive, diffuse intra-alveolar accumulation of pigment-laden macrophages, most commonly associated with long-term exposure to tobacco smoke. Patients present with slowly progressive shortness of breath on exertion and chronic cough with bilateral crackles. Digital clubbing is also frequently observed. Pulmonary function test reveals a restrictive pattern. Computed tomography typically shows diffuse ground-glass opacities with subpleural and lower zone predominance.