Developmental and epileptic encephalopathy with spike-wave activation in sleep

Continuous spikes and waves during sleep (CSWS) is a rare epileptic encephalopathy of childhood characterized by seizures, an electroencephalographic (EEG) pattern of electrical status epilepticus in sleep (ESES) and neurocognitive regression in at least 2 domains of development.

Summary:
Epidemiology
The prevalence is unknown. CSWS is a rare condition that affects 0.5-1.5% of children with epilepsy (in some series) and has a 3:2 male to female ratio.
Clinical description
CSWS is an age-related epileptic encephalopathy in which the clinical features evolve over time. After a normal or only moderately abnormal baseline development, seizures usually present at around 2-4 years of age. They are often unilateral, tonic-clonic or clonic and typically occur out of sleep. Seizures become more frequent, severe, and treatment-resistant with a marked deterioration in seizures, EEG, and developmental aspects (i.e. language, social interactions, global intelligence, motor skills and behavior) at approximately 5-6 years of age. During this acute stage, the seizures (absence seizures, clonic, tonic-clonic and others) and EEG abnormalities are difficult to control. Spontaneous improvement in seizures and EEG features occurs before puberty, but most patients remain with severe developmental delay.
Etiology
Early developmental lesions such as vascular insults, especially affecting the thalamus, or malformations of cortical development have been found in approximately half of all cases. Genetic factors, especially mutations in the GRIN2A gene (16p13.2) have been recently linked to CSWS.
Diagnostic methods
Diagnosis is based on characteristic clinical evolution (with seizures and neurocognitive regression in at least 2 domains) and EEG findings. The main EEG feature of CSWS is ESES. ESES is characterized by marked potentiation of epileptiform discharges during the transition from wakefulness to sleep leading to (near-) continuous, bilateral or occasionally lateralized slow spikes and waves that occur during a significant proportion of non-rapid eye movement (REM) sleep. Magnetic resonance imaging (MRI) is performed in order to identify any brain lesions. As of now it is not routine clinical practice to perform genetic tests for GRIN2A in CSWS, but testing is available in certain specialized centers.
Differential diagnosis
Differential diagnosis includes any epileptic syndrome with sleep potentiation of epileptiform activity such as Landau-Kleffner syndrome, Panayiotopoulos and Gastaut types of benign childhood occipital epilepsy and rolandic epilepsy (see these terms).
Genetic counseling
An autosomal dominant transmission has been proposed in families with a GRIN2A mutation.
Management and treatment
The main aim of treatment is to control seizures. It is unknown whether improvement of EEG abnormalities improves the long-term developmental outcome. High-dose nocturnal benzodiazepines like diazepam or clobazam are successful in reducing epileptiform activity acutely and subacutely. The antiepileptic drugs most often used include valproate, levetiracetam, lamotrigine, and ethosuximide. Corticosteroids are useful but associated with long-term side effects. Epilepsy surgery is an efficacious therapy in selected cases, even when epileptiform discharges are bilateral.
Prognosis
Although seizures and EEG abnormalities tend to normalize by adolescence, the developmental prognosis is generally poor as neurocognitive regression is permanent in most cases.

                            Last update:
                            April 2014

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


Developmental and speech delay due to SOX5 deficiency is a rare genetic syndromic intellectual disability characterized by mild to severe global developmental delay, intellectual disability and behavioral abnormalities, hypotonia, strabismus, optic nerve hypoplasia and mild facial dysmorphic features (down slanting palpebral fissures, frontal bossing, crowded teeth, auricular abnormalities and prominent philtral ridges). Other associated clinical features may include seizures and skeletal anomalies (kyphosis/scoliosis, pectus deformities).


Developmental delay due to methylmalonate semialdehyde dehydrogenase deficiency

A rare, genetic, inborn error of branched-chain amino acid metabolism disorder, with a highly variable clinical and biochemical phenotype, typically characterized by mild to severe global developmental delay, elevated methylmalonic acid and, occasionally, lactic acid plasma levels, and chronic methylmalonic aciduria, which may be accompanied by elevation of additional organic or amino acids in urine (e.g. beta-alanine, methionine, 3-hydroxypropionic, 3-aminoisobutyric and/or 3-hydroxyisobutyric acid). Microcephaly, mild craniofacial dysmorphism, axial hypotonia, liver failure, and central nervous system abnormalities on MRI have also been reported.


Developmental delay with autism spectrum disorder and gait instability is a rare, genetic, neurological disorder characterized by infant hypotonia and feeding difficulties, global development delay, mild to moderated intellectual disability, delayed independent ambulation, broad-based gait with arms upheld and flexed at the elbow with brisk walking or running, and limited language skills. Behavior patterns are highly variable and range from sociable and affectionate to autistic behavior.


Developmental delay-facial dysmorphism syndrome due to MED13L deficiency

A rare, genetic syndromic intellectual disability characterized by developmental delay, mild to severe intellectual disability, facial features (bulbous nasal tip, and macroglossia, macrostomia, or open mouth appearance) and a wide spectrum of other nonspecific variable clinical features.

Summary:
Epidemiology
To date, more than 70 cases have been reported.
Clinical description
Patients have a variable degree of intellectual disability, global developmental delay (notably with severe speech and language impairment), muscular hypotonia, and facial features (including broad forehead, bitemporal narrowing, upslanting palpebral fissures, low-set ears, flat nasal bridge, bulbous nose, thin vermillion border and open mouth with tongue protrusion). Highly variable additional features include cardiac defects (persistent foramen ovale, ventricular septal defects or tetralogy of Fallot), cerebellar ataxia, seizures, growth difficulties, microcephaly, ventriculomegaly or myelination defects.
Etiology
The disorder is sporadic caused by either a sequence variation in the mediator complex subunit 13-like gene (MED13L), an intragenic microdeletion within the gene, or by a larger microdeletion encompassing the entire gene. Rare intragenic microduplications within MED13L are also reported.
Diagnostic methods
The syndrome could be suspected on the association of developmental delay, speech impairment, motor delay, and facial features (notably, an open mouth with a protruding tongue, a thin vermillion border, upslanting palpebral fissures and a bulbous nasal tip). Molecular genetic testing approaches include array-comparative genomic hybridization for microdeletion identification, and sequencing of the entire MED13L coding region for sequence variants (gene panel, exome sequencing).
Differential diagnosis
Some patients share some clinical features observed in Kleefstra syndome, Mowat-Wilson syndrome, Kabuki syndrome and 1p36 microdeletion.
Antenatal diagnosis
Pathogenic variations are de novo. However, very rare cases of parental mosaicism are described and prenatal genetic testing may be possible in such families with a proband. No specific prenatal signs are reported.
Genetic counseling
Most cases arise de novo and thus the sibling recurrence risk is low. The disorder is autosomal dominant with 50% risk of transmission from affect individuals to their offspring; however, transmission of the condition has never been reported.
Management and treatment
Management is mainly supportive and symptomatic. Affected patients should benefit from speech therapy. Development, walking evolution, hearing and vision should be monitored closely.
Prognosis
The prognosis and function consequences are variable and dependent on the associated anomalies and intellectual disability.

                            Last update:
                            November 2020

                            - Expert reviewer(s):
                            Dr Jamal GHOUMID | ITHACA* - Dr Thomas SMOL | ITHACA*

                                * European Reference Network


Developmental delay-language impairment-dopa responsive dystonia-parkinsonism syndrome due to 2q24 microdeletion

2q24 microdeletion syndrome is a chromosomal anomaly consisting of a partial long arm deletion of chromosome 2 and characterized clinically by a wide range of manifestations (depending on the specific region deleted) which can include seizures, microcephaly, dysmorphic features, cleft palate, eye abnormalities (coloboma, cataract and microphthalmia), growth retardation, failure to thrive, heart defects, limb anomalies, developmental delay and autism.


Developmental malformations-deafness-dystonia syndrome is characterised by the association of midline malformations, sensory hearing loss, and a delayed-onset generalised dystonia syndrome.

Summary:
Epidemiology
It has been described in two monozygotic twins.
Etiology
The syndrome is caused by a missense point mutation in the gene coding for beta-actin, a nonmuscle actin isoform. Mutations in nonmuscle actin isoforms may be associated with developmental anomalies and neurological disorders such as dystonia.

                            Last update:
                            June 2006


A rare, congenital, non-syndromic, developmental defect during embryogenesis characterized by positioning of the heart in the right hemithorax, with the base and apex of the heart pointing caudally and to the right, due to abnormalities of embryologic origin that are intrinsic to the heart itself. Situs inversus or situs solitus may be associated, with extracardiac visceral transposition anomalies usually present in the former case and additional cardiac defects (e.g. septal defects, transposition of the great arteries, double-outlet right ventricle, anomalous pulmonary venous return, tetralogy of Fallot) frequently observed in both cases.


A rare disorder characterized by congenital anomalies or foetal/neonatal complications in an infant that are linked to diabetes in the mother.

Summary:
Epidemiology
Several reports show that the birth prevalence of congenital malformations can be cut by a third by using strict preconception glycemia control, but the challenge of implementing this approach remains.
Clinical description
Macrosomia is also a common problem among infants of women with established insulin-dependent diabetes mellitus. Excess mortality among infants of women with preexisting insulin-dependent diabetes mellitus is predominantly due to congenital malformations. All types of congenital malformations are involved, but some are more common. Notably, the risk of cardiovascular malformations (CVM) is increased, and specific studies show that preconceptional maternal diabetes is strongly associated with CVM of early embryonic origin and with cardiomyopathy (respective odds ratios are 5 and 15). CVM of early embryonic origin are laterality defects (cardiovisceral and atrioventricular discordance), outflow tract anomalies (an association was found between truncus arteriosus and double outlet right ventricle, and other anomalies with normally related great arteries but no association was found with simple transpositions), and anomalies of the endocardial cushion (an association was found with complete but not with partial forms of atrioventricular septal defects). CMV also include hypertrophic cardiomyopathy, which is generally benign and transient, although it may be lethal if associated with hydrops fetalis, especially in case of severe macrosomia. Other anomalies associated with maternal preconceptional diabetes are renal malformations, especially uni- or bilateral kidney agenesis. These ageneses are described as either isolated or of part of multiple malformation syndromes that are more common in individuals with maternal diabetes: caudal regression syndrome (a rare anomaly of the lower body pole that represents a continuum of congenital malformations ranging from isolated sacral agenesis to absence of the lumbosacral spine and major visceral anomalies) and DiGeorge anomaly (velo-cardio-facial syndrome).
Etiology
Cytogenetic studies of DiGeorge anomaly in individuals with maternal diabetes usually detect no abnormalities (i.e. do not uncover a 22q11 microdeletion).
Genetic counseling
In infants of women with established insulin-dependent diabetes mellitus, the risk of congenital malformations is 10 times higher than that in the general population, and the rate of stillbirths is five times higher than that in the general population.

                            Last update:
                            February 2006

                            - Expert reviewer(s):
                            Dr Elisabeth ROBERT-GNANSIA


Blackfan-Diamond anemia (DBA) is a congenital aregenerative and often macrocytic anemia with erythroblastopenia.

Summary:
Epidemiology
Annual incidence in the general population of Europe is estimated at around 1/150,000. Both sexes are equally affected and no ethnic predisposition has been identified.
Clinical description
The anemia is discovered early in life, usually within the first 2 years; diagnosis after 4 years of age is very unlikely. Pallor and dyspnea, especially during feeding or while sucking, are the principal warning signs. Pallor is isolated, without organomegaly, signs suggestive of hemolysis or involvement of other hematopoietic cell lines. Over half of all DBA patients present with short stature and congenital anomalies, the most frequent being craniofacial (Pierre-Robin syndrome and cleft palate), thumb and urogenital anomalies. Pregnancies in DBA-affected women are now identified as high-risk, for both mother and child. DBA patients may also be at a higher risk of leukemia and cancer.
Etiology
At present, disease-causing mutations are identified in 40-45% of patients. All involved genes code for ribosomal proteins (RPs) from either the small (RPS7, RPS17, RPS19, RPS24) or the large (RPL5, RPL11, RPL35a) ribosomal subunit. Mutations in RPS19, RPL5 and RPL11 are found in 25%, 9% and 6.5% of patients respectively, whereas the other genes are each involved in only 1 to 3% of cases. The only clear genotype/phenotype correlation made so far is the frequent occurrence of craniofacial abnormalities in RPL5 and RPL11 mutation carriers and the rarity of these anomalies in RPS19 mutation carriers.
Diagnostic methods
In a child with anemia and erythroblastopenia, the diagnosis can be supported by a familial history (10-20% of cases), associated malformations (40% of cases), and elevated erythrocyte adenosine deaminase (EAD), which is a frequent but non-specific sign that may also be elevated in relatives in the absence of other DBA symptoms. Detection of a disease-causing mutation is of diagnostic value.
Differential diagnosis
The differential diagnosis should include transient erythroblastopenia (see this term), chronic parvovirus B19 infection, and other congenital anemias.
Antenatal diagnosis
Genetic counseling and prenatal diagnosis are difficult because of the variability of clinical expression and the fact that only 40-45% of patients have an identified mutation within a RP gene. In familial cases, the risk of recurrence is 50%. Close ultrasound follow-up during the pregnancy is recommended in all cases.
Genetic counseling
DBA is inherited as an autosomal dominant trait with variable penetrance.
Management and treatment
The two main therapeutic approaches are regular transfusions and long-term corticosteroid therapy. Treatment must be adapted to each case and according to the age of the patient. Steroids should not be administered during the first year of life. Short stature, occurring both as part of the syndrome and due to treatment-related complications (steroids, hemochromatosis), is a major issue for these patients. Allogenic bone-marrow transplantation must be discussed in corticoresistant patients when an unaffected and HLA-identical sib is available.
Prognosis
The prognosis is generally good. However, complications of treatment and a higher incidence of cancer may reduce life expectancy. Disease severity depends on the quality and response to treatment. For patients undergoing regular transfusions, quality of life is clearly altered.

                            Last update:
                            February 2009

                            - Expert reviewer(s):
                            Dr Thierry LEBLANC


Dianzani autoimmune lymphoproliferative disease (DALD) is a very rare disorder characterized by autoimmunity, lymphadenopathy and/or splenomegaly.

Summary:
Epidemiology
The prevalence of DALD is not known. The disorder has been reported in fewer than 30 patients to date.
Clinical description
Age of onset is highly variable, ranging from childhood to young adulthood. In patients with DALD, signs of autoimmunity include recurrent episodes of thrombocytopenia, neutropenia, and/or autoimmune hemolytic anemia. Lymphoadenopathy and/or splenomegaly are invariably noted. A possible increased risk of cancer has been suggested in these patients.
Etiology
The cause of DALD is not known but it is thought to be hereditary.
Diagnostic methods
Biologically, DALD is characterized by normal double-negative T-cells (DNTs) and defective in vitro FAS-mediated apoptosis.
Genetic counseling
The pattern of inheritance of DALD is not known.

                            Last update:
                            June 2014

                            - Expert reviewer(s):
                            Dr Koneti RAO


DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome

A rare genetic disease characterized by progressive and severe sensorineural hearing loss with onset in the first decade of life, associated with mild thrombocytopenia, often with enlarged platelets. Most patients do not show significant bleeding tendency.


A rare primary bone dysplasia characterized by costovertebral ossification defects with small chest, abnormal vertebral segmentation, and posterior rib gaps containing incompletely differentiated mesenchymal tissue. Consistent dysmorphic craniofacial features include ocular hypertelorism, epicanthal folds, depressed nasal bridge with short nose, and low-set ears. The most common extraosseous manifestations are renal abnormalities such as multicystic kidneys. The disease is usually perinatally lethal due to respiratory insufficiency.


Diaphragmatic defect-limb deficiency-skull defect syndrome

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by diaphragmatic hernia, lung hypoplasia, ossification defect of the skull, and severe limb hypoplasia. Other clinicial features may include, syndactyly, clinodactyly, extra spleen, absence of the femur or pelvic bone, partial intestinal malrotation, omphalocele and testicular atrophy.


Diaphragmatic hernia-short bowel-asplenia syndrome

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by congenital diaphragmatic hernia, short bowel, and asplenia. Dysmorphic facial features include long forehead, hypertelorism, upturned nares, and small mandible. Atresia of the duodenum has also been reported.


Diaphyseal medullary stenosis-bone malignancy syndrome

Diaphyseal medullary stenosis with malignant fibrous histiocytoma is a very rare autosomal dominant bone dysplasia/cancer syndrome characterized clinically by bone infarctions, cortical growth abnormalities, pathological fractures, and development of bone sarcoma (malignant fibrous histiocytoma).


A rare disorder marked by short stature with short extremities (final adult height is 120cm +/- 10cm), and joint malformations leading to multiple joint contractures (principally involving the shoulders, elbows, interphalangeal joints and hips).

Summary:
Epidemiology
Prevalence is estimated at 1-1.3/100,000. The disorder affects both males and females.
Clinical description
At birth, infants have bilateral clubfoot, short limb deformation of the wrists and abducted thumbs. Cleft palate and mandible hypoplasia are also common findings. Cysts appear on the external ear within the first months of life. Growth is slow and scoliosis is frequent and develops progressively. Joint deformations are severe and can lead to either limitation of joint movement or hyperlaxity. The severity of the clinical manifestations is variable, ranging from very severe to moderate forms that may be diagnosed very late.
Etiology
The syndrome is caused by mutations in the SLC26A2 (or diastrophic dysplasia sulfate transporter; DTDST) gene (5q31-q34), which encodes a sulfate transporter that is predominantly expressed in the cartilage. Mutations in the same gene have been implicated in a moderate form of epiphyseal dysplasia and in several lethal disorders such as achondrogenesis type 1b and atelosteogenesis type 2 (see these terms).
Diagnostic methods
Diagnosis is based on radiological findings: short and thick tubular bones, wide metaphyses, short and oval-shaped first metacarpals, subluxation of the thumb (hitchhiker thumb) and subluxation of the cervical vertebrae.
Antenatal diagnosis
Prenatal diagnosis may be suspected on the basis of ultrasound findings (clubfoot and short limbs).
Genetic counseling
The syndrome is transmitted in an autosomal recessive manner.
Management and treatment
Management should include careful monitoring and eventual correction of the progressive scoliosis, and surgical correction of the joint malformations.
Prognosis
In the absence of severe complications (spinal cord compression) associated with spinal malformations, life expectancy is good but the short stature and deformity are usually severe.

                            Last update:
                            November 2008

                            - Expert reviewer(s):
                            Dr Martine LE MERRER


Diazoxide-resistant diffuse hyperinsulism (DRDH) is a form of Diazoxide resistant hyperinsulinism (see this term) characterized by recurrent episodes of profound hypoglycemia caused by an excessive/ uncontrolled insulin secretion (inappropriate for the level of glycemia) due to diffuse involvement of pancreas that is unresponsive to medical treatment with diazoxide, often necessitating near total/total pancreatectomy.


Diazoxide-resistant focal hyperinsulinism due to Kir6.2 deficiency

A rare, congenital, isolated hyperinsulinism disorder characterized by diazoxide unresponsive recurrent episodes of hyperinsulinemic hypoglycemia resulting from an excessive insulin secretion by the pancreatic bêta-cells due to Kir6.2 deficiency. Hypoglycemia may lead to variable clinical manifestation, ranging from asymptomatic hypoglycemia revealed by routine blood glucose monitoring to macrosomia at birth, mild to moderate hepatomegaly and life-threatening hypoglycemic coma or status epilepticus, further leading to poor neurological outcome.


Diazoxide-resistant focal hyperinsulinism due to SUR1 deficiency

A rare, congenital, isolated hyperinsulinism disorder characterized by diazoxide unresponsive recurrent episodes of hyperinsulinemic hypoglycemia resulting from an excessive insulin secretion by the pancreatic beta-cells due to a mutation in the ABCC8 gene. Pancreatic involvement is focal and can be cured by a selective partial pancreatectomy. Hypoglycemia may lead to variable clinical manifestations, ranging from asymptomatic hypoglycemia revealed by routine blood glucose monitoring to macrosomia at birth, mild to moderate hepatomegaly and life-threatening hypoglycemic coma or status epilepticus, further leading to poor neurological outcome.


A form of congenital diazoxide-resistant hyperinsulinism characterized by recurrent episodes of profound hypoglycemia caused by an excessive/uncontrolled insulin secretion (inappropriate for the level of glycemia) due to a focal adenomatous hyperplasia of pancreas, that is unresponsive to medical treatment with diazoxide.


A form of congenital isolated hyperinsulism characterized by an excessive/ uncontrolled insulin secretion (inappropriate for the level of glycemia), recurrent episodes of profound hypoglycemia and resistance to medical management with diazoxide. Pancreatic involvement can be diffuse or focal.


A rare autosomal recessive inborn error of metabolism characterized by increased urinary excretion of dicarboxylic amino acids, glutamate and aspartate, that can be associated with kidney stones and neuropsychiatric manifestations.


A rare non-syndromic uterovaginal malformation characterized by two separate uterine cavities and cervices, due to failure of the Müllerian ducts to fuse. A longitudinal vaginal septum of variable thickness and elasticity is also present. Patients may be asymptomatic or experience dyspareunia or dysmenorrhea. There is increased frequency of endometriosis, as well as fertility and gestational issues with significantly reduced chances of seeing a pregnancy to term. The condition may be associated with renal agenesis.


A rare skin disorder characterized by the co-ocurrence of sebaceous nevi with aplasia cutis congenita located directly adjacent or in close proximity and ocular abnormalities including limbal dermoids and coloboma of the conjunctiva.


Diencephalic syndrome (DS) is a rare condition characterized by profound emaciation and failure to thrive (with normal caloric intake and normal linear growth), hyperalertness, hyperkinesia and euphoria, in the presence of hypothalamic tumors.

Summary:
Epidemiology
The prevalence is unknown.
Clinical description
DS usually presents in infants or young children (mean age 6 months), but can also occur rarely in older children and adults. DS usually occurs in the presence of low grade astrocytoma/glioma brain tumors of the hypothalamus, which may extend into the optic pathway. These tumors are usually more aggressive and appear at a younger age when associated with DS. Rarely, DS can be secondary to craniopharyngioma, as well as other suprasellar tumors. Manifestations of DS include weight loss, eventually leading to severe emaciation (despite normal caloric intake and linear growth) with an absence of subcutaneous fat, as well as hyperalertness, hyperkinesia, and cheerfulness extending to euphoria in some. Nystagmus, strabismus, decreased visual acuity (and very rarely blindness), optic pallor, hydrocephalus, headache, somnolence, and vomiting have also been reported in some cases. Hypothalamic obesity may occur due to hypothalamic damage. Normal or precocious intellectual development is noted. Rarely, tumors may also be associated with neurofibromatosis type 1.
Etiology
A variety of chiasmatic and hypothalamic low-grade gliomas have been reported to be associated with DS, most commonly pilocytic and pilomyxoid astrocytoma, but there are case reports of craniopharyngioma, suprasellar ependymoma, suprasellar germinoma, suprasellar epidermoid cyst, and hypothalamic spongioblastoma. These tumors may lead to hypothalamic dysfunction and/or degeneration of the optic nerve. The pathogenesis of DS is unknown. Recently, it was proposed that leptin may be dysregulated, but further studies are needed.
Diagnostic methods
When DS is suspected clinically (failure to thrive in children despite normal caloric intake), gadolinium-enhanced magnetic resonance imaging of the cranium, as well as of the spine (due to frequent leptomeningeal seeding) is performed, and cerebrospinal fluid analysis may also be necessary. Ophthalmologic examination should be performed to check for any visual abnormalities. Growth hormone and ghrelin levels are increased and insulin and leptin levels are decreased, but those changes may be secondary to the patient's body mass index.
Differential diagnosis
The differential diagnosis includes gastrointestinal disorders that lead to severe weight loss such celiac disease.
Management and treatment
Treatment aims at removing or reducing the size of the tumor, by surgical or non-surgical methods. Since complete resection of the tumor is not possible due to its location, tumor resection is usually partial and is generally followed by chemotherapy. Radiotherapy is not commonly used, as the patients are young. Patients also require nutritional supplementation (orally or via nasogastric feeding tube or gastrostomy) for malnutrition while symptomatic. Follow-up after completion of treatment includes regular life-long oncologic, neurologic, ophthalmologic and clinical assessments as precocious puberty and pituitary hormone deficiencies may develop.
Prognosis
Prognosis depends on the histological type and grade of tumor but is poorer in patients with DS than in patients with similar tumors who do not present with DS. Frequently, these tumors continue to progress despite treatment. If untreated, patients have an average survival time of less than 12 months after diagnosis, but with proper treatment the long-term survival is greatly improved.

                            Last update:
                            October 2015

                            - Expert reviewer(s):
                            Dr Laurie E. COHEN


Diencephalic-mesencephalic junction dysplasia is a rare, genetic, non-syndromic cerebral malformation characterized by severe intellectual disability, progressive postnatal microcephaly, axial hypotonia, spastic quadriparesis, seizures and facial dysmorphism (bushy eyebrows, hairy forehead, broad nasal root, long flat philtrum, V-shaped upper lip). Additionaly, talipes equinovarus, non-obstructive cardiomyopathy, persistent hyperplastic primary vitreous, obstructive hydrocephalus and autistic features may also be associated. On brain magnetic resonance imaging, the 'butterfly sign' is characterisitcally observed and cortical calcifications, agenesis of the corpus callosum, ventriculomegaly, brainstem dysplasia and cerebellar vermis hypoplasia have also been described.


A rare disorder described in sub-Saharan African populations and characterized by iron overload due to excess dietary iron intake and possibly genetic factors, leading to hepatic portal fibrosis and micronodular cirrhosis.


A malformation syndrome reported in offspring (children and grandchildren) of women exposed to diethylstilbestrol (DES) during pregnancy and is characterized by reproductive tract malformations, decreased fertility and increased risk of developing clear cell carcinoma of the vagina and cervix in young women. Reproductive malformations reported in DES syndrome include small, T-shaped uteri and other uterotubal anomalies that increase the risk of miscarriages in women and epididymal cysts, microphallus, cryptorchidism, or testicular hypoplasia in men. DES, a synthetic nonsteroidal estrogen was widely prescribed from 1940-1970 to prevent miscarriage.


Difference of sex development-intellectual disability syndrome

A rare syndrome with 46,XY difference of sex development characterized by variable degrees of intellectual disability, short stature, severe genital anomalies resulting in sexual ambiguity (such as pseudovaginal perineoscrotal hypospadias and persistence of Müllerian structures), and ocular anomalies (microphthalmia, coloboma). Craniofacial peculiarities (coarse features, deep set eyes), spina bifida, imperforate anus, and sensorineural hearing loss were also described. No new cases have been reported since 1994.


A rare, slow-growing, epithelial thyroid carcinoma typically presenting as an asymptomatic thyroid mass and is classed as either papillary thyroid cancer (PTC), follicular thyroid cancer (FTC) or Hurthle cell thyroid cancer (HCTC).

Summary:
Epidemiology
The annual incidence of differentiated thyroid cancer (DTC) is about 1/10,000, and the incidence appears to be increasing. The female to male ratio is about 3:1.
Clinical description
PTC, FTC, and HCTC have similar presentations, and constitute about 75, 20, and 5 percent of cases, respectively. About 10 percent of PTC are classified as tall cell variant, the most aggressive form of PTC. HCTC is generally considered slightly more aggressive than PTC and FTC. The age at diagnosis is usually over 30 years. Presentation is typically with an asymptomatic thyroid nodule. Rare but worrisome presentations include hoarseness due to vocal cord paralysis and obstruction of the airway or esophagus, and may suggest an aggressive variant of DTC or anaplastic thyroid carcinoma. DTC grows slowly, and distant metastases are rare at the time of presentation. The most common metastatic site is the cervical lymph nodes. Distant metastasis to lungs or bones is rare (about 5%). Pediatric cases are rare. They are more frequently present with lymph node involvement. Despite this apparently more aggressive presentation, the prognosis is excellent. Pathologically, PTC are usually composed of a mixture of papillae and follicles, frequently with relatively large nuclei containing folds and a clear center. About 50% contain calcium deposits. Different histological PTC subtypes have been described. FTC are characterized by microfollicles and presence of capsular and vascular invasion. HCTC, pathologically similar to FTC, are distinguished by mitochondria-rich, eosinophilic cytoplasm. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is a recently described variant; it is currently unclear if it is a pre-malignant lesion or a DTC variant.
Etiology
DTC arise from the epithelial cells of the thyroid gland. Most DTCs are sporadic and without known cause. Ionizing radiation predisposes to PTC. Iodine deficiency is associated with an increased risk of FTC. The sporadic molecular pathogenesis of these three malignancies is partially understood. In PTC, the V600E BRAF mutation (7q34) as well as fusion genes involving RET (10q11.2) and NTRK1 (1q23.1) are common. Activating RAS mutations occur in both PTC and FTC as well as in benign thyroid lesions. The PAX8/PPARG fusion gene (2q13) is more frequently observed in FTC. About 5% of PTCs have a familial predisposition although the associated germline alterations are unknown. HCTC has a unique and complex genetic profile that includes somatic mutations (including DAXX, TERT, TP53, NRAS, NF1, CDKN1A, ARHGAP35 and complex I mtDNA) and widespread chromosomal loss.
Diagnostic methods
DTC usually presents on physical examination or ultrasound as an asymptomatic nodule within the thyroid gland. Serum concentrations of thyroid hormone are usually normal. Thyroid fine needle aspiration biopsy cytology is frequently used to distinguish between the benign and malignant nodules. Additional diagnostic techniques include ultrasound characteristics and genetic analyses of the fine needle biopsy material. Diagnosis is confirmed on pathology review following surgical resection.
Differential diagnosis
Differential diagnosis of thyroid nodules includes benign thyroid nodules (nodular goiter, thyroid cyst, follicular adenoma), other thyroid malignancies, as well as Hashimoto's thyroiditis and thyroid lymphoma.
Management and treatment
The treatment of DTC is prioritized. First, complete surgical resection is essential for cure. Second, thyroid hormone administration to suppress TSH to appropriate concentrations helps prevent recurrence. Third, since most DTCs maintain the ability to take up iodine, 131-iodine therapy is useful in eradicating residual microscopic disease. For those few patients refractory to conventional therapy, external radiation and multikinase inhibitors are effective. Long-term follow-up is essential due to the cumulative risk of recurrence (about 20% at 20 years).
Prognosis
Prognosis is generally good in most patients, but about 5% of cases are fatal. Good prognosis is associated with age below 55 years and tumors below 4 cm. Poor prognosis is associated with distant metastatic disease, progression to anaplastic thyroid cancer (occasional), and tumors with a TERT promoter mutation plus either an activating V600E BRAF mutation or activating RAS mutation.

                            Last update:
                            June 2020

                            - Expert reviewer(s):
                            Dr Carl MALCHOFF


A rare clinical situation for which there is a European and/or American orphan designation. Characteristics include diffuse bleeding into the alveolar spaces that originate from the pulmonary microvasculature, including the alveolar capillaries, arterioles and venules. Patients present with cough, dyspnea, chest pain, fever, anemia and hemoptysis.


A rare low-grade astrocytoma characterized by a high degree of cellular differentiation, slow growth, and diffuse infiltration of adjacent brain structures, and corresponding to WHO grade II. The tumor typically affects young adults and has an intrinsic tendency for progression to high-grade glioma. Histological variants are fibrillary, gemistocytic, and protoplasmic astrocytoma. Patients most commonly present with seizures, but also with other neurological or neuropsychological abnormalities, depending on the location.


Diffuse cerebral and cerebellar atrophy-intractable seizures-progressive microcephaly syndrome

A rare, genetic, central nervous system malformation syndrome characterized by congenital, progressive microcephaly, neonatal to infancy-onset of severe, intractable seizures, and diffuse cerebral cortex and cerebellar vermis atrophy with mild cerebellar hemisphere atrophy, associated with profound global developmental delay. Hypotonia or hypertonia with brisk reflexes, variable dysmorphic facial features, ophthalmological signs (cortical visual impairment, nystagmus, eye deviation) and episodes of sudden extreme agitation caused by severe illness may also be associated.


Diffuse cutaneous mastocytosis (DCM) is a rare form of cutaneous mastocytosis (CM; see this term) characterized by generalized erythroderma, various degrees of blistering, skin with a ''peau d'orange'' appearance and the accumulation of mast cells in the skin. At least two DCM variants are recognized, one with extreme blistering (Bullous DCM; see this term) and one with infiltrations (Pseudoxanthomatous DCM; see this term).

Summary:
Epidemiology
DCM accounts for around 1-2% of all cases of CM and almost exclusively presents during infancy, mainly in the neonatal period. Less than 30 cases of neonatal onset DCM have been described in the literature so far.
Clinical description
The majority of patients present with generalized erythroderma with a reddish to brown-orange discoloration and extensive bullae. The blisters may become hemorrhagic, may be grouped or linear, and are usually located on the trunk, extremities or scalp. The bullous lesions typically resolve by 3-5 years of age. A small number of patients have been reported with yellow-orange infiltrated and xanthogranuloma-like abnormalities as the presenting feature of DCM (Pseudoxanthomatous DCM). Over time, the skin becomes thickened and has a doughy consistency. Other cutaneous manifestations may include pruritus, urticaria, a positive Darier's sign and marked dermographism. Systemic symptoms (including flushing, hypotension, severe anaphylaxis, hepatomegaly, diarrhea and gastrointestinal bleeding) appear to be more common in DCM than in other forms of CM with systemic symptoms.
Etiology
DCM generally occurs sporadically but a few familial cases have been reported. Mutations in the KIT gene (4q11-q12) have been identified in patients with some forms of mastocytosis and mutations in this gene have been identified in a few patients with DCM.
Diagnostic methods
Diagnosis may be suspected on the basis of the clinical findings and can be confirmed by histological examination using mast cell stains (Giemsa and toluidine blue) or immunohistochemical staining for tryptase or kit. Measurements of serum tryptase and urinary N-methylhistamine levels may also be useful for diagnosis and follow-up.
Differential diagnosis
For patients presenting with widespread bullous lesions the differential diagnosis should include bullous congenital ichthyosiform erythroderma, early-onset forms of epidermolysis bullosa, Poikiloderma of Kindler (see these terms) and staphylococcal scalded skin syndrome.
Management and treatment
Treatment is symptomatic with administration of antihistamines (H1 and H2 in cases with gastrointestinal symptoms), topical steroids and mast cell membrane stabilizers. Factors that trigger mast cell degradation (non-steroidal anti-inflammatory drugs, physical stimuli, emotional stress, insect venom and certain foods) should be avoided. Oral steroid treatment and photochemotherapy with UVA therapy may be of benefit but should only be used in infancy in severe cases that are refractory to alternative treatment options. Close follow-up is required for early detection and management of systemic symptoms.
Prognosis
Although spontaneous resolution of the bullous lesions occurs before 5 years of age in most DCM patients, the prognosis is variable: DCM is associated with an increased risk of systemic involvement with life-threatening manifestations (gastrointestinal bleeding, anaphylaxis etc.). The association of DCM with mast cell leukemia has been reported in a few patients and persistence of DCM into adult life with transformation to indolent systemic mastocytosis has been described.

                            Last update:
                            June 2013

                            - Expert reviewer(s):
                            Pr A.P. [Arnold] ORANJE


Diffuse cutaneous systemic sclerosis (dcSSc) is a subtype of Systemic Sclerosis (SSc; see this term) characterized by truncal and acral skin fibrosis with an early and significant incidence of diffuse involvement (interstitial lung disease, oliguric renal failure, diffuse gastrointestinal disease, and myocardial involvement).

Summary:
Epidemiology
The prevalence is estimated at about 1/25,000 adults. Women are predominantly affected (F/M sex ratio around 4:1).
Clinical description
The disease usually manifests at between 40 and 50 years of age. Pediatric onset can occur but is extremely rare. Raynaud's phenomenon is often the first sign of the disease. The other signs usually appear a few months later. Skin hardening first occurs on the fingers and face, but rapidly becomes generalized. Telangiectasias are sometimes present on the thorax, face, lips, tongue, and fingers. Tendon friction rubs are observed. Esophageal dysmotility is common and provokes gastroesophageal reflux and sometimes dysphagia. Gastrointestinal malabsorption and dysmotility may also be present and are associated with weight loss, vomiting, diarrhea or occlusion. Dry mouth and dental involvement can occur. Arthralgias and acroosteolysis are frequent. Muscular involvement can lead to muscular pain and weakness, and cramps. Severe life-threatening renal involvement may occur (about 2% of cases). Pulmonary fibrosis is frequently seen (60% of cases). Pulmonary hypertension may also occur (10-15% of cases).
Etiology
The exact cause of diffuse cutaneous SSc is unknown. The disease originates from an autoimmune reaction which leads to overproduction of collagen. In some cases, the condition is associated with exposure to chemicals (including silica, solvents and hydrocarbons).
Diagnostic methods
Diagnosis is based on typical clinical manifestations and on evidence of specific microangiopathy with giant loops on nailfold capillaroscopy. Skin biopsy is usually not needed. Blood tests must be performed, and show typical antitopoisomerase autoantibodies in 30-40% of cases. The extent of the disease should be evaluated by computed tomography (CT), electrocardiogram, echocardiography, radiography of the hands and esophageal and gastric fibroscopy if needed.
Differential diagnosis
Differential diagnoses include Sharp syndrome, systemic lupus erythematosus, antiphospholipid syndrome, polyarteritis nodosa, polymyositis, and rheumatoid arthritis (see these terms).
Management and treatment
Management is mostly symptomatic. Raynaud's phenomenon can be treated with calcium channel blockers. Proton pomp inhibitors are given for gastric reflux. Surgical resection of severe calcinosis may be required. Low doses of corticosteroids with immunosuppressive agents are needed in cases with recent severe cutaneous involvement or in progressive lung fibrosis. Pulmonary vasodilators are given in case of pulmonary arterial hypertension. Patients require regular clinical follow-up with early pulmonary function tests and echocardiography.
Prognosis
The prognosis is severe (10-year survival rate of 60-80%) because of the high risk of life-threatening complications: renal crisis, severe digestive involvement, severe lung fibrosis, and, sometimes, severe heart involvement and pulmonary arterial hypertension.

                            Last update:
                            July 2010

                            - Expert reviewer(s):
                            Pr Eric HACHULLA


A rare glial tumor characterized by a highly aggressive, diffusely infiltrative pontine lesion generally occurring in children, affecting local nerve fiber tracts and spreading contiguously to involve adjacent structures, but also metastasizing within the central nervous system. Patients mostly present with a short history of symptoms, typically including the classic triad of multiple cranial neuropathies, long tract signs, and ataxia. Signs and symptoms of increased intracranial pressure may present due to obstructive hydrocephalus. Prognosis is poor and not related to histological grade.


Diffuse large B-cell lymphoma with chronic inflammation is an Epstein-Barr virus-associated malignant lymphoproliferative disorder, developing in a context of long-standing or slow-growing, chronically inflamed lesions, such as chronic pyothorax, metallic implants in bones and joints, chronic osteomyelitis, chronic venous ulcer, or, rarely granulomatous inflammation. The tumor is usually primarily localized, with no involvement of other organs.


Diffuse large B-cell lymphoma is the most common subtype of non-Hodgkin lymphoma (NHL; see this term) in adults characterized by a median age of presentation in the sixth decade of life (but also rarely occurring in adolescents and children) with the initial presentation being single or multiple rapidly growing masses (that may or may not be painful) in nodal or extranodal sites (such as thyroid, skin, breast, gastrointestinal tract, testes, bone, or brain) and that can be accompanied by symptoms of fever, night sweats and weight loss. DLBCL has an aggressive disease course, with the elderly having a poorer prognosis than younger patients, and with relapses being common.


Diffuse leptomeningeal melanocytosis is a rare tumor of meninges arising from leptomeningeal melanocytes, characterized by diffuse infiltration of the leptomeninges (pia mater and arachnoidea) anywhere in the central nervous system. Clinical features may include stillbirth, intracranial hypertension and hydrocephalus, seizure, ataxia, syringomyelia, cranial nerve palsy, intracranial haemorrhage, sphincter dysfunction and neuropsychiatric symptoms. Transformation into malignant melanoma of the central nervous system was reported. It may be associated with congenital nevi, as a part of neurocutaneous melanosis.


A rare developmental defect during embryogenesis characterized by multifocal dilated lymphatic vessels involving multiple organs and tissues. Patients mostly present in infancy and childhood. Clinical course and prognosis depend on the affected sites and extent of the condition, deterioration of lung function being a major cause of morbidity and mortality.


Diffuse palmoplantar keratoderma with painful fissures

A rare, genetic, isolated palmoplantar keratoderma characterized by non-epidermolytic, diffuse hyperkeratotic lesions affecting both the palms and the soles, associated with a tendency of painful fissuring. Contrary to the clinical findings, histologic examination reveals findings suggestive of keratosis palmoplantaris striata, with orthohyperkeratosis featuring widening of the intercellular spaces and disadhesion of keratocytes in the upper epidermal layers.


A rare isolated diffuse palmoplantar keratoderma characterized by diffuse, homogeneous, mild to thick, brown-to-yellowish palmoplantar hyperkeratosis (sometimes spreading over the dorsal aspect of fingers). Skin biopsy shows non-epidermolytic changes. There are no changes in hair, teeth or nails, and no syndromic involvement of other organs.

Summary:
Epidemiology
The disease was first described in Northern Sweden, and subsequently in Denmark and in the United Kingdom. Both sexes are affected. Precise epidemiologic data are not available. A 1994 publication states a point prevalence of 0.3-0.5% in Sweden. It is possible that the prevalence was underestimated prior to the availability of genetic diagnosis.
Clinical description
Diffuse palmoplantar keratoderma, Bothnian type, presents in the first few months of life with brown-to-yellow keratoderma with an erythematous margin, and extension to dorsal aspects of hands/feet in some patients (transgrediens). Following exposure to water, the keratoderma takes a white, spongy appearance, exhibiting a margin between affected and normal skin. Hyperhidrosis is usually present. Patients can develop superinfections. Histological analysis reveals orthohyperkeratosis without epidermolysis. Superinfection by dermatophytes can be visualized with periodic acid-Schiff-staining.
Etiology
Bothnian type is due to heterozygous missense mutations in aquaporin 5 (AQP5), which encodes for a water-channel protein.
Diagnostic methods
Clinical distinction from keratoderma with associated features or syndromic forms, as well as histologic assessment (absence of epidermolysis, see above), helps to narrow down the differential diagnosis. The clinical diagnosis is confirmed by genetic testing.
Differential diagnosis
Differential diagnosis is broad for diffuse keratoderma and includes aquagenic palmoplantar keratoderma (seen in patients with cystic fibrosis, but also sporadically), KRT1-related diffuse nonepidermolytic keratoderma, epidermolytic palmoplantar keratoderma, localized forms of keratoderma (of which pachyonychia congenita due to keratin 6 mutations can sometimes present with a rather diffuse keratoderma), diffuse recessive keratoderma such as Nagashima type, mal de Meleda, Gamborg-Nielson type, and syndromes presenting with diffuse keratoderma such as palmoplantar keratoderma-esophageal carcinoma syndrome, tyrosinemia type 2, keratoderma hereditarium mutilans, Huriez syndrome, Papillon-Lefevre syndrome, loricrin keratoderma, etc.
Antenatal diagnosis
The disease is benign. Antenatal diagnosis is therefore not recommended.
Genetic counseling
This autosomal-dominant disease has a 50% risk of transmission. Genetic counseling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy
Management and treatment
Topical medication (emollients, keratolytics, retinoids, steroids) and systemic retinoids are used, but only case series are available, and prospective studies are lacking. New targeted treatments, according to the specific mechanisms of the disease, are in development.
Prognosis
No impact on life expectancy has been documented. Disease severity is variable. The phenotype includes mild cases. More severe cases impair finger grip and walking, thus negatively affecting quality of life.

                            Last update:
                            December 2023

                            - Expert reviewer(s):
                            Pr Aldona PIETRZAK  - Pr Matthias SCHMUTH | ERN-Skin*

                                * European Reference Network


Diffuse palmoplantar keratoderma-acrocyanosis syndrome is characterised by the association of diffuse palmoplantar keratoderma and acrocyanosis. It has been described in eight members of one family and in two sporadic cases. The mode of inheritance in the familial cases was autosomal dominant.


Diffuse panbronchiolitis is a rare chronic inflammatory obstructive pulmonary disease primarily affecting the respiratory bronchioles throughout both lungs and inducing sinobronchial infection. Onset occurs in the second to fifth decade of life and manifests by chronic cough, exertional dyspnea, and sputum production. Most patients also have chronic paranasal sinusitis


Digestive duplication cyst of the tongue is an extremely rare otorhinolaryngological malformation which occurs during early embryogenesis and is characterized by a single, and on occasion multiple, cystic lesion that is most frequently located in the anterior portion of the tongue, either deeply embedded within it or superficially on it. Depending mostly on size and location of the cyst, patients could be asymptomatic or could present a wide array of symptoms, such as varying degrees of respiratory and feeding difficulties, lingual swelling and protrusion, dysphagia, and more rarely, recurrent bleeding or brownish discharge from a lingual sinus.


Digital extensor muscle aplasia-polyneuropathy is a rare, hereditary motor and sensory neuropathy characterized by flexion deformities of the thumb and fingers, sensory deficit in the hand and polyneuropathic electrophysiologic findings in the limbs. Operation on the hands reveals extensor muscles and their tendons to be absent or hypoplastic. There have been no further descriptions in the literature since 1986.


A rare, potentially life-threatening poisoning that provokes conduction disturbances, characterized by increased automaticity and decreased conduction. Acute poisoning presents with the common initial manifestations of nausea and vomiting, cardiovascular manifestations (bradycardia, heart block and a variety of dysrhythmias), central nervous system manifestations (lethargy, confusion and weakness) and hyperkalemia. Chronic poisoning is more insidious, manifesting with gastrointestinal symptoms, altered mental status, and visual disturbances.


A rare form of hyperphenylalaninemia due to tetrahydropterin (BH4) recycling deficiency, leading to central dopamine and serotonin deficiency, clinically characterized by infantile-onset neurological disease of variable severity ranging from mild forms with minor neurological development to severe forms with hypotonia, developmental delay, complex movement disorder dominated by dystonia or dystonia parkinsonism. Some patients may present refractory neurological symptoms like a degree of developmental delay, epilepsy and brain abnormalities.

Summary:
Epidemiology
The global prevalence of BH4 deficiencies remains unknown and great variance can be found among different countries. European newborn screening programs (NBS) reveal that the mean incidence of all hyperphenylalaninemias (HPA) is approximately 1/10,000, with BH4 deficiencies representing 1-2% of cases dihydropteridine reductase deficiency (DHPRD) is the second most frequent of all HPA-associated BH4 deficiencies, representing approximately one third of cases. It is more frequent in regions around the Mediterranean Sea.
Clinical description
When left untreated, the deficiency leads to neurological symptoms typically starting at 4-5 months of age. Neonatal onset has been described in single cases characterized by hypotonia, poor sucking and decreased spontaneous movements. Very frequent symptoms (occurring in >50% of patients) are developmental delay and axial hypotonia. Frequent symptoms (occurring in 25-50% of patients) are, hypertonia of the extremities, epilepsy, impaired speech development and microcephaly. Brain imaging might show progressive calcifications in basal ganglia, white or grey matter, and a pattern of bilateral parietooccipital, and to a lesser extent, frontal and/or cerebellar changes in arterial watershed areas. There are no consistent reports on genotype-phenotype correlation.
Etiology
DHPR deficiency is caused by variants in the QDPR gene, which encodes quinoid dihydropteridine reductase involved in the second step of BH4 regeneration. BH4 is an essential cofactor for phenylalanine hydroxylase (PAH), tyrosine (TH) and tryptophan hydroxylase (TPH). Therefore, the tetrahydrobiopterin deficiency causes not only HPA, but also a central dopamine and serotonin deficiency.
Diagnostic methods
DHPRD should be suspected in all infants with a positive neonatal screening test for phenylketonuria, especially when HPA is moderate. The analysis of pterins in urine or dried blood spot (DBS) in patients and the analysis of dihydropteridine reductase (DHPR) enzyme activity in DBS has to follow in all patients with HPA on NBS. The suspected diagnosis can be further confirmed by genetic evaluation of the QDPR gene and/or the measuring of neurotransmitters 5-hydroxyindolacetic acid (5-HIAA), homovanillic acid (HVA) and pterins in cerebrospinal fluid. Clinical consensus guidelines on the different diagnostic options are available with open access.
Differential diagnosis
The differential diagnosis includes classical phenylketonuria and hyperphenylalaninemia due to autosomal recessive GTP cyclohydrolase I, pterin-4-alpha-carbinolamine dehydratase, 6-pyruvoyl-tetrahydropterin synthase, and DNAJC12 deficiencies.
Antenatal diagnosis
Prenatal diagnosis is possible by molecular analysis where the pathogenic variant has previously been identified in a family member.
Genetic counseling
DHPR deficiency is an autosomal recessive genetic disorder. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Treatment attempts to bring phenylalaninemia levels back to normal (diet with restricted phenylalanine intake or prescription of sapropterin hydrochlorid) and to restore normal monoaminergic neurotransmission by administering precursors (L-dopa/carbidopa and 5-hydroxytryptophan). Administration of methylfolate or folinic acid can restore cerebral folate levels. In case of insufficient clinical response or L-dopa-induced hyperkinesia long-acting dopamine agonists (e.g. pramipexole) can be used to stabilize the clinical and biochemical picture. Monoamino oxidase inhibitors (selegiline) are also useful to prolong the action of neurotransmitter precursors.
Prognosis
Levodopa/carbidopa supplementation drastically improves motor function. However, long-term prognosis correlates with early diagnosis and treatment initiation. In DHPRD, even with treatment, some patients have a degree of developmental delay, epilepsy and, in some cases, brain abnormalities.

                            Last update:
                            April 2024

                            - Expert reviewer(s):
                            Dr Oya KUSEYRI HÜBSCHMANN | MetabERN* - Pr Thomas OPLADEN | MetabERN*

                                * European Reference Network


A rare disorder of pyrimidine metabolism characterized by a variable phenotype ranging from absence of symptoms to severe neurological involvement with developmental delay, intellectual disability, and seizures. Additional signs and symptoms may include hypotonia, microcephaly, ocular abnormalities (such as microphthalmia, nystagmus, and strabismus), and autistic behavior, among others. Analysis of urine typically shows high levels of uracil and thymine. Patients are at risk of suffering from severe toxicity after the administration of the anti-neoplastic agent 5-fluorouracil.


Dihydropyrimidinase (DPD) deficiency is a very rare pyrimidine metabolism disorder with a variable clinical presentation including gastrointestinal manifestations (feeding problems, cyclic vomiting, gastroesophageal reflux, malabsorption with villous atrophy), hypotonia, intellectual deficit, seizures, and less frequently growth retardation, failure to thrive, microcephaly and autism. Asymptomatic cases are also reported. DPD deficiency increases the risk of 5-FU toxicity.


Dilated cardiomyopathy with ataxia (DCMA) is characterized by severe early onset (before the age of three years) dilated cardiomyopathy (DCM) with conduction defects (long QT syndrome), non-progressive cerebellar ataxia, testicular dysgenesis, and 3-methylglutaconic aciduria.

Summary:
Epidemiology
To date, all cases of DCMA reported involve individuals from the Dariusleut Hutterite population, an endogamous population of the Great Plains region of Canada and the northern United States.
Clinical description
Prenatal or postnatal growth failure, significant motor delay (due to cerebellar syndrome with ataxia) and male genital anomalies (ranging from isolated cryptorchidism to severe perineal hypospadias) are very frequent clinical signs. Additional features include optic atrophy, a mild increase in hepatic enzymes with microvesicular hepatic steatosis, a normochromic microcytic anemia, and mild to borderline non-progressive intellectual deficit.
Etiology
DCMA is caused by mutation of the DNAJC19 gene (encoding the DNAJC19 protein localized to the mitochondria in cardiac myocytes).
Differential diagnosis
DCMA syndrome shares some clinical features with the X-linked Barth syndrome and the other 3-methylglutaconic acidurias (types I, III and IV; see these terms).
Genetic counseling
DCMA is an autosomal recessive condition.
Prognosis
In a clinical study of 18 DCMA patients, over 70% of patients died from either progressive cardiac failure or sudden cardiac death. Improvement with standard medical treatment or complete resolution of the DCM has been reported in some patients.

                            Last update:
                            January 2007


Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome

This syndrome is characterized by the association of dilated cardiomyopathy and hypergonadotropic hypogonadism (DCM-HH).

Summary:
Epidemiology
Prevalence is unknown but less than 20 affected families have been described in the literature so far.
Clinical description
Occasional findings include a broad nasal base, blepharoptosis, mild intellectual deficit, mild skeletal anomalies, metabolic abnormalities, thyroid hemiagenesis, collagenoma, diabetes mellitus, and thyroid hemiagenesis.
Etiology
Mutations in the LMNA gene were recently detected in two sisters with an overlapping clinical phenotype (ovarian failure and progressive dilated cardiomyopathy) but with additional findings that included a narrow chest, sloping shoulders, aged appearance of the hands and feet and facial dysmorphism (beaked nose and severe retrognathia).
Genetic counseling
Transmission appears to be autosomal recessive.

                            Last update:
                            May 2009


Dimethylglycine dehydrogenase deficiency is an extremely rare autosomal recessive glycine metabolism disorder characterized clinically in the single reported case to date by muscle fatigue and a fish-like odor.


A rare, non-syndromic, urogenital tract malformation characterized by complete or partial penile duplication, ranging from only glans duplication to the presence of two penis shafts with either one (i.e. bifid phallus) or two (i.e. true diphallia) corpora cavernosum in each. Additional anomalies, such as urethra duplication, an abnormal voiding pattern, hypo- or epispadias, bifid/ectopic scrotum, bladder exstrophy or duplication, are frequently associated, but it may also present as an isolated anomaly. In severe cases, pubic symphysis diastasis, imperforate or duplicated anus, colon/ rectosigmoidal duplication, inguinal hernia and vertebral anomalies may be observed.


A rare bacterial infectious disease characterized by an affliction of the upper respiratory tract mediated by the toxin of Corynebacterium diphtheriae. Symptoms include formation of an inflammatory pseudomembrane, fever, sore throat, headaches, coughing, dysphagia, dyspnea, and prominently swollen cervical lymph nodes. The disease may lead to respiratory failure and severe toxin-mediated damage of internal organs, including the heart and kidneys. A cutaneous form of diphtheria is more common in tropical climates and usually follows an indolent course.


Bothriocephalosis is a mammalian cosmopolitan intestinal parasitosis. In addition to non-specific digestive problems (nausea, abdominal pain, lack of appetite), bothriocephalosis provokes an anaemia caused by vitamin B12 deficiency that resembles Biermer anaemia (anaemia characterised by abnormally large red blood cells).

Summary:
Epidemiology
The prevalence is Europe is unknown but more than 10 cases are reported each year, principally from the Italian, Swiss and French Alps.
Etiology
It is an adult cestodosis caused by the large (more than 10 metres) fish tapeworm Diphyllobothrium latum. The life cycle of the parasite is complex and involves two intermediate hosts: a microscopic crustacean, followed by a freshwater fish. Mammals are contaminated through eating fleshy parts of lightly cooked, smoked or undersalted fish.
Diagnostic methods
Diagnosis is made by examination of the stools.
Management and treatment
Standard tapeworm treatments (niclosamide or praziquantel) are effective at treating this parasitosis.

                            Last update:
                            December 2006

                            - Expert reviewer(s):
                            Dr Luc PARIS


Diprosopus is a rare, life-threatening developmental defect during embryogenesis, and a subtype of conjoined twins, characterized by partial or complete duplication of the facial structures on a single head, neck, trunk and body. It may be associated with congenital anomalies involving the cardiovascular, gastrointestinal, respiratory and central nervous systems. Cleft lip and palate have been reported in rare cases.


Dirofilariasis is a form of filariasis (see this term), caused by the filarial nematode of the genus Dirofilaria (including Dirofilaria repens, Dirofilaria immitis), which is transmitted by mosquitoes. The disease is characterized by the presence of subcutaneous nodules (or a conjunctival form that develops slowly and that can be painless to tender), edema and erythema at the site of parasite localization, a feeling of 'crawling' under the skin, and the ''Calabar'' swelling (similar to thatin loiasis (see this term). The latter may last a few days and recurrences are possible. Common localizations of dirofilaria are head and neck, most commonly in the periorbital region, the limbs and trunk.


A rare form of chronic cutaneous lupus erythematosus characterized by erythematous, scaly papules and plaques preferentially occurring on sun-exposed skin areas (scalp, face, and ears) and exhibiting follicular plugging, pigmentary changes, and central atrophy, scarring, and telangiectasia. Skin biopsy shows a perivascular and periadnexal lymphocytic infiltrate and involvement of the dermoepidermal junction with thickening of the basement membrane and vacuolar degeneration of the basal cells. A small percentage of patients may develop systemic lupus erythematosus.


Discrete papular lichen myxedematosus is a rare chronic, slowly progressive form of localized lichen myxedematosus (see this term) characterized by the development of a few to multiple small symmetrical skin-coloured mucinous papules on the limbs and trunk.


Dislocation of the hip-dysmorphism syndrome is a rare multiple congenital anomalies syndrome characterized by bilateral congenital dislocation of the hip, characteristic facial features (flat mid-face, hypertelorism, epicanthus, puffiness around the eyes, broad nasal bridge, carp-shaped mouth), and joint hyperextensibility. Congenital heart defects, congenital dislocation of the knee, congenital inguinal hernia, and vesicoureteric reflux have also been reported. There have been no further descriptions in the literature since 1995.


A group of sterol metabolism disorders due to enzyme deficiencies of bile acid synthesis (BAS) in infants, children and adults, with variable manifestations that include cholestasis, neurological disease, and fat malabsorption. Nine inborn errors have been described, 7 of which lead to liver cholestasis.

Summary:
Epidemiology
Overall prevalence is unknown but estimated prevalence may be around 1-9/1,000,000 for overall BAS defects, excluding cerebrotendinous xanthomatosis. Inborn errors in BAS probably account for 1-2% of cases of unexplained liver disease in infants, children and adolescents.
Clinical description
Age at diagnosis is variable. Presentation may be in infancy with liver cholestasis, in childhood with unexplained liver disease or in adulthood with neurologic disease. Infants and children may present with complications secondary to fat malabsorption and fat-soluble vitamin deficiency including rickets, bleeding diathesis, neuroaxonal dystrophy and night blindness.
Etiology
The seven inborn errors of BAS leading to liver cholestasis include: 3-beta-hydroxy-C27-steroid oxidoreductase deficiency (BAS defect type 1) that is the most common, delta4-3-oxosteriod-5-beta reductase deficiency (BAS defect type 2), oxysterol 7alpha-hydroxylase deficiency (BAS defect type 3), 2-methylacyl-CoA racemase deficiency (BAS defect type 4;), trihydroxycholestanoic acid (THCA) CoA oxidase deficiency (see this term), bile acid CoA ligase deficiency and defective amidation (see this term), and cerebrotendinous xanthomatosis (see these terms). Cholesterol 7alpha-hydroxylase deficiency (see this term) leads to hypercholesterolemia without liver cholestasis. A reported defect in side chain oxidation in the alternate 25-hydroxylation pathway needs further confirmation.
Diagnostic methods
Diagnosis is based on serum hepatic enzyme and bilirubin profile, and analysis of urine, serum and bile using liquid secondary ionization mass spectrometry (LSIMS) and gas chromatography - mass spectrometry (GC-MS).
Differential diagnosis
The spectrumof differential diagnoses is large and is that of neonatal cholestasis, unexplained fat-soluble vitamin deficiency in infancy and childhood, unexplained liver disease in infancy, childhood and adolescence and unexplained neurologic disease in adults.
Antenatal diagnosis
Most defects can be diagnosed antenatally from embryonic tissue when there has been a previously affected sibling. Urine from suspected cases may be screened by LSIMS in the first neonatal days and therapy initiated before significant morbidity develops.
Management and treatment
Treatment is based on primary bile acid therapy. Cholic acid creates a bile acid pool that stimulates bile flow and fat absorption. It does not appear to be effective for type 3. Ursodeoxycholic acid (UDCA) therapy creates a bile acid pool, but does not suppress production of toxic intermediates and is not very effective at facilitating fat absorption. Glycocholic acid therapy is the treatment of choice for bile acid CoA ligase deficiency and defective amidation, improving fat absorption and growth.
Prognosis
Prognosis depends on the type of defect. In all defects that affect the steroid nucleus of the bile acid molecule, if untreated, progressive liver disease may develop or reduced intestinal bile acid concentrations may lead to serious morbidity or mortality. Long-term survival and clinical improvement is possible with early treatment. In those defects that affect the side chain, liver disease is milder and neurological disease may predominate.

                            Last update:
                            January 2011

                            - Expert reviewer(s):
                            Pr James HEUBI


Dissecting cellulitis of the scalp is a rare chronic suppurative dermatosis of the scalp that mainly affects black men and that is characterized by multiple painful inflammatory follicular and perifollicular nodules, pustules, and abscesses that interconnect via sinus tracts and eventually result in scarring alopecia.


Disseminated peritoneal leiomyomatosis (DPL) is characterized by the proliferation of multiple benign smooth muscle cell-containing nodules in the peritoneal cavity.

Summary:
Epidemiology
Fewer than 150 cases have been reported in the literature to date.
Clinical description
DPL manifests during adulthood and is predominantly found in women. Most patients are asymptomatic but clinical features such as abdominal and pelvic pain, rectal or vaginal bleeding and, more rarely, gastrointestinal disorders have been reported. Malignant transformation is rare and in a few cases, metastases have been found in the liver and lungs.
Etiology
Etiology is unknown but DPL seems to be a multifactorial disease with a genetic or hormonal component (high levels of estrogen and progesterone) leading to metaplasia of peritoneal mesenchymal cells. In some women, DPL seems to originate from proliferation of fragments of uterine leiomyoma in the abdominal cavity after laparoscopic surgery.
Diagnostic methods
Imaging techniques such as ultrasound examination are required for detection of DPL. Diagnosis is confirmed by biopsy of the nodules which reveals the presence of smooth-muscle cells with no atypia or necrosis, fibroblasts and myofibroblasts.
Differential diagnosis
Differential diagnosis includes parasitic leiomyoma, intravenous leiomyomatosis and other primitive or secondary peritoneal carcinomatoses.
Management and treatment
Depending on the extent of the disease, first-line treatment for DPL is surgical excision or cytoreductive surgery. Hormone intake (e.g. oral contraceptives) must be discontinued. Systemic chemotherapy (off-label use) has been suggested as a treatment option for the rare cases of unresectable or metastatic tumors.
Prognosis
Prognosis is usually good. Death has however been observed in some cases presenting unresectable or metastatic tumors.

                            Last update:
                            March 2011

                            - Expert reviewer(s):
                            Pr Olivier GLEHEN


A rare skin disease that is the most common form of porokeratosis characterized by the presence of several small annular plaques with a distinctive keratotic rim found most commonly on sun-exposed areas of the skin, particularly the extremities.

Summary:
Epidemiology
Disseminated superficial actinic porokeratosis (DSAP) prevalence is not precisely known, although DSAP is the most common form of porokeratosis. It is more frequently seen in women, probably because they more readily seek advice for cosmetic concerns.
Clinical description
The disease usually starts during the third to fourth decade of life (only rarely during childhood). DSAP is characterized by several small (0.5-1 cm), round, pink-brownish plaques, surrounded by a distinctive keratotic rim, corresponding microscopically to the cornoid lamella. They are painless, but pruritus is reported in one third of patients. The lesions appear on skin that is exposed to sunlight (usually the extremities) but never on the palms or soles. They usually appear in summer and may improve or disappear during winter. DSAP is usually a benign disease, although squamous cell carcinoma can very rarely develop within the lesions.
Etiology
Mutations in the mevalonate kinase (MVK) gene, located to chromosome 12q24, have been found in up to one third of DSAP cases. MVK encodes an enzyme in the mevalonate pathway, which is thought to be crucial for the biosynthesis of cholesterol and isoprenoid as well as the regulation of calcium-induced keratinocyte differentiation. More recently, pathogenic mutations in the SLC17A9 gene (20q13.33) were also found in DSAP patients. Risk factors for DSAP include exposure to ultraviolet light and immunosuppression.
Diagnostic methods
Histopathological examination of a cutaneous biopsy confirms the clinical diagnosis of DSAP. The characteristic feature is the presence of a cornoid lamella, i.e. a vertical stack of parakeratotic corneocytes within the horny layer, seated on a shallow depression of the underlying epidermis that is devoid of a granular layer. Molecular genetic testing for a mutation in the MVK gene can also confirm diagnosis.
Differential diagnosis
Differential diagnoses include (pre)neoplastic or hyperplastic keratotic skin lesions as well as other forms of porokeratosis, such as porokeratosis of Mibelli or superficial disseminated porokeratosis (similar to DSAP but not triggered by sunlight).
Genetic counseling
DSAP often follows an autosomal dominant pattern of inheritance, but sporadic cases have also been reported.
Management and treatment
There is no standard treatment for DSAP. Topical imiquimod 5% cream, topical 5-fluorouracil (5-FU) and topical vitamin D-analogues (tacalcitol, calcipotriol) have shown to be beneficial in treating the lesions of DSAP in some patients. Cryotherapy, electrodessication, laser ablation and photodynamic therapy have been tested with varying results. DSAP patients should limit their exposure to sun.
Prognosis
DSAP has a good prognosis as it very rarely progresses to carcinoma. However the disease may cause cosmetic concern and thereby exerts a negative effect on a patient's quality of life.

                            Last update:
                            August 2020

                            - Expert reviewer(s):
                            Pr Jean KANITAKIS


Distal 16p11.2 microdeletion syndrome is a rare chromosomal anomaly syndrome resulting from the partial deletion of the short arm of chromosome 16 with a highly variable phenotype typically characterized by developmental delay, mild intellectual disability and autism spectrum disorder. Macrocephaly (apparent by 2 years of age), structural brain malformations, epilepsy, vertebral anomalies and obesity are frequently associated.


Distal 17p13.1 microdeletion syndrome is a rare chromosomal anomaly syndrome characterized by mild global developmental delay/intellectual disability with poor to absent speech, dysmorphic features (long midface, retrognathia with overbite, protruding ears), microcephaly, failure to thrive, wide-based gait and a body posture with knee and elbow flexion and hands held in a midline.


Distal 17p13.3 microdeletion syndrome is a rare partial monosomy of the short arm of chromosome 17 with a variable phenotype characterized by prenatal and postnatal growth retardation, developmental delay, mild intellectual disability, macrocephaly, mild facial dysmorphisms including prominent forehead, hypertelorism, thick upper and/or lower lip vermillion, and structural abnormalities of the brain variably including white matter abnormalities, prominent Virchow-Robin spaces, Chiari I malformation, corpus callosum hypoplasia, but no lissencephaly.


A rare chromosomal anomaly syndrome, resulting from the partial deletion of the long arm of chromosome 22, outside the DiGeorge critical region. The phenotype is characterized by prematurity, pre- and post-natal growth retardation, developmental delay (particularly speech), mild intellectual disability, variable cardiac defects, and minor skeletal anomalies (such as clinodactyly). Dysmorphic features present in half of the individuals include microcephaly, arched eyebrows, deep set eyes, narrow upslanting palpebral fissures, ear abnormalities (low-set ears, tags and pits), hypoplastic alae nasi, smooth philtrum, down-turned mouth, thin upper lip, retro/micrognatia and pointed chin. For certain very distal deletions including the SMARCB1 gene, there is a risk of developing malignant rhabdoid tumours. Most deletions are de novo .


Distal 22q11.2 microduplication syndrome

A rare chromosomal anomaly syndrome, resulting from the partial duplication of the long arm of chromosome 22, with a highly variable phenotype principally characterized by developmental delay, intellectual disability, behavioral anomalies, and non-specific craniofacial dysmorphism. Congenital heart malformations, visual and hearing impairment, urogenital abnormalities, and seizures have also been reported. Penetrance is incomplete. In 70% of cases, the duplication is inherited from as asymptomatic parent.


Distal 7q11.23 microdeletion syndrome is a rare chromosomal anomaly characterized by epilepsy, neurodevelopmental disorder variably including developmental delays and intellectual disabilities of variable severity, learning disability and neurobehavioral abnormalities (autism spectrum disorder, hyperactivity, impulsivity, aggression, self-abusive behaviors, depression).


Distal 7q11.23 microduplication syndrome is a rare chromosomal anomaly characterized by a predominantly neuropsychiatric phenotype with a few dysmorphic characteristics. Speech delay, learning difficulties, attention deficit hyperactivity disorder, bipolar disorder and aggressiveness have been reported.


Distal anoctaminopathy is a rare, autosomal recessive distal myopathy characterized by early adult-onset, slowly progressive, often asymmetrical, lower limb muscle weakness initially affecting the calves (with relative anterior muscle sparing) and later proximal muscle involvement, as well as highly elevated creatine kinase (CK) serum levels.

Summary:
Epidemiology
Worldwide prevalence of distal anoctaminopathy is unknown, but it may represent up to 10% of anoctamin-5 related muscle disease. To date, more than 20 cases have been described in the literature with males being predominantly affected.
Clinical description
Age at onset ranges from 20 to 50 years (with first symptoms as early as late teens) with patients typically presenting hypertrophy of distal lower leg muscles (predominantly the calf muscles (gastrocnemius medialis and soleus muscles)) which evolves into muscle atrophy with disease progression. Muscle weakness and wasting are usually asymmetrical and early symptoms include calf muscle tightness during running, reduced sports performance and difficulty to walk on tiptoes. Uncomfortable burning muscle sensation preceding muscle weakness may also be observed. In advanced stages of the disease, muscle weakness and wasting in the proximal lower and upper limbs (especially in the biceps brachii) appears. Clinical manifestations can be mild, or subjectively nonexistent, in spite of presenting clear changes on muscle imaging. Bulbar or respiratory symptoms have not been reported, however rhabdomyolysis has been observed in some patients. Intrafamilial clinical variability has been observed.
Etiology
Distal anoctaminopathy is caused by loss of function mutations in the gene ANO5 (11p14.3) which encodes a protein highly expressed in skeletal and cardiac muscle, as well as bone. ANO5 functions are largely unknown. It has been proposed that ANO5 may participate in membrane repair pathway, possibly at levels different from that of dysferlin.
Diagnostic methods
Diagnosis is based on clinical, muscle histology and laboratory examinations. Muscle biopsy shows non-specific myopathic changes, whereas blood biochemistry reveals markedly increased CK levels (typically >10 times the normal). Diagnosis is confirmed by genetic screening of ANO5.
Differential diagnosis
Differential diagnosis includes other distal myopathies, in particular Miyoshi myopathy (which is differentiated by absence of dysferlin on biopsy).
Genetic counseling
Transmission is autosomal recessive and genetic counseling is recommended for at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child.
Management and treatment
Currently no specific treatment exists and management is mainly supportive. To prolong survival and improve quality of life, weight control to avoid obesity, physical therapy and stretching exercises to promote mobility, and use of mechanical aids to help ambulation and mobility are recommended.
Prognosis
The progression of the disease is slow and patients generally maintain the ability to walk, although use of ambulatory aids are usually needed in the later stages of the disease.

                            Last update:
                            September 2018

                            - Expert reviewer(s):
                            Dr Johanna PALMIO  - Pr Bjarne UDD


A form of arthrogryposis characterized by contractures of the distal regions of the hands and feet in the absence of a primary neurological and/or muscle disease affecting limb function. Facial involvement is limited to a small mouth and impaired mouth opening. No additional anomalies are reported.

Summary:
Epidemiology
Epidemiological data is limited regarding Distal arthrogryposis type 1 (DA1). The prevalence of arthrogryposis overall is estimated between 1/4,300-5,100 live births and the birth prevalence of distal arthrogryposis (DA) has been suggested at 1/20,000. DA1 is the second most frequent type of DA, after DA2B (Sheldon-Hall syndrome). However, the overlap between the two conditions favors a similar frequency of the two forms.
Clinical description
In 25% of cases DA1 is suspected prior to delivery, due to joint contractures (camptodactyly and/or clubfoot) and reduce fetal movements, in particular in familial cases. In the newborn a consistent pattern of hand and foot involvement, limited involvement of proximal joints and variable expressivity can be seen. Camptodactyly and clubfoot are largely present. Hypoplasia and/or absence of some interphalangeal creases is common. The shoulders and hips are less frequently affected. While the pattern of affected joints is consistent, the degree to which the joints are affected is highly variable, with equinovarus deformities ranging from mild to severe and hand involvement ranging from isolated hypoplasia of the distal interphalangeal crease of the fifth digit, to severely clenched fist and ulnar deviation of the wrist. In the mildest form of DA1, affected individuals have only hypoplasia of the gastrocnemius. Short stature, small mouth with limited opening and mild microretrognathia are frequently seen. A linear vertical crease along the anterior tibia, usually bilaterally, is described in some patients. Intelligence is normal.
Etiology
DA1 is caused by a heterozygous mutation in a gene encoding sarcomeric components of skeletal muscle fibers (TNNI2, 11p15.5; TNNT3, 11p15.5 ; TPM2, 9p13.3; MYH3, 17p13.1; MYBPC1, 12q23.2). The same genes are also responsible for DA2B. Recently, variants in MYLPF (16p11.2), encoding light chains of skeletal muscle myosin, have been described and appears to be more frequently associated with short stature and proximal joint contractures (ie, elbows, hips, knees).
Diagnostic methods
Diagnosis is based on clinical examination and molecular studies. Instrumental investigations generally do not show any significant alterations.
Differential diagnosis
The principal differential diagnosis includes a different type of DA (in particular DA2B), congenital amyoplasia and situations with limitation of fetal joint mobility (neurological/neuromuscular diseases, metabolic disturbances, skeletal dysplasias/connective tissue abnormalities, maternal illness or exposures, space limitation in utero, and intrauterine vascular compromise).
Antenatal diagnosis
Some cases can be detected prenatally by ultrasonography. Detection of a known pathogenic mutation by chorionic villus sampling and amniocentesis should be discussed with couples at risk.
Genetic counseling
Transmission is autosomal dominant, with a 50% recurrence risk for the offspring of affected individuals. Reduced penetrance and variable expressivity are reported, and some relatives with the mutation are asymptomatic. Some de novo mutations are reported, with a recurrence risk for sibs of approximately 1%. MYLPF variants can be autosomal dominant (50% recurrence risk) or autosomal recessive (25% recurrence risk).
Management and treatment
Long-term orthopedic management and physiotherapy is required. Physiotherapy soon after birth is helpful in mobilizing joints and preventing disuse atrophy. Sometimes surgical procedures are required.
Prognosis
Life expectancy is normal. The course of the disease is non-progressive. Significant improvements are achieved with physical and orthopedic therapy. Autonomy is generally unlimited.

                            Last update:
                            December 2020

                            - Expert reviewer(s):
                            Dr Livia GARAVELLI | ITHACA* - Dr Marzia POLLAZZON | ITHACA*

                                * European Reference Network


A rare, genetic, distal arthrogryposis syndrome characterized by plantar flexion contractures, typically presenting with toe-walking in infancy, variably associated with milder contractures of the hip, elbow, wrist and finger joints. No ocular or neurological abnormalities are associated and serum creatine phosphokinase levels are normal.


Distal arthrogryposis type 5D is a rare subtype of distal arthrogryposis syndrome characterized by arthrogryposis multiplex congenita affecting the hands, feet, ankle, shoulders and/or neck, with camptodactyly of the fingers and limited knee and hip extension, associated with asymmetric ptosis and, less frequently, other ocular manifestations (e.g. ophthalmoplegia, strabismus). Affected individuals frequently have a bulbous nose, furrowed tongue, micro/retrognathia, a short neck, congenital hip dislocation, club feet, scoliosis and short stature.


A group of rare arthrogryposis syndromes characterized by congenital contractures of two or more areas of the body, primarily involving the hands and feet, while the proximal joints are largely spared, in the absence of primary neurologic and/or muscle disease affecting limb function. Diagnostic features include camptodactyly or pseudocamptodactyly, hypoplastic or absent flexion creases, overriding fingers, ulnar deviation at the wrist, talipes equinovarus, calcaneovalgus deformities, vertical talus, and/or metatarsus varus.


Distal monosomy 10p is a rare chromosomal disorder in which the tip of the short arm (p arm) of chromosome 10 is deleted resulting in a variable phenotype depending on the size of the deletion. The deletion may involve only the terminal 10p15 band, or extend towards the centromere to bands 10p14 or 10p13.

Summary:
Epidemiology
Around 50 cases of pure distal monosomy 10p have been reported.
Clinical description
Distal monosomy 10p encompassing the 10p13 band is associated with cardiac malformations and immune anomalies that overlap with the anomalies reported in the deletion 22q11 syndrome (DiGeorge syndrome/velocardiofacial syndrome spectrum (DGS/VCFS); see this term) with hypoparathyroidism, hypocalcemia, congenital conotruncal heart defects, thymus hypoplasia leading to T-cell deficiency and intellectual deficit. More than 25 patients have been reported with del(10)(p13). In addition to the anomalies related to the DiGeorge syndrome (e.g. conotruncal malformation with thymic hypoplasia), these patients often show an abnormally shaped skull, microcephaly, a long face, high forehead, broad nasal bridge, downslanting palpebral fissures, anteverted nares, hand and foot abnormalities, genitourinary anomalies, hearing loss and severe psychomotor retardation, resulting in a clinical picture that clearly differs from that of the classic 22q11 deletion syndrome. However, due to the similarities in the malformations observed in the two syndromes, del(10)(p13) is referred to as DGS2. The critical region for DGS2 has been mapped to within a 1cM interval in 10p13 which contains the CUGBP2 gene, a candidate gene for developmental heart defects. Smaller deletions involving the region 10p14-pter have been described in < than 10 patients. Some of these patients exhibited the triad: Hypoparathyroidism, sensorineural Deafness, and Renal anomaly (HDR syndrome; see this term). Haploinsufficiency for the trans-acting T-cell-specific transcription factor GATA-3 (encoded by the  GATA3 gene, and mapped to the 10p14-pter region) is responsible for this phenotype. Pure subtelomeric deletions involving 10p15-ter are very rare (< 6 children reported so far).
Etiology
The phenotype remains unclear: low birth weight, persistent growth delay, mild psychomotor retardation and hypotonia have been reported, together with single reports of ventricular septal defect, hydrocephalus and hypogenitalia. Distal monosomy 10p generally occurs de novo or may be associated with a parental translocation.
Diagnostic methods
Diagnosis requires cytogenetic analysis and molecular characterization and should include a search for a translocation because deletion may be the result of transmission of a derivative chromosome.
Differential diagnosis
The differential diagnosis for patients with distal monosomy 10p should include deletion 22q11 syndrome and other causes of hypoparathyroidism, depending on the phenotype.
Antenatal diagnosis
Prenatal diagnosis is feasible and genetic counseling should be proposed and depends on the cytogenetic rearrangement responsible for the deletion (de novo or translocation).
Management and treatment
Management of 10p monosomy includes a comprehensive evaluation of the major clinical criteria: developmental delay, feeding difficulties, hypocalcemia, deafness, cardiac defects, and recurrent infections. Pediatricians, neurologists, nephrologists and endocrinologists should be involved as appropriate. Developmental assessments with speech, physical and occupational therapists are required.
Prognosis
The prognosis is variable, depending on the malformations associated.

                            Last update:
                            January 2009


Distal monosomy 10q is a chromosomal anomaly involving terminal deletion of the long arm of chromosome 10 and is characterized by facial dysmorphism, pre- and postnatal growth retardation, cardiac and genital anomalies, and developmental delay.

Summary:
Epidemiology
Prevalence is unknown but around 40 cases have been described in the literature so far.
Clinical description
There is no specific clinical feature associated with this chromosome anomaly. Craniofacial features include hypertelorism, strabismus, a prominent or broad nasal bridge, and posteriorly rotated low-set ears. Hypotonia is frequent, and limited joint extensions and early scoliosis have been reported in a few cases. Cardiac defects are not a constant finding and vary to include patent ductus arteriosus, ventricular septal defect, tetralogy of Fallot and truncus arteriosus (see these terms). Genital abnormalities have been mostly reported in males and include undescended testis, micropenis and a posterior urethral valve. Bladder distension due to cervical dysfunction may occur in females and may be evident during the antenatal period. Severe genital abnormalities (ambiguous external genitalia) have been reported in a few cases. Psychomotor retardation (generally described as mild) was present in all reported cases.
Etiology
Distal monosomy 10q results from a subterminal 10q deletion with breakpoints in the 10q25 or 10q26 band leading to partial monosomy for the genes located in this area. Most of the reported cases involved de novo terminal deletions resulting from abnormal non-allelic homolog recombination during meiosis.
Diagnostic methods
Diagnosis is made by molecular analysis. Comparative genomic hybridization (CGH) microarray or subterminal chromosome multiplex ligation-dependent probe amplification (MLPA) may be necessary since conventional cytogenetic analysis may not be sensitive enough to detect very short subterminal deletions.
Antenatal diagnosis
Antenatal molecular testing for the presence of a subterminal 10q deletion may be proposed in case of suspicion of a posterior urethral valve in males (associated or not with genital abnormalities) or in case of bladder distension in female fetuses. The risk of recurrence is low but prenatal screening for chromosomal abnormalities must be proposed, with the use of FISH markers for the 10q subterminal region.
Management and treatment
Management is symptomatic only. Bladder dysfunction may require transient cystostomy. Special education programs to improve cognitive development are needed in most cases.
Prognosis
The prognosis is unclear as there are no available data concerning long-term follow up, especially up until adult age.

                            Last update:
                            September 2008

                            - Expert reviewer(s):
                            Pr Bruno LEHEUP


A rare partial autosomal monosomy characterized by language development delay with childhood apraxia of speech, mild intellectual disability, behavourial abnormalities (autistic spectrum disorder, attention deficit hyperactivity disorder, anxiety) and mildly dysmorphic nonspecific features. Additional clinical features may include muscular hypotonia and joint laxity, hernias and microcephaly.


A rare partial deletion of the long arm of chromosome 12 characterized by variable combinations of developmental delay, intellectual disability, behavioral abnormalities, variable dysmorphic facial features (including microcephalus, coarse face, synophrys, epicanthal folds, large bulbous nose, small ears, low-set and posteriorly rotated ears, or large tongue, among others), and other anomalies such as malformations of the hands and fingers/feet and toes, skin and nail abnormalities, and genitourinary and cardiac abnormalities, among others.


Distal monosomy 13q is a rare chromosomal anomaly syndrome, resulting from a partial deletion of the long arm of chromosome 13, with a highly variable phenotype typically characterized by varying degrees of intellectual disability and developmental delay, as well as CNS malformations (e.g. holoprosencephaly, anencephaly, ventriculomegaly, Dandy-Walker malformation), ocular abnormalities (e.g. hypertelorism, microphthalmia, strabismus, aniridia, retinal dysplasia) and craniofacial dysmorphism (microcephaly, trigonocephaly, large and malformed ears, broad prominent nasal bridge, micrognathia). Cardiac, genitourinary, gastrointestinal and skeletal manifestations have also been reported.


Distal monosomy 14q is a rare chromosomal anomaly associated with various phenotypic features depending on the size of the deletion. The clinical features may include global developmental delay, hypotonia, congenital heart defects, dysmorphic features (high forehead, small palpebral fissures, epicanthi, blepharophimosis, broad and flat nasal bridge, broad philtrum, thin upper lip, high arched palate, pointed chin, malformed ears). High-pitched, weak cry, seizures and various dental and oftalmological anomalies were also reported.