A rare form of microcephalic primordial dwarfism characterized by a proportionate dwarfism of prenatal onset, a severe microcephaly, a typical dysmorphic face (bird-like), and mild to severe intellectual disability.

Summary:
Epidemiology
Seckel syndrome is the most common of the microcephalic osteodysplastic dwarfisms.
Clinical description
Seckel syndrome is characterized by a proportionate dwarfism of prenatal onset, a severe microcephaly with a bird-headed like appearance and mental retardation. Hematological abnormalities with chromosome breakage have only been found in 15 to 25% of patients.
Etiology
Besides to a wide phenotypic heterogeneity between affected patients, genetic heterogeneity has also been proven, with three loci identified to date by homozygosity mapping: SCKL1 (3q22.1-q24, ataxia-telangiectasia and Rad3-related protein (ATR) gene), SCKL2 (18p11.31-q11.2, unknown gene) and SCKL3 (14q23, unknown gene). SCKL3 seems to be the predominant locus for Seckel syndrome. Approaching the function of the ATR gene, the genes with a role in DNA repair are good candidates for SCKL2 and 3.
Differential diagnosis
The differential diagnosis with microcephalic osteodysplastic dwarfism type II can only be made with a complete radiographic survey in the first years of life.
Genetic counseling
Seckel syndrome is an autosomal recessive disorder.
Management and treatment
Intellectual disability is usually severe and families should be helped for social problems. In case of associated hematological abnormalities (anemia, pancytopenia, acute myeloid leukaemia), medical treatment should be provided.

                            Last update:
                            April 2005

                            - Expert reviewer(s):
                            Pr Valérie CORMIER-DAIRE  - Pr Laurence OLIVIER-FAIVRE


A rare otorhinolaryngological malformation characterized by the presence of a cyst, sinus or fistula occuring along the anterior border of the sternocleidomastoid muscle. Second branchial cleft fistulae and sinuses present with skin opening with chronic discharge and recurrent infections, whereas second branchial cleft cysts present as a painless, nontender, stable in size or slowly enlarging lateral neck masses. Cysts occasionally acutely increase in size during upper respiratory tract infection, leading to respiratory compromise, torticollis, and dysphagia.


A rare neurologic disease characterized by intermittent pain, erythema, swelling, and heat of the extremities which is aggravated by warming and improved by cooling. Attacks can last between minutes and days and tend to be precipitated by heat, exercise, or physical dependence. The disease may be linked to a variety of underlying conditions including hematological, metabolic, connective tissue or neurological disorders, neoplasia, infections, and certain drug side effects, among others.


A rare hypereosinophilic syndrome characterized by hypereosinophilia produced by reactive/non-clonal eosinophils secondary to an underlying medical condition and persisting for at least six months. The disorder can derive from non-neoplastic conditions (such as chronic infections and infestations, allergic reactions, intoxications, or autoimmune and chronic inflammatory disorders) or from neoplasms including non-myeloid malignancies, among others. It is associated with signs of organ infiltration, dysfunction, and damage. Clinical manifestations are highly variable, depending on the organ systems involved, and most commonly include dermatologic, pulmonary, cardiac, gastrointestinal, and cerebral manifestations.


Secondary intestinal lymphangiectasia is an acquired from of intestinal lymphangiectasia (see this term) manifesting as a protein-losing enteropathy due to another disorder such as Crohns disease, congestive heart failure, sarcoidosis, Turner syndrome (see these terms) and often in patients who have undergone a Fontan operation. It is characterized by malabsorption, diarrhea, edema due hypoproteinemia, steatorrhea and serosal effusions.


Secondary non-traumatic avascular necrosis

A rare osteonecrosis disease characterized by death of bone cellular components secondary to an interruption of the subchondral blood supply, typically manifesting with unilateral or bilateral, unifocal or multifocal lesions usually located on the epiphysis, metaphysis and/or diaphysis of the femoral heads, knees, shoulders, ankles and/or wrists, leading to gradual onset of pain and progressive joint degeneration resulting in loss of function. Association with corticosteroid usage, alcoholism, hyperbaric events, radiation or cytotoxic agent exposure, hemoglobinopathies, and/or underlying autoimmune or metabolic disease, amongst others, has been observed.


Secondary polyarteritis nodosa (PAN) is a rare serious form of PAN (see this term) characterized by vasculitis in a background of viral infection, primarily with hepatitis B virus (HBV).


Secondary polycythemia is an elevated absolute red blood cell mass caused by enhanced stimulation of red blood cell production by an otherwise normal erythroid lineage that may be congenital or acquired (congenital secondary polycythemia and acquired secondary polycythemia; see these terms).

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
Clinical features vary according to the origin of the disease but may include plethora or ruddy complexion, headache and tinnitus. The congenital form may be complicated by superficial or deep vein thrombophlebitis, or present with associated symptoms as in Chuvash erythrocytosis (see this term), or the course of the disease may be indolent. Patients with a specific sub-type of congenital secondary polycythemia, known as Chuvash erythrocytosis, present with lower systolic or diastolic blood pressure, venous varicosities, and vertebral body hemangiomas and may be complicated by cerebrovascular events or mesenteric thrombosis. The acquired form of secondary polycythemia may present with cyanosis, hypertension, clubbing of the fingers and toes and lethargy.
Etiology
Secondary polycythemia may be congenital and caused by defects in the oxygen sensing pathway due to autosomal recessive mutations in the VHL, EGLN1 and EPAS1 genes (3p26-p25, 1q42-q43 and 2p21-p16 respectively) which result in enhanced erythropoietin (EPO) production in hypoxic conditions, or by other autosomal dominant congenital defects including high oxygen-affinity hemoglobin and biphosphoglycerate mutase deficiency, which result in tissue hypoxia and a secondary erythrocytosis. Alternatively, secondary polycythemia may be acquired and caused by increased amounts of EPO. This may be due to tissue hypoxia that may be central and caused by pulmonary or cardiac disease or high altitude, or local and caused by hypoxia in the kidney such as renal artery stenosis. EPO production may be pathologic and caused by EPO secreting tumors such as renal cell cancer, hepatocellular carcinoma, cerebellar hemangioblastoma, meningioma and parathyroid carcinoma/adenoma (see these terms). In addition EPO may be administered deliberately to produce erythrocytosis and enhance performance.
Diagnostic methods
Diagnosis is based on evidence of increased total red blood cells and normal to high serum EPO levels. Secondary causes of erythrocytosis must be diagnosed individually and will require a comprehensive history.
Differential diagnosis
Differential diagnoses include polycythemia vera and primary familial polycythemia (see these terms), which can be excluded on the basis of low EPO levels and the presence of a mutation in the JAK2 gene (9p24) for polycythemia vera.
Management and treatment
There is little evidence to guide management of congenital secondary polycythemia. Phlebotomy or venesection may be of benefit, particularly in patients at increased risk of thrombosis. A target hematocrit (Hct) of 50% may be the most practical. In patients with no specific contraindication, low-dose aspirin may be of benefit. In acquired cases of secondary polycythemia, management is based on treating the underlying condition.
Prognosis
Prognosis depends mainly on the associated disease in the acquired forms of secondary erythrocytosis and on the severity of thrombotic complications in the inherited forms such as in Chuvash erythrocytosis.

                            Last update:
                            July 2010

                            - Expert reviewer(s):
                            Pr Jean BRIERE


Secondary pulmonary alveolar proteinosis

A rare, acquired, interstitial lung disease, characterized by alveolar surfactant accumulation, cough, progressive dyspnea and respiratory insufficiency. The disease may be secondary to hematological disorder, toxic inhalation, and infection or may occur within the setting of immunosuppression after transplantation.


Secondary pulmonary hemosiderosis is a respiratory disease due to the deposition of hemosiderin-laden macrophages in lungs as a result of repeated alveolar hemorrhage secondary to another disease, especially dysimmunitary disorders (i.e. Heiner syndrome (see this term), autoimmune diseases), thrombotic disorders and cardiovascular disorders such as mitral stenosis. It manifests as a triad of hemoptysis, anemia and diffuse parenchymal infiltrates on chest radiography


A rare, biliary tract disease characterized by development of sclerosing cholangitis due to a known primary insult to the biliary tree, including infections, autoimmune disease, exposure to toxic agents, obstructive and ischemic injuries. Patients may be initially asymptomatic with only elevated alkaline phosphatase and gamma glutamyltransferase levels. Later presentation includes abdominal pain, jaundice, pruritus, fever and bacterial cholangitis from ascending infection.


Secondary short bowel syndrome is an intestinal failure caused by any condition that results in a functional small intestine of less than 200 cm in length and is characterized by diarrhea, nutrient malabsoption, bowel dilation and dysmobility.


Secondary syringomyelia is a rare medullar disease defined as a development of a fluid-filled cavity or syrinx within the spinal cord due to blockage of CSF circulation (e.g., due to basal archnoiditis, meningeal carcinomatosis, various mass lesions), spinal cord injury (e.g., due to trauma, radiation necrosis, hemorrhage, spinal abscess), spinal dysraphism or intramedullary tumours. It presents with neuropathic pain, numbness, muscular weakness, changes in tone or spasticity or autonomic changes (hyperhidrosis, heart rate or blood pressure instability). Selective loss of pain and temperature with relative preservation of dorsal column function (touch and pressure) are classic findings.


A rare oral disease characterized by unilateral enlargement of the right or left maxillary alveolar bone and gingiva in the region distal to the canines towards the maxillary tuberosity. In the enlarged region, dental abnormalities such as missing teeth, abnormal spacing and delayed eruption occur.

Summary:
Epidemiology
The term segmental odontomaxillary dysplasia (SOD) was introduced by Danforth et al. in 1990. More than 60 cases of SOD have been described. SOD is often diagnosed in childhood both in males and females, with a slight male predominance.
Clinical description
The 2022, 5th edition, of the World Health Organization (WHO) Classification of Head and Neck Tumours has added Segmental odontomaxillary dysplasia (SOD) within the group of fibro-osseous lesions. SOD is asymptomatic with onset in 1st-2nd decades that usually halts around puberty. Unilateral facial signs: nonprogressive or slowly progressive overgrowth or undergrowth of soft tissues and/or bones (typically centred on the posterior maxilla, and leading to facial asymmetry), dental anomalies (missing teeth or abnormal dentition), gingival hyperplasia or abnormal gingivae, commissural lip fissures, hypertrichosis, cutaneous hyperpigmentation and/or erythema, cutaneous depression, and lip hypopigmentation. The main clinical features include: 1) an alveolar process characterized by unilateral enlargement of the maxillary alveolar bone and gingiva. Buccal as well as palatal enlargement of the alveolar bone is observed, although it is more pronounced on the buccal side. 2) Dentition is marked by abnormal spacing between erupted primary/permanent molars and adjacent teeth. The first permanent molars are often distally displaced. A depression in the palate can appear in the molar region. The canines erupt normally. Malformations of the primary molars, absence of one or both premolars and delayed eruption of adjacent teeth are regular findings. 3) On radiograph, the bone appears dense and sclerotic with abnormal trabeculation. Decreased size of the maxillary sinus in the affected side is observed. Primary teeth are characterized by enlargement of pulps. 4) Histological findings reveal immature bone with irregular trabecular and basophilic cemental lines resulting from alternating bone resorption and bone formation. Sparse narrow spaces with only a few fat cells are observed. The gingiva shows slight fibrosis without pathological changes. Tubular defects in the coronal dentine are present. An irregular pulp/dentin interface is present. A deficient osteoblast layer and widespread external resorption is also observed. Sometimes homolateral, subtle, cutaneous manifestations (hypertrichosis, cutaneous hyperpigmentation and/or erythema, cutaneous depression) might be present.
Etiology
It is a non-hereditary, unilateral developmental disorder. Somatic mosaic variants in PIK3CA, or ACTB genes have been described.
Diagnostic methods
Diagnosis is suspected on clinical presentation.
Differential diagnosis
Differential diagnosis includes hemimaxillofacial dysplasia (HMD), regional odontodysplasia, fibrous dysplasia (causes enlargement of bone tissue, but in this case affected bone growth is out of proportion with that of unaffected bones, and tooth malformations and missing premolars are not characteristics of the disease), focal cemento-osseous dysplasia (occurring in adults with no gingival enlargement or absence of teeth), and hemifacial hyperplasia (unilateral facial enlargement and precocious eruption and enlarged teeth in the affected region but not report of premolars absence). In HMD, ipsilateral facial hypertrichosis is present in addition to the SOD symptoms. Some authors consider SOD and HMD to be different manifestations of the same syndrome. The incisors and canines of the permanent dentition are commonly involved and agenesis of premolars is not a typical feature.
Genetic counseling
It is a non-hereditary, unilateral developmental disorder.
Management and treatment
Multidisciplinary treatment of SOD should include long-term follow-up as it is important for guidance in the management of this disorder. Implants have been successful in one reported case.
Prognosis
Life-long treatment is expected.

                            Last update:
                            November 2023

                            - Expert reviewer(s):
                            Pr Agnès BLOCH-ZUPAN | ERN CRANIO*

                                * European Reference Network


Segmental outgrowth-lipomatosis-arteriovenous malformation-epidermal nevus syndrome

A rare developmental defect during embryogenesis characterized by progressive, proportionate, asymmetric segmental overgrowth (with soft tissue hypertrophy and ballooning effect) that develops and progresses rapidly in early childhood, arteriovenous and lymphatic vascular malformations, lipomatosis and linear epidermal nevus (arranged in whorls along the lines of Blaschko). Clinical symptoms of Cowden syndrome, such as macrocephaly and progressive development of numerous hypertrophic hamartomatous and neoplastic lesions involving multiple organs and systems, are also associated. Patients present an increased risk of developing cancer.


Segmental progressive overgrowth syndrome with fibroadipose hyperplasia

A rare PIK3CA-related overgrowth syndrome disease characterized by segmental and progressive overgrowth, predominantly involving the adipose tissue, or a mixture of adipose and fibrous tissue, with variable involvement of subcutaneous and muscular tissue, as well as skeletal overgrowth. Overgrowth severity and range is highly variable, although frequently it is asymmetric and disproportionate, it affects lower extremities more than the upper ones, and progresses in a distal to proximal pattern. Congenital overgrowth is typically associated.


Seizures-intellectual disability due to hydroxylysinuria syndrome

A rare inborn error of metabolism characterized by infantile onset of global developmental delay, severe intellectual disability, seizures, and movement disorder (including tremor, hyperkinesia, and myoclonus), associated with excessive excretion of hydroxylysine in urine. There have been no further descriptions in the literature since 1970.


Seizures-scoliosis-macrocephaly syndrome is a rare, genetic neurometabolic disorder characterized by seizures, macrocephaly, delayed motor milestones, moderate intellectual disability, scoliosis with no exostoses, muscular hypotonia present since birth, as well as renal dysfunction. Coarse facial features (including hypertelorism and long hypoplastic philtrum) and bilateral cryptorchidism (in males) are also commonly reported. Additional manifestations include abnormal gastrointestinal motility (resulting in constipation, diarrhea, gastroesophageal reflux and dysphagia), gait disturbances, strabismus and ventricular septal defects.


A rare primary immunodeficiency characterized by recurrent and/or invasive bacterial, viral, and fungal infections, associated with low to absent blood IgM levels, while IgG, IgG subclasses, and IgA levels, as well as IgG antibody response to vaccinations, are normal. Patients may also present allergic diatheses, and the prevalence of autoimmune diseases is increased.


Self-healing papular mucinosis is a rare form of localized lichen myxedematosus (see this term) occurring primarily in children and characterized by the development of mucinous papules on various parts of the body (face, neck, trunk, and limbs) that resolve spontaneously within some weeks to months. Systemic symptoms can be observed such as fever, arthralgias and weakness.


Self-healing collodion baby (SHCB) is a minor variant of autosomal recessive congenital ichthyosis (ARCI; see this term) characterized by the presence of a collodion membrane at birth that heals within the first weeks of life.

Summary:
Epidemiology
The exact prevalence is unknown. Approximately 25 cases have been reported in the literature.
Clinical description
Affected babies are born in a collodion membrane. They also display ectropion and eclabium and a limited joint mobility. After the shedding of the membrane, patients present with mild scaling.
Etiology
SCHB is due to mutations in the TGM1, ALOXE3 or ALOX12B genes encoding respectively transglutaminase 1, involved in the cornification of the stratum corneum, and arachidonate 3 and 12(R) lipoxygenases involved in lipid metabolism. Transmission is autosomal recessive.

                            Last update:
                            January 2012

                            - Expert reviewer(s):
                            Pr Juliette MAZEREEUW-HAUTIER


Self-improving dystrophic epidermolysis bullosa

A rare dystrophic epidermolysis bullosa (DEB) characterized by generalized blistering at birth that usually regresses within the first 6 to 24 months of life.

Summary:
Epidemiology
Prevalence is unknown. To date, 52 cases have been reported.
Clinical description
The disease usually manifests at birth, or soon after. Skin blisters generally affect the whole body. Blisters can also affect the oral cavity. Healing of blisters is associated with mild, mostly atrophic, scarring and milia formation. Disease activity usually ceases within the first 6 to 24 months of life, although there are a few cases with continued blistering past age 3 years. Nail dystrophy and some degree of skin fragility can persist in adulthood. Ultrastructurally, the presence in basal keratinocytes of peculiar cytoplasmic inclusions, known as stellate bodies, filled with unsecreted procollagen VII, is typical of the disease.
Etiology
The disorder is caused by mutations within the type VII collagen gene (COL7A1; 3p21.31). Mutations in this gene lead to reduced amounts or an alteration in function of collagen VII. This impairs its assembly into anchoring fibrils that anchor the basement membrane to the underlying dermis.
Diagnostic methods
Diagnosis is based on identification of granular intraepidermal type VII collagen by immunofluorescence mapping and electron-dense stellate bodies on ultrastructural examination. Genetic testing can confirm diagnosis.
Differential diagnosis
The differential diagnosis includes other types of epidermolysis bullosa.
Antenatal diagnosis
Because of the mild course of the disease, antenatal diagnosis is usually not required.
Genetic counseling
Genetic counseling will depend on the mode of inheritance which can be autosomal dominant or recessive.
Management and treatment
Treatment is symptomatic with wound care to prevent secondary infection and reduce scarring.
Prognosis
Overall the prognosis is good.

                            Last update:
                            May 2021

                            - Expert reviewer(s):
                            Pr Carmen SALAVASTRU | ERN-Skin*

                                * European Reference Network


Self-limited childhood occipital epilepsy

Benign occipital epilepsy is a rare, genetic neurological disorder characterized by visual seizures and occipital epileptiform paroxysms reactive to ocular opening which present in infancy to mid-adolescence. Vomiting, tonic eye deviation and impairment of consciousness are typically associated with the Panayiotopoulos type, while visual hallucinations, ictal blindness and post-ictal headache are commonly observed in the Gastaut type. Electroencephalographic findings in both types are similar and include bilateral, synchronous, high voltage spike-wave complexes in a normal background activity located predominantly in the occipital lobes.


Self-limited epilepsy with autonomic seizures

Benign childhood occipital epilepsy, Panayiotopoulos type is a rare, genetic neurological disorder characterized by late infancy to early-adolescence onset of prolonged, nocturnal seizures which begin with autonomic features (e.g. vomiting, pallor, sweating) and associate tonic eye deviation, impairment of consciousness and may evolve to a hemi-clonic or generalized convulsion. Autonomic status epilepticus may be the only clinical event in some cases.


Self-limited epilepsy with centrotemporal spikes

Rolandic epilepsy (RE) is a focal childhood epilepsy characterized by seizures consisting of unilateral facial sensory-motor symptoms, with electroencephalogram (EEG) showing sharp biphasic waves over the rolandic region. It is an age-related epilepsy, with excellent outcome.

Summary:
Epidemiology
RE is the most common childhood epilepsy and accounts for 8-25% of all childhood epilepsies. Its incidence has been estimated to be approximately 1/5,000 in children within 15 years.
Clinical description
Onset is between 3 and 12 years, in otherwise normal children (peak of onset is 5-8 years). Seizures typically occur during sleep or drowsy states; they are brief with unilateral sensorimotor (such as numbness, tingling, drooling) that involves pharynx, tongue, face, lips and sometimes hand. Speech arrest often occurs, while comprehension is preserved. Seizures may alternate from one side to the other and may become generalized. Longer attacks can be followed by post-ictal hemiplegia. Some children may have selective neuropsychological impairment affecting language, attention, visuomotor skills and behavior. They usually do not outlast the period of active seizures. Seizure remission occurs within 2-4 years from the onset. The majority of patients have <10 seizures and 10-20% have a single seizure.
Etiology
Etiology of RE is still unknown. There is probably a genetic predisposition: an increased rate of RE, febrile seizures, and epilepsy-aphasia spectrum disorders were found among relatives. Pathogenesis seems to be related with the critical and vulnerable phase of brain maturation.
Diagnostic methods
Diagnosis of RE relies on the clinical features and on EEG findings that show slow, diphasic, high voltage, centrotemporal spikes, activated by sleep. Brain magnetic resonance imaging (MRI) is normal.
Differential diagnosis
Differential diagnosis includes other idiopathic focal childhood epilepsies (benign childhood occipital epilepsy, Panayiotopoulos type and Gastaut type. Other etiologies causing similar symptoms are excluded with brain MRI.
Genetic counseling
Autosomal dominant transmission has been reported in some cases.
Management and treatment
The majority of patients, who have a single or few seizures, do not require treatment. Differently, patients with frequent seizures (10-20%) may need treatment for a short time. In such cases, carbamazepine or valproate are preferred even if, in rare cases, carbamazepine may have a paradoxical effect.
Prognosis
Prognosis of RE is favorable since nearly 90% of patients remit before puberty. In rare cases (<1%), RE may evolve to atypical RE with linguistic, behavioral and neuropsychological deficits. An aggressive treatment with steroids, in these cases might change the evolution of the disease and a remission of neuropsychological deficits might be seen.

                            Last update:
                            May 2015

                            - Expert reviewer(s):
                            Pr Nicola SPECCHIO  - Dr Marina TRIVISANO


Benign familial infantile epilepsy (BFIE) is a genetic epileptic syndrome characterized by the occurrence of afebrile repeated seizures in healthy infants, between the third and eighth month of life.

Summary:
Epidemiology
Although BFIE cases have been reported worldwide, prevalence and incidence remain unknown. In an Argentinian case series, BFIE have been listed as the third most common type of epilepsy in the first two years of life.
Clinical description
Seizures usually occur between 3 to 8 months of life, with clusters (8-10 a day) of repeated and brief episodes (2-5 minutes) over a few days. They are usually focal but can sometimes become generalized. Patients present with motor arrest, unresponsiveness, head and/or eye deviation to one side, staring, fluttering of eyelids, grunting, cyanosis, diffuse hypertonia and unilateral or bilateral clonic jerks of the limbs. During the interictal period, patients regain full consciousness and activity. Psychomotor development is normal. A family history of the same epilepsy is a constant finding. A syndrome called familial infantile convulsions and choreoathetosis (ICCA; see this term) has been observed in which BFIE patients present in childhood and/or adolescence with choreoathetotic dyskinetic attacks occurring spontaneously or following diverse stimuli (e.g. exercise, stress). In some rare cases, BFIE has been associated with familial or sporadic hemiplegic migraine.
Etiology
BFIE is a genetically heterogeneous disease. In the majority of cases, mutations in the proline-rich transmembrane protein 2 (PRRT2) gene located at 16p11.2 have been found. This gene encodes a membrane protein that interacts with the presynaptic protein SNAP-25. Mutations have also been found in the SCN2A gene (2q24.3) encoding the brain sodium channel NaV1.2 and rarely in the KCNQ2 (20q13.33) and KCNQ3 (8q24) genes both encoding potassium channels. Additionally, three other chromosomal loci have been identified that are mapped to chromosome 19q, 16p and 1p.
Diagnostic methods
Family history can orient the diagnosis which is based on electroencephalography (EEG) and video recordings. Ictal EEG shows that partial seizures originate from the parietal-occipital region and that the side of the hemisphere involved can vary between episodes. Seizures can sometimes spread and involve the entire brain. During a cluster of seizures, postictal EEG shows lateralized occipito-parietal delta waves and spikes. Outside the cluster, waking and sleeping interictal EEG is normal. Interictal neurological examination and brain imaging (brain CT and/or MRI) are normal. Genetic testing confirms the diagnosis.
Differential diagnosis
Differential diagnosis includes benign familial neonatal-infantile seizures (see this term), an epileptic syndrome with an intermediate onset between the neonatal and infantile age that shares overlapping clinical characteristics with BFIE and that is mainly due to mutations in the SCN2A gene. Other differential diagnoses are benign non-familial infantile seizures, benign infantile seizures associated with mild gastroenteritis and benign infantile focal epilepsy with midline spikes and waves during sleep (BIMSE) (see these terms).
Genetic counseling
BFIE is transmitted as an autosomal dominant trait with incomplete penetrance.
Management and treatment
With anti-epileptic treatment (e.g. carbamazepine, valproate, phenobarbital), symptoms quickly disappear and no other type of epilepsy has been reported to reappear. In patients with a clear familial history the treatment can be interrupted within a few months.
Prognosis
Prognosis is good. Seizures normally disappear after the first year of life and patients do not display any neurological sequelae.

                            Last update:
                            May 2013

                            - Expert reviewer(s):
                            Pr Federico VIGEVANO


Benign familial neonatal epilepsy (BFNE) is a rare genetic epilepsy syndrome characterized by the occurrence of afebrile seizures in otherwise healthy newborns with onset in the first few days of life.

Summary:
Epidemiology
Prevalence is currently unknown since this disorder is possibly overlooked. About 100 families have been reported to date.
Clinical description
Seizure onset is usually between the second and the eighth day of life, in otherwise healthy newborns. Seizures are mostly focal involving alternatively both sides of the body and apnea is frequently associated. Seizures can be isolated or in clusters, are generally brief and last 1-2 minutes. However, they can be very frequent, occurring up to 20 times a day, and may evolve into status epilepticus. Seizures can occur during wakefulness and/or sleep, and are of a mixed type, starting with tonic posture and apnea, and often progressing to clonic movements and motor automatisms. During the interictal period, neonates are neurologically normal, although some degree of sedation can be seen in response to anti-epileptic medications. Although most patients do receive antiepileptic treatment in the neonatal period, seizures have been shown to remit spontaneously after the first months of life, and are usually not seen after the first year of life. However, about 10 to 15% of patients have febrile or afebrile seizures later in childhood. Subsequent psychomotor development is normal.
Etiology
BFNE is a genetically heterogeneous disorder due to mutations in the KCNQ2 (20q13.33) and KCNQ3 (8q24) genes that both code for voltage-gated potassium channel subunits. Mutations in KCNQ2 are also responsible for KCNQ2-related epileptic encephalopathy, a severe form of neonatal epilepsy.
Diagnostic methods
Electroclinical events are suggestive of the disorder. Asymmetric tonic posturing associated with apnea and followed by focal or bilateral clonic jerking is the typical seizure type. In BFNE, neonates are neurologically normal and neurocognitive development is normal. Ictal electroencephalogram (EEG) may show focal interictal abnormalities, mainly over the central regions, but otherwise the EEG background is normal. The diagnosis is confirmed by genetic testing.
Differential diagnosis
Differential diagnosis includes benign familial neonatal-infantile seizures and benign familial infantile epilepsy.
Antenatal diagnosis
Prenatal diagnosis is possible if the disease-causing mutation has already been identified in the family.
Genetic counseling
Transmission is autosomal dominant with incomplete penetrance. Genetic counseling should be offered to affected families informing them of the 50% risk the offspring has of inheriting the disease-causing mutation and therefore being affected with the disorder. Rare cases are due to de novo mutations.
Management and treatment
The use of anticonvulsant therapy (e.g. phenobarbital, phenytoin, valproate, carbamazepine) is needed in most cases to stop seizures in the neonatal period, particularly in cases with very frequent seizures or status epilepticus. Usually, patients require treatment for the first 6-12 months of life. However, it is important for clinicians and family to be aware that some patients require treatment beyond 12 months of age.
Prognosis
Prognosis is good. Seizures normally disappear during the first year of life and patients do not display any neurological sequelae. Later seizures have been reported, including occasional febrile seizures and idiopathic epilepsy syndromes in childhood, in particular Rolandic epilepsy.

                            Last update:
                            July 2015

                            - Expert reviewer(s):
                            Pr Maria-Roberta CILIO


Benign familial neonatal-infantile seizures (BFNIS) is a benign familial epilepsy syndrome with an intermediate phenotype between benign familial neonatal seizures (BFNS) and benign familial infantile seizures (BFIS; see these terms). So far, this syndrome has been described in multiple members of 10 families. Age of onset in these BFNIS families varied from 2 days to 6 months, with spontaneous resolution in most cases before the age of 12 months. Like BFNS and BFIS, seizures in BFNIS generally occur in clusters over one or a few days with posterior focal seizure onset. BFNIS is caused by mutations in the SCN2A gene (2q24.3), encoding the voltage-gated sodium channel alpha-subunit Na(V)1.2. Transmission is autosomal dominant.


Semantic dementia (SD) is a form of frontotemporal dementia (FTD; see this term), characterized by the progressive, amodal and profound loss of semantic knowledge (combination of visual associative agnosia, anomia, surface dyslexia or dysgraphia and disrupted comprehension of word meaning) and behavioral abnormalities, attributable to the degeneration of the anterior temporal lobes.


A rare otorhinolaryngologic disease characterized by the uni- or bilateral dehiscence of the bone(s) overlying the superior (most common), lateral or posterior semicircular canal(s). Patients present audiological (autophony, aural fullness, conductive hearing loss, pulsatile tinnitus) and/or vestibular symptoms (sound or pressure-evoked oscillopsia or vertigo, characteristic vertical-torsional eye movements), depending on which semicircular canal is affected. Posterior SCD syndrome is associated with high-riding jugular bulb and fibrous dysplasia, while lateral SCD syndrome is associated with chronic otitis media and cholesteatoma, with or without audiological and vestibular symptoms.


A form of holoprosencephaly characterized by fusion of the left and right frontal and parietal lobes with only a posterior interhemispheric fissure. Craniofacial features variably include ocular hypotelorism, midline cleft lip (complete or partial) and a flat nose.


A rare ciliopathy characterized by the association of nephronophthisis and liver fibrosis. Renal manifestations include chronic renal failure, polyuria, polydipsia, anemia, as well as increased echogenicity on renal ultrasound and interstitial fibrosis and tubular dilation on biopsy. Hepatic involvement manifests as hepatosplenomegaly with extensive fibrosis, destruction of the bile ducts, and cholestasis. Mild psychomotor retardation and ocular symptoms, such as strabismus, nystagmus, retinal degeneration, and anisocoria, have been reported in some patients.


A rare autosomal recessive oculo-renal ciliopathy characterized by the association of nephronophthisis (NPHP), a chronic kidney disease, with retinal dystrophy.

Summary:
Epidemiology
The worldwide prevalence is estimated at around 1/1,000,000.
Clinical description
The disease typically presents in the first two decades of life as a combination of nephronophthisis (NPH) with retinal degeneration. Depending on the genetic background either the visual disorder or chronic kidney disease determine the clinical picture. NPH typically presents with symptoms such as polyuria, polydipsia, secondary enuresis and anemia. Chronic kidney disease usually slowly progresses to end-stage kidney disease (ESKD). Ocular features include congenital or early-onset severe visual loss due to retinal dystrophy (Leber congenital amaurosis) or a milder phenotype determined by a slowly progressing tube-like restriction of visual fields and night blindness (tapeto-retinal degeneration). Funduscopy reveals various degrees of atrophic and pigmentary retinal alterations. In rare occasions, other additional clinical signs may be observed like liver fibrosis, obesity and neurologic disorders.
Etiology
Senior-Loken syndrome (SLS) is a genetically heterogeneous ciliopathy. Mutations in 10 different genes (NPHP1, INVS, NPHP3, NPHP4, IQCB1, CEP290, SDCCAG8, WDR19, CEP164 and TRAF3IP1) have been described. These genes encode for proteins of the primary cilia playing key roles in the development and function of several cell types, including retinal photoreceptor and renal tubular epithelial cells. Epistatic interactions, oligogenic inheritance or modifying alleles have been also suggested to influence the expressivity of the different extrarenal phenotypes.
Diagnostic methods
Complete renal (kidney function, urinary analysis and abdominal ultrasound) and ophthalmologic (funduscopy, visual acuity test, refraction defects, color vision test, ocular motility and electroretinogram) evaluations are recommended. Hepatic evaluation to exclude liver fibrosis (liver function and abdominal ultrasounds) and neurological examination for infant patients are also highly recommended. Genetic diagnosis of SLS requires the mutational screening of the implicated genes; deletion of the NPHP1 gene is the most common anomaly.
Differential diagnosis
SLS presents genetic and clinical overlap with other ciliopathies, in particular with isolated NPH and Joubert syndrome related diseases (JSRD) such as Joubert syndrome with oculorenal defect, Bardet-Biedl syndrome (BBS) and Alström syndrome. Physical examination should consider the presence of the main clinical signs of JSRD (hypotonia, ataxia and breathing abnormalities in infants) and BBS (polydactyly and obesity). The phenotypic hallmark of JSRD is the presence of a 'molar tooth sign' (a midbrain-hindbrain malformation) on MRI. Other extrarenal signs to consider are nystagmus, psychomotor and learning delay, diabetes mellitus, deafness, hypogonadism, and/or scoliosis.
Antenatal diagnosis
Prenatal diagnosis is feasible only when the genetic mutation has been previously identified in another member of the family.
Genetic counseling
Transmission of SLS is autosomal recessive and genetic counseling should be offered to affected families. Where both parents are unaffected carriers, the risk of disease transmission to offspring is 25%. Offspring of an affected individual are obligate carriers.
Management and treatment
Regular follow up by a pediatric nephrologist is recommended with the monitoring of growth, blood pressure, renal function (including urinary concentration and sodium excretion). In order to delay the progression of renal failure and minimize possible complications, early management of NPH is necessary. So far, there is no specific therapy correcting the genetic or functional defects in NPH. Thus, in the early stage of renal disease the main goal is the correction of water and electrolyte imbalances by replacing the ongoing loss of water and salt. Once end-stage renal disease is reached, dialysis and renal transplantation are the therapies of choice. Disease does not recur after kidney transplantation. No treatment is currently available to prevent the progression of visual loss.
Prognosis
Prognosis mostly depends on the progression of the disease in the two affected organs (kidney and eye).

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Dr Valentina CAPONE | ERKNet* - Dr Jens KÖNIG | ERKNet* - Pr Giovanni MONTINI | ERKNet*

                                * European Reference Network


Sensorineural deafness with dilated cardiomyopathy is an extremely rare autosomal dominant syndrome described in two families to date and characterized by moderate to severe sensorineural hearing loss manifesting during childhood, and associated with late-onset dilated cardiomyopathy that generally progresses to heart failure.


Sensorineural hearing loss-early graying-essential tremor syndrome

A rare genetic disease characterized by the triad of adult-onset moderate to severe bilateral sensorineural hearing loss, premature graying of scalp hair, and essential tremor manifesting as involuntary shaking of the head. Additional pigmentation abnormalities have not been reported in this syndrome.


Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome

A rare mitochondrial disease characterized by adult onset of the triad of sensory ataxic neuropathy, dysarthria, and ophthalmoparesis. Additional signs and symptoms are highly variable and include myopathy, seizures, and hearing loss, among others. Brain imaging may show cerebellar white matter abnormalities and/or bilateral thalamic lesions.


A rare systemic condition affecting neonates born at less than 37 weeks gestational age and characterized by life-threatening organ dysfunction caused by a dysregulated host response to an infection, which may have been acquired shortly before or during birth (resulting in early-onset neonatal sepsis during the first 72 hours of life), or after birth (leading to late-onset neonatal sepsis between 72 hours and three months). Prematurity constitutes one of the primary risk factors for neonatal sepsis. The clinical picture may develop gradually with signs and symptoms like irritability, lethargy, or poor feeding, or progress rapidly to respiratory distress, fever, hypothermia, hypotension, shock, and multiple organ failure.


A rare vaginal malformation characterized by the presence of a complete or incomplete longitudinal or transverse septum in the vagina due to disrupted fusion or canalization of the solid vaginal plate during embryogenesis. Signs and symptoms depend on the type of septum.


A rare clinically heterogeneous disorder characterized by the classical triad of optic nerve hypoplasia, pituitary hormone abnormalities and midline brain defects.

Summary:
Epidemiology
Incidence is estimated at 1/10,000 live births.
Clinical description
Severity varies and only 30% of patients manifest the complete clinical triad with many patients having associated findings. Some patients present at birth with SOD associated with multiple congenital anomalies, whereas others present during childhood with growth failure and/or visual anomalies (most frequently strabismus or nystagmus). The optic nerve hypoplasia can be uni- or bilateral (57% and 32% of cases, respectively) and significant visual impairment occurs in 23% of patients. Hypopituitarism is present in 62-80% of patients and although growth hormone deficiency (leading to short stature in childhood) is the most frequent endocrine anomaly, additional hormone insufficiencies may develop (thyroid-stimulating, adrenocorticotropic and gonadotropin-releasing hormone deficiencies). Midline brain defects include agenesis of the septum pellucidum (60% of cases) and/or corpus callosum. Associated cortical malformations have also been reported (sometimes referred to as SOD-plus syndrome). Intellectual deficit and neurological manifestations (developmental delay, seizures and cerebral palsy) may be present. Additional findings may include diabetes insipidus, sleep disorders, autism, precocious puberty, obesity, thermoregulatory disturbances, anosmia, sensorineural hearing loss and cardiac and digital anomalies.
Etiology
The majority of SOD cases are sporadic but familial cases have been described. Both homozygous (autosomal recessive transmission) and heterozygous (autosomal dominant transmission) HESX1 mutations (3p21.2-p21.1) have been described in familial cases. Three additional genes have been implicated in associated phenotypes that may be considered as part of the SOD spectrum: SOX2 mutations (3q26.3-q27) associated with anophthalmia/microphthalmia and features of SOD; mutations/duplications in the SOX3 gene (Xq26.3) associated with midline brain anomalies and hypopituitarism (although no eye defects have yet been described); and OTX2 mutations (14q21-q22) associated with hypopituitarism and anterior pituitary hypoplasia, with or without eye defects. Mutations in these genes are detected in < 1% of patients and environmental factors (drug and alcohol abuse, young maternal age) may also be involved.
Diagnostic methods
Clinical diagnosis requires the presence of at least two of the features of the classical triad and can be confirmed by ophthalmological studies, MRI, and dynamic pituitary function tests. SOD should be suspected in newborns with hypoglycemia, jaundice, microphallus (with or without undescended testes) and nystagmus with or without associated midline abnormalities (such as cleft palate).
Differential diagnosis
Differential diagnoses include congenital hypopituitarism and holoprosencephaly (see these terms).
Antenatal diagnosis
OD may be suspected antenatally by ultrasound and subsequent fetal MRI studies.
Genetic counseling
Genetic prenatal diagnosis and genetic counseling may be proposed to families in which the disease-causing mutation has been identified, but caution needs to be exercised in cases with autosomal dominant inheritance as the phenotype and penetrance may be highly variable.
Management and treatment
Treatment is symptomatic and SOD patients should be managed by a multidisciplinary team with regular follow-up. Hormone insufficiencies can be treated with hormone replacement therapy but close monitoring is required as the hormone deficiencies evolve with age. Children may benefit from developmental programs for the visually impaired, as well as from physical, and occupational therapies.
Prognosis
Prognosis is variable, depending on the severity of the disease. Early diagnosis is associated with a better outcome as it allows timely management of hormone insufficiencies.

                            Last update:
                            February 2010

                            - Expert reviewer(s):
                            Pr Mehul DATTANI  - Dr Emma WEBB


A rare subtype of holoprosencephaly characterized by midline fusion limited to the septal and/or preoptic regions of the telencephalon without a significant frontal neocortical fusion. Midline craniofacial malformations are generally mild and include solitary median maxillary incisor and pyriform sinus stenosis. Other reported manifestations include language delay, learning difficulties, and behavioral disorders. Imaging reveals abnormal fornix, absent or hypoplasic anterior corpus callosum, and unpaired anterior cerebral artery.


Serine biosynthesis pathway deficiency, infantile/juvenile form

A rare inborn error of metabolism comprising 3-phosphoglycerate dehydrogenase deficiency, 3-phosphoserine phosphatase deficiency, and phosphoserine aminotransferase deficiency, and characterized by a phenotypic spectrum ranging from congenital microcephaly, psychomotor retardation, and intractable seizures in the infantile forms to milder juvenile forms with moderate developmental delay and intellectual disability.


SERKAL (SEx Reversion, Kidneys, Adrenal and Lung dysgenesis) syndrome is characterised by female to male sex reversal and developmental anomalies of the kidneys, adrenal glands and lungs.

Summary:
Epidemiology
The syndrome is lethal and has been described in three foetuses.
Etiology
It is caused by homozygous missense mutations in the WNT4 gene.
Genetic counseling
It is transmitted as an autosomal recessive trait.

                            Last update:
                            May 2008


A form of autoimmune hepatitis characterized by the features of classic autoimmune hepatitis (i. e. clinical presentation as acute or chronic cryptogenic hepatitis, interface hepatitis on histological examination, elevated serum aspartate aminotransferase and alanine aminotransferase levels, hypergammaglobulinemia/elevated immunoglobulin G, therapeutic response to corticosteroids) in the absence of serum autoantibodies. Clinical manifestations include fatigue, malaise, arthralgia, jaundice, at later stages also signs of advanced chronic liver disease, such as spider nevi, caput medusae, splenomegaly, ascites, and palmar erythema. Presence of concurrent autoimmune diseases is frequently observed.


A rare neurologic disease characterized by an excess of serotonin in the central nervous system, associated with the use of various agents, including selective serotonin reuptake inhibitors (SSRIs) and recreational stimulants.

Summary:
Epidemiology
Data regarding prevalence in Europe are not available.
Clinical description
Serotoninergic syndrome may result in muscle rigidity, myoclonus, agitation, confusion, hyperthermia, hyperreflexia as well as dysautonomic symptoms, with a risk of shock with low peripheral vascular resistance, seizures, coma, rhabdomyolysis and/or disseminated intravascular coagulation (DIC).
Etiology
SSRIs and monoamine oxidase inhibitors (MAOIs) may be responsible for this syndrome at toxic but also at therapeutic concentrations. The syndrome may appear: a few hours to a few days after the initiation of the treatment; following simultaneous combination (counter-indication) of MAOIs-A (toloxatone, moclobemide) and SSRIs or successive combination with an excessively short pill-free interval; as the result of drug-drug interactions; or in some cases of acute poisoning. Individual susceptibility and severity of clinical effects may be explained by interindividual pharmacokinetic and pharmacodynamic differences. Various recreational stimulants including amphetamines (especially MDMA), synthetic cathinones, and cannabinoids are also increasingly involved.
Diagnostic methods
Diagnosis is based on clinical examination and compatible medical history. Additional investigations (electrocardiogram, laboratory examinations, toxicological analysis, electroencephalogram) are essential as clinical manifestations are not specific. Any acute infectious, neurological or metabolic diseases should be first excluded.
Differential diagnosis
Differential toxicological diagnoses include neuroleptic malignant syndrome, adrenergic or anticholinergic syndromes as well as alcohol withdrawal syndrome.
Management and treatment
Treatment is mainly supportive, based on sedation (benzodiazepines), mechanical ventilation, and even neuromuscular blockade, if necessary. In case of malignant hyperthermia, body cooling is mandatory. Dantrolene was proved inefficient. Cyproheptadine is the specific antidote for serotonin syndrome.
Prognosis
Prognosis is generally good if adequate supportive treatments are administered. However, deaths have been reported, due to multiorgan failure or brain anoxia.

                            Last update:
                            January 2024

                            - Expert reviewer(s):
                            Pr Bruno MÉGARBANE


Serotonin-producing neuroendocrine tumor of pancreas

A rare functioning neuroendocrine tumor of pancreas characterized by a typically well-differentiated neoplasm composed of cells expressing serotonin. Patients may present with atypical carcinoid syndrome with abdominal pain, diarrhea, weight loss, and/or flushing. Carcinoid syndrome is usually present only when there are liver metastases. The tumors tend to be larger than non-functioning tumors and are associated with a poorer prognosis because they are almost always metastatic.


A rare high-grade endometrial carcinoma characterized by diffuse, marked nuclear pleomorphism, typically exhibiting complex papillary and/or glandular growth patterns and showing abnormal p53 and diffuse p16 immunohistochemistry. The tumor typically arises in atrophic endometrium or in an endometrial polyp. Most patients present with postmenopausal bleeding. Extrauterine metastasis is present in 40-50% of surgically staged cases, most frequently involving lymph nodes or peritoneal sites and omentum. Patients with extrauterine spread have poor outcomes, while endometrium-limited carcinoma has a better prognosis.


A very rare, malignant, epithelial tumor of the pancreas composed of cystic structures lined by glycogen-rich clear cells, associated with local invasiveness often involving the spleen, duodenum and/or stomach and metastatic spread to the liver, peritoneum and/or lymph nodes. Presenting symptoms are variable and usually non-specific and include abdominal and/or flank pain, palpable abdominal mass, upper gastrointestinal bleeding, jaundice or abnormal serum liver enzymes, vomiting, anorexia and/or weight loss.


A rare non-infectious posterior uveitis characterized by usually bilateral, chronic, progressive, recurrent inflammation of the choroid, retinal pigment epithelium, and choriocapillaris. In the classic or peripapillary geographic type of the disease, infiltrates originating in the peripapillary region progress in an irregular serpentine fashion centrifugally and resolve spontaneously after several weeks, leaving atrophic scars. Multiple recurrences, often with months to years of quiescence in between, result in progressive visual loss in one or both eyes.


A rare, genetic intestinal disease characterized by the presence of multiple (usually large) hyperplastic/serrated colorectal polyps, usually with a pancolonic distribution. Histology reveals hyperplastic polyps, sessile serrated adenomas (most common), traditional serrated adenomas or mixed polyps. It is associated with an increased personal and familial (first-degree relatives) risk of colorectal cancer.


SETD2-related microcephaly-severe intellectual disability-multiple congenital anomalies syndrome

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by microcephaly, severe global developmental delay and intellectual disability, hypotonia, respiratory insufficiency, failure to thrive, and congenital anomalies affecting the skeleton, eyes, and several organ systems. Seizures and hearing loss are sometimes observed. Independent ambulation and meaningful speech are not attained. Common dysmorphic facial features include small forehead, biparietal narrowing, flat face, hypertelorism, arched eyebrows, short, upslanting palpebral fissures, wide nasal bridge, small, upturned nose, forward facing ears, and micrognathia. Brain imaging shows structural abnormalities in all patients.


Severe achondroplasia-developmental delay-acanthosis nigricans syndrome is characterised by the association of severe achondroplasia with developmental delay and acanthosis nigricans. It has been described in four unrelated individuals. Structural central nervous system anomalies, seizures and hearing loss were also reported, together with bowing of the clavicle, femur, tibia and fibula in some cases. The syndrome is caused by a Lys650Met substitution in the kinase domain of fibroblast growth factor receptor 3 (encoded by the FGFR3 gene; 4p16.3).


A rare pulmonary disease induced by SARS-CoV coronavirus infection, with a reported incubation period varying from 2 to 7 days. Patients present flu-like symptoms, including fever, malaise, myalgia, headache, diarrhoea, and rigors. Dry, nonproductive, cough and dyspnea are frequently reported. Severe cases evolve rapidly, progressing to respiratory distress and failure, requiring intensive care. Mortality rate is 10%. The disease appeared in 2002 in southern China, subsequently spreading in 2003 to 26 countries. Reported human-to-human transmission occurred in Toronto (Canada), Hong Kong Special Administrative Region of China, Chinese Taipei, Singapore, and Hanoi (Viet Nam).


Severe autosomal recessive macrothrombocytopenia

A rare isolated hereditary giant platelet disorder characterized by severe thrombocytopenia and thrombopathy due to defects in proplatelet formation and platelet activation in homozygous patients. Clinical manifestation are recurrent bleeding episodes including epistaxis, spontaneous hematomas, and menorrhagia.


Severe Canavan disease (CD) is a rapidly progressing neurodegenerative disorder characterized by leukodystrophy with macrocephaly, severe developmental delay and hypotonia.

Summary:
Epidemiology
The disease has been reported worldwide, but is more frequent in Ashkenazi Jewish population. The incidence of the severe form of CD in the non-Jewish population has been estimated at approximately 1:100,000 births. If both parents are of Ashkenazi Jewish descent, the incidence is 1:6,400 to 1:13,500.
Clinical description
Onset of severe CD is in infancy. Patients have hypotonia, head lag, and macrocephaly. Developmental delay is most frequently noticed between the 3rd and 5th months of life: patients fail to achieve independent sitting, ambulation and speech. The head circumference increases after the age of 6 months and is usually above the 90th percentile by one year of age. With age, hypotonia progresses to spasticity, seizures may occur and optic atrophy is apparent. Children are often irritable and exhibit sleep disturbance. Gastro-esophageal reflux leads to feeding difficulties, requiring nasogastric feeding or permanent feeding gastrostomy.
Etiology
CD is caused by mutations in the ASPA gene (17p13.3), coding for the aspartoacylase enzyme, the only enzyme responsible for the deacetylation of N-acetyl-L-aspartic acid (NAA) in the brain. Enzymatic activity is usually totally absent in severe CD. The most frequent mutations found in Ashkenazi Jews are a missense (E285A) and a nonsense (Y231X) mutation (84% and 13.4%, respectively). In the non-Jewish population the mutations are different and more diverse, the most common being the A305E missense mutation.
Diagnostic methods
Diagnosis is suspected based on the clinical findings of hypotonia, macrocephaly and head lag. The urine reveals a very high concentration of NAA. Cerebro-spinal fluid and blood also contain high levels of NAA. Brain CT scan or MRI show diffuse white matter degeneration and leukodystrophy progressing with age. Mutation screening can be performed for molecular diagnosis.
Differential diagnosis
Differential diagnosis includes other neurodegenerative disorders such as Alexander disease, Tay-Sachs disease, metachromatic leukodystrophy, and glutaric acidemia type 1 (see these terms). Spongy degeneration of the brain can be observed in Leigh syndrome and glycine encephalopathy (see these terms) or other mitochondrial disorders and viral infections.
Antenatal diagnosis
Antenatal diagnosis is feasible by DNA analysis when the proband mutation is known. Preimplantation diagnosis using a single cell mutation analysis is feasible in an at-risk pregnancy. When mutation analysis is not available, determining the concentration of NAA in the amniotic fluid may be used for the diagnosis.
Genetic counseling
CD is an autosomal recessively transmitted disease, recurrence risk is 25%. Carrier molecular genetic testing is available in a clinical setting. Ashkenazi Jewish individuals are tested for the most prevalent mutations. For non-Jewish couples, genotype should be determined using molecular diagnostic techniques.
Management and treatment
There is no curative treatment for severe CD. Management is supportive and relies on feeding assistance, physical therapy to improve the muscular status, antiepileptic drugs and therapies to improve communication skills. Research for gene therapy and enzyme replacement therapy is ongoing.
Prognosis
Prognosis is variable but globally poor. Life expectancy is about one decade, although with advances in medical and nursing care, some patients survive into their adolescence or young adulthood. Morbidity is also severe, with a total dependence for daily living activities.

                            Last update:
                            December 2012

                            - Expert reviewer(s):
                            Dr Kimberlee MATALON  - Dr Reuben MATALON


Severe combined immunodeficiency due to adenosine deaminase deficiency

Severe combined immunodeficiency (SCID) due to adenosine deaminase (ADA) deficiency is a form of SCID characterized by profound lymphopenia and very low immunoglobulin levels of all isotypes resulting in severe and recurrent opportunistic infections.

Summary:
Epidemiology
SCID due to ADA deficiency accounts for 10-15% of all cases of SCID. Its annual incidence is estimated to be between 1/200,000 and 1/1,000,000 live births. Both males and females are affected.
Clinical description
SCID due to ADA deficiency has a variable clinical presentation. The most common form presents in infancy with severe and recurrent opportunistic infections (including respiratory tract infections and candidiasis), failure to thrive, and usually results in early death. Ten to 15% of patients have a delayed clinical onset by age 6-24 months, and a smaller percentage have a partial form of ADA deficiency with later onset between ages 4 years and adulthood, both types showing less severe infections and gradual immunologic deterioration. Patients may also present with extraimmune manifestations (including neurodevelopmental deficits, behavioral disorders, sensorineural deafness, and skeletal and hepatic abnormalities) as a result of the systemic nature of ADA expression.
Etiology
SCID due to ADA deficiency is caused by mutations in the ADA gene (20q13.11). The extraimmune manifestations are caused by toxic levels of purine metabolites that result from the deficiency of ADA.
Diagnostic methods
Diagnosis is based on evidence of low or undetectable ADA activity in erythrocytes in combination with evidence of a marked reduction of T, B and NK cell counts when compared to age-matched healthy controls. Diagnosis can be confirmed by raised levels of dATP and reduced S-adenosyl homocysteine hydrolase (SAHH) activity in red cells and elevated amounts of deoxyadenosine in urine.
Differential diagnosis
Differential diagnosis includes all forms of SCID.
Antenatal diagnosis
Prenatal diagnosis can be carried out through mutation analysis or measurement of enzyme activity in trophoblasts cultured from chorionic villus sampling or in cultured amniocytes.
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Treatment is based on allogenic hematopoietic stem cell transplantation (HSCT), enzyme replacement therapy with pegylated adenosine deaminase enzyme or gene therapy by infusion of CD34+ marrow cells that have been transduced with an ADA-containing vector.
Prognosis
Prognosis depends on the severity of the disease. Without treatment, SCID due to ADA deficiency that presents in infancy usually results in early death. Survival rates after allogenic hematopoietic stem cell transplantation or gene therapy are high.

                            Last update:
                            July 2012

                            - Expert reviewer(s):
                            Pr Andrew GENNERY


Severe combined immunodeficiency due to complete RAG1/2 deficiency is a rare, genetic T-B- severe combined immunodeficiency disorder due to null mutations in recombination activating gene (RAG) 1 and/or RAG2 resulting in less than 1% of wild type V(D)J recombination activity. Patients present with neonatal onset of life-threatening, severe, recurrent infections by opportunistic fungal, viral and bacterial micro-organisms, as well as skin rashes, chronic diarrhea, failure to thrive and fever. Immunologic observations include profound T- and B-cell lymphopenia, normal NK counts and low or absent serum immunoglobulins; some patients may have eosinophilia.


Severe combined immunodeficiency due to CORO1A deficiency

A rare T-B+ severe combined immunodeficiency characterized by profoundly decreased levels of T-cells, normal B-cells, and low immunoglobulin levels. The thymus is present. Patients typically become symptomatic in infancy or early childhood with recurrent infections. Epstein-Barr virus (EBV)-associated B-cell lymphoproliferative syndrome/lymphoma and mucocutaneous-immunodeficiency syndrome have been reported in association. Some patients may show developmental delay, neurocognitive impairment, and behavioral dysfunction (in particular attention deficit-hyperactivity disorder).


Severe combined immunodeficiency due to CTPS1 deficiency

A rare primary immunodeficiency disorder due to impaired capacity of activated T- and B-cells to proliferate in response to antigen receptor-mediated activation characterized by early-onset, severe, persistent and/or recurrent viral infections due to Epstein-Barr virus (EBV) and Varicella Zoster virus (VZV, including generalized varicella), as well as recurrent sino-pulmonary bacterial infections due to encapsulated pathogens.


Severe combined immunodeficiency due to DCLRE1C deficiency

Severe combined immunodeficiency (SCID) due to DCLRE1C deficiency is a type of SCID (see this term) characterized by severe and recurrent infections, diarrhea, failure to thrive, and cell sensitivity to ionizing radiation.

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
Patients present with the classical features of SCID such as failure to thrive, severe infections (pneumonia, gastrointestinal infections, sepsis), recurrent or persistent thrush, and chronic diarrhea. Materno-fetal transfusion-associated graft versus host disease is also associated with the disease. Immunological findings include absence of T and B lymphocytes with normal natural killer (NK) cell count.
Etiology
SCID due to DCLRE1C deficiency results from null mutations in the  DCLRE1C gene (10p13) that lead to a defect in the V(D)J recombination and thus to an early arrest of both B and T cell maturation.
Genetic counseling
Transmission is autosomal recessive.

                            Last update:
                            March 2013

                            - Expert reviewer(s):
                            Pr Andrew GENNERY


Severe combined immunodeficiency due to DNA-PKcs deficiency

Severe combined immunodeficiency (SCID) due to DNA-PKcs deficiency is an extremely rare type of SCID (see this term) characterized by the classical signs of SCID (severe and recurrent infections, diarrhea, failure to thrive), absence of T and B lymphocytes, and cell sensitivity to ionizing radiation.


Severe combined immunodeficiency due to FOXN1 deficiency

A rare, genetic, primary immunodeficiency due to a defect in adaptive immunity characterized by the triad of congenital athymia (resulting in severe T-cell immunodeficiency), congenital alopecia totalis and nail dystrophy. Patients present neonatal or infantile-onset, severe, recurrent, life-threatening infections and low or absent circulating T cells. Additional features reported include erythroderma, lymphoadenopathy, diarrhea and failure to thrive.


Severe combined immunodeficiency due to IKK2 deficiency

A rare, genetic form of primary immunodeficiency characterized by life-threatening bacterial, fungal and viral infections with the onset in infancy, and failure to thrive. Typically, hypogammaglobulinemia or agammaglobulinemia and normal levels of T and B cells are present.


Severe combined immunodeficiency due to LAT deficiency

A rare severe combined immunodeficiency characterized by T-cell lymphopenia and absent T-cell proliferative responses, and normal B-cell and natural killer cell counts. Patients present in the first months of life with severe recurrent infections, failure to thrive, hematologic autoimmune disorders, and/or lymphoproliferation with splenomegaly.


Severe combined immunodeficiency due to LCK deficiency

A rare, combined T- and B-cell immunodeficiency characterized by failure to thrive, severe diarrhea, opportunistic infections, and abnormal T-cell differentiation and function due to LCK deficiency, leading to an important risk factor for inflammation and autoimmunity.


Severe combined immunodeficiency (SCID) comprises a group of rare monogenic primary immunodeficiency disorders characterized by a lack of functional peripheral T lymphocytes resulting in early-onset severe respiratory infections and failure to thrive. They are classified according to immunological phenotype into SCID with absence of T cells but presence of B cells (T-B+ SCID) or SCID with absence of both (T-B- SCID) (see these terms). Both of these groups include several forms, with or without natural killer (NK) cells.

Summary:
Epidemiology
Overall incidence is estimated at about 1/50,000 live births, with regional differences and higher incidences among populations with a higher consanguinity rate. The disease affects more males because of the X-linked variant (SCID T-B+ due to gamma chain deficiency; see this term) that represents about 30% of SCID cases in Western countries.
Clinical description
SCID usually presents within the first few months of life with failure to thrive, severe infections (pneumonia, gastrointestinal infections, sepsis), recurrent or persistent thrush, chronic diarrhea, and/or absent lymph nodes. Patients have an increased susceptibility to opportunistic infections (usually in the respiratory tract and the gut) most often due to P. jiroveci, some viruses (e.g. Cytomegalovirus, adenovirus) and fungi. Alopecia and skin rash may be present depending on the form (e.g. SCID due to gamma chain deficiency or SCID due to JAK3 deficiency; see this term). Patients are unable to produce specific antibodies after vaccination or natural infection. They may also present with extraimmune manifestations like neurodevelopmental deficit, sensorineural deafness, and hepatic abnormalities (SCID due to adenosine deaminase (ADA) deficiency;) with sensorineural deafness (reticular dysgenesis).Others may show microcephaly with neurodevelopmental delay (e.g. LIG4 syndrome; see these terms).
Etiology
The X-linked form is caused by mutations of the IL2RG gene (Xq13) encoding the common gamma chain. Mutations in around 15 genes have been identified to date for the other forms of SCID, which all follow an autosomal recessive mode of inheritance.
Diagnostic methods
The diagnosis is based on evidence of lymphopenia and a marked reduction of T-cell counts. In 50% of cases, transplacental passage of maternally-derived T lymphocytes occurs. In this case, the T cell count may be preserved but the circulating T lymphocytes have an activated phenotype (they express the CD45R0 marker while in normal infants they express CD45RA). Levels of circulating B and NK cells may help to better define the underlying cause of SCID which can then be confirmed with genetic testing. Newborn screening for SCID is now available, and is based on the measurement of levels of T-cell receptor excision circles (TRECs) in dried blood spots collected at birth.
Differential diagnosis
Differential diagnoses include other combined B-cell and T-cell disorders, 22q11.2 deletion syndrome, congenital TORCH infection, X-linked or autosomal recessive agammaglobulinemia, and other forms of hypogammaglobulinemia (see these terms).
Antenatal diagnosis
Prenatal diagnosis is possible and can aid in preparation of a bone marrow transplant.
Genetic counseling
Genetic counseling should be offered and, if the genetic defect is known, prenatal testing (by chorionic villus sampling) is recommended.
Management and treatment
Treatment is based on use of continuous antimicrobial prophylaxis, immunoglobulin replacement therapy, and strict hygiene measures. However, permanent cure requires immune reconstitution, most often achieved by allogenic hematopoietic stem-cell transplantation (HSCT). Gene therapy has been shown to be effective for patients with ADA deficiency (as well as enzyme replacement therapy) and X-linked SCID.
Prognosis
Without treatment SCID usually results in severe infection and death in children by age of 2. When performed from an HLA-identical sibling, and in the first few months of life, HSCT can result in a greater than 90% long-term survival rate.

                            Last update:
                            February 2013

                            - Expert reviewer(s):
                            Pr Luigi NOTARANGELO


Severe congenital hypochromic anemia with ringed sideroblasts

STEAP3/TSAP6-related sideroblastic anemia is a very rare severe non-syndromic hypochromic anemia, which is characterized by transfusion-dependent hypochromic, poorly regenerative anemia, iron overload, resembling non-syndromic sideroblastic anemia (see this term) except for increased erythrocyte protoporphyrin levels.

Summary:
Epidemiology
It has been reported in 3 siblings to date.
Etiology
STEAP3/TSAP6-related sideroblastic anemia is caused by a nonsense heterozygous mutation in the STEAP3/TSAP6 gene. Transmission is most likely recessive with a low expression allele.

                            Last update:
                            July 2013

                            - Expert reviewer(s):
                            Pr Clara CAMASCHELLA


Severe congenital nemaline myopathy is a severe form of nemaline myopathy (NM; see this term) characterized by severe hypotonia with little spontaneous movement in neonates.

Summary:
Epidemiology
The annual incidence of NM has been estimated at 1/50,000 live births and the severe congenital form might represent 10-20% of all cases.
Clinical description
Neonates have sucking and swallowing difficulties, and gastroesophageal reflux, which leads to failure to thrive. Involvement of diaphragm and intercostal muscles contributes to respiratory insufficiency. Cardiomyopathy and arthrogryposis may occur.
Etiology
The ACTA1 (1q42.13) and NEB (2q22) genes are associated with this form of NM.
Genetic counseling
NM is transmitted in an autosomal recessive fashion or occurs sporadically.
Prognosis
Survival after infancy is rare.

                            Last update:
                            October 2011

                            - Expert reviewer(s):
                            Dr Monique RYAN


Severe congenital neutropenia due to G6PC3 deficiency

Autosomal recessive severe congenital neutropenia due to G6PC3 deficiency is a rare, genetic, primary immunodeficiency disorder characterized by increased susceptibility to recurrent, life-threatening bacterial infections, in association with typically severe neutropenia in peripheral blood and bone marrow and a prominent ectatic superficial vein pattern, resulting from recessively inherited mutations in the G6PC3 gene. Cardiac malformations (e.g. atrial septal defects, patent ductus arteriosus,valvular defects), urogenital anomalies (incl. cryptorchidism), growth and developmental delay, facial dysmorphism (e.g. frontal bossing, upturned nose, malar hypoplasia), and intermittent thrombocytopenia are frequently associated.


Severe congenital neutropenia due to JAGN1 deficiency

Autosomal recessive severe congenital neutropenia due to JAGN1 deficiency is a rare, genetic, primary immunodeficiency disorder characterized by early-onset, recurrent, severe bacterial infections, granulopoiesis maturation arrest at the promyelocyte/myelocyte stage and markedly reduced absolute neutrophil counts, resulting from recessively inherited mutations in the JAGN1 gene. Mild facial dysmorphism (i.e. triangular face), short stature, failure to thrive, hypothyroidism, developmental delay, pancreatic insufficiency and coarctation of aorta, as well as bone and urogenital abnormalities, may also be associated.


Severe congenital neutropenia is an immunodeficiency characterized by low levels of granulocytes (< 200/mm3) without an associated lymphocyte deficit.

Summary:
Epidemiology
The prevalence in the general population is estimated at 1-1.7/333,300. Annual incidence is around 1/250,000 births.
Clinical description
This neutropenia leads to repeated bacterial or mycotic infections in various locations, mostly cutaneo-mucous, ear, nose, and throat, and pulmonary. Stomatological signs are almost always present after 2 years of age and are distinguished by erosive gingivitis, hemorrhage and pain, associated with papilla on the tongue and mucous membranes. Infections may be very severe or even lethal. Around 15% of patients evolve to acute leukemia or a myelodysplastic syndrome.
Etiology
To date, mutations in four genes have been implicated in severe congenital neutropenia. These include the neutrophil elastase gene (ELA2), the GFI1 gene, the HAX1 gene and activation genes of Wiskott Aldrich disease (WASP). The combination of these mutations leads to a deficit in the production of neutrophils.
Diagnostic methods
The defining characteristic is cytology showing profound neutropenia associated with monocytosis. An isolated blockage at the promyelocyte stage of the myeloid series associated with eosinophilia and monocytosis is seen on myelogram.
Differential diagnosis
On the discovery of these features a complete biological assessment should be conducted to rule out several differential diagnoses, particularly lymphocytic immune deficiencies and autoimmune neutropenia.
Antenatal diagnosis
Prenatal diagnosis may be offered if the genotype is known.
Genetic counseling
The four mutations are transmitted differently: ELA2 and GFI1 are autosomal dominant, HAX1 is autosomal recessive, and WASP is X-linked recessive. Genetic counseling is essential and should take into account family history and the causal mutation.
Management and treatment
All febrile episodes or infections should be reviewed by a hospital and treated actively. Prophylactic antibiotics are used to prevent infections. If this is ineffective, hematopoietic growth factors (G-CSF in particular) can correct both neutropenia and the susceptibility to infections and can be administered either in response to infections or continuously. The dose of G-CSF required varies greatly. Continuous high dose G-CSF (more than 20µg/kg/day) encourages the onset of leukemia in the long term and therefore, in cases requiring continuous high dose treatment, bone marrow transplant should be considered.
Prognosis
The prognosis depends heavily on the quality of care and timeliness of treatment of severe infections, but also on the possibility of a bone marrow transplant, particularly in cases with malignant transformation.

                            Last update:
                            July 2007

                            - Expert reviewer(s):
                            Dr Jean DONADIEU


Severe dermatitis-multiple allergies-metabolic wasting syndrome

A rare genetic epidermal disorder characterized by congenital erythroderma with severe psoriasiform dermatitis, ichthyosis, severe palmoplantar keratoderma, yellow keratosis on the hands and feet, elevated immunoglobulin E, multiple food allergies, and metabolic wasting. Other variable features may include hypotrichosis, nail dystrophy, recurrent infections, mild global developmental delay, eosinophillia, nystagmus, growth impairment and cardiac defects.


Severe disseminated cytomegalovirus infection in immunocompetent patients

A rare viral disease characterized by fulminant cytomegalovirus infection with multiple organ involvement including the brain, lung, liver, and/or heart, among others, and marked constitutional symptoms in immunocompetent patients. The condition is associated with a high case fatality rate.


Severe early-childhood-onset retinal dystrophy

Severe early childhood onset retinal dystrophy (SECORD) is an inherited retinal dystrophy characterized by a severe congenital night blindness, progressive retinal dystrophy and nystagmus. Best corrected visual acuity can reach 0.3 in the first decade of life and can pertain well into the second decade of life. Blindness is often complete by the age of 30 years.

Summary:
Epidemiology
The prevalence is hard to predict as many SECORD patients have been previously diagnosed as Leber congenital amaurosis (LCA) patients.
Clinical description
SECORD occurs during childhood and covers patients with severe congenital night blindness, nystagmus, a significantly reduced visual acuity (less or equal than 0.3) along with a progressive panretinal dystrophy of diverse extent and affection of the macula. The first symptoms can be recognized in the first year of life. Color vision is impaired in saturated and desaturated tests. An overlap with Leber congenital amaurosis (LCA) occurs when patients are characterized by their visual acuity and panretinal dystrophy. However, compared to LCA, the visual function in SECORD is much better, despite the progressive loss of visual function early in the disease that can lead to blindness in the second to third decade of life, depending on the underlying gene and mutation.
Etiology
SECORD is genetically heterogeneous, being caused by many genes including those causing LCA (ABCA4 (1p22), ADAMTS18 (16q23), AIPL1 (17p13.1), BEST1 (11q12), CRB1 (1q31.3), CRX (19q13.3), GUCY2D (17p13.1), IMPDH1 (7q31.3-q32), IMPG1 (6q14.2-q15), IMPG2 (3q12.2-q12.3), IQCB1 (3q21.1), KCNJ13 (2q37), LCA5 (6q14), LRAT (4q32.1), MERTK (2q14.1), NMNAT1 (1p36.22), RDH12 (14q24.1), RPE65 (1p31), RPGR (Xp11.4), RPGRIP1 (14q11.2), SPATA7 (14q31.3), TULP1 (6p21.3)). SECORD has however been primarily associated with mutations in RPE65 (2-10% of SECORD patients) and LRAT.
Diagnostic methods
Diagnosis of SECORD includes rod and cone responses below or near threshold in electroretinography. Psychophysical testing predicts cone-rod and rod-cone dystrophies. Patients may show a normal appearing fundus at birth but develop a panretinal dystrophy including the macula later in infancy and early childhood. Corresponding alterations of retinal layers are seen with spectral domain optical coherence tomography. A lack of fundus auto fluorescence is observed from early childhood in a subset of patients with RPE65 or LRAT mutations. Goldmann perimetry reveals severe visual field constriction and central scotomata depending on the type of progression. Bone spicules are usually not detected but pigment accumulations develop with the progress of the disease. Molecular diagnosis is performed by using next generation sequencing panel covering the whole sequence of the known reported genes (90% cases). Identified mutations and segregation analysis in the parents is confirmed by Sanger sequencing.
Differential diagnosis
Differential diagnosis includes LCA, Alström syndrome, autosomal recessive bestrophinopathy, Bardet-Biedl syndrome, achromatopsia, Stargardt disease, Usher syndrome, Senior-Loken syndrome, Saldino-Mainzer syndrome, Joubert syndrome, abetalipoproteinemia, infantile Refsum disease, neonatal adrenoleukodystrophy, Zellweger syndrome and juvenile neuronal ceroid lipofuscinosis.
Genetic counseling
SECORD is usually inherited in an autosomal recessive manner but autosomal dominant (CRX, GUCY2D, IMPDH1, IMPG1, IMPG2) and X-linked inheritance have also been observed.
Management and treatment
SECORD is currently incurable and therapies are being investigated, including gene therapy for RPE65, ABCA4 and MERTK. Retinoid supplementation therapy (9-cis-retinoid) is used for patients with mutations in RPE65 and LRAT. Treatment is supportive and includes correction of refractive error and use of low-vision aids.
Prognosis
The visual performance in bright light permits attendance at regular schools during the elementary years. Due to the genetic heterogeneity, a broad spectrum of progression exists that does not correlate with specific mutations. Useful visual function is frequently preserved beyond the second decade of life and a number of patients retain residual islands of peripheral vision, albeit considerably compromised, in the third decade of life.

                            Last update:
                            December 2017

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


Severe early-onset axonal neuropathy due to MFN2 deficiency is a rare axonal hereditary motor and sensory neuropathy characterized by early onset (<10 years) progressive distal muscle weakness and wasting of the lower limbs and later, to a lesser extent the upper limbs resulting in foot and wrist drop, areflexia, skeletal deformities (kyphoscoliosis, pes cavus with flattening, joint contractures), mild sensory impairment with vibration sense reduced to a greater extent than pain, optic atrophy and hearing loss. Wheelchair dependence by adolescence is usual and respiratory impairment with diaphragmatic paralysis may develop.


Severe early-onset obesity-insulin resistance syndrome due to SH2B1 deficiency

A rare, genetic form of obesity characterized by severe early-onset obesity, hyperphagia, insulin resistance with hyperinsulinemia, reduced adult final height, delayed speech and language development and a tendency for social isolation and aggressive behavior.


Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency

A rare, genetic interstitial lung disease characterized by accumulation of lipoproteins in the pulmonary alveoli leading to restrictive lung disease and respiratory failure. Patients present with dyspnea, tachypnea, cough, failure to thrive, and digital clubbing. Liver disease have been described in some cases including hepatomegaly, steatosis, fibrosis or cirrhosis.


Severe generalized junctional epidermolysis bullosa

A severe form of junctional epidermolysis bullosa (JEB) characterized by blisters and extensive erosions, localized to the skin and mucous membranes.

Summary:
Epidemiology
Prevalence at birth is estimated to range between 1/200,000-2,500,000 worldwide. According to data from U.S. and Italian EB registries, about 20% of patients with JEB have the severe type.
Clinical description
The extreme severity of this condition is apparent at birth. Bullae present spontaneously even with a gentle touch, with an onset within the first several months to one to two years of life. After the eruption, blisters lose their roof and remain visible as erosions that do not heal. Exuberant granulation tissue is a characteristic manifestation which arises on such eroded epithelium and may involve the skin (around nail folds, in a mask-like distribution on the face, and at sites of friction, such as shoulders and buttocks), and the upper airways. Involvement of mucous membranes may affect the entire gastrointestinal (GI) tract, genitourinary tract, and respiratory tract to the bronchioles. However, the most significant and frequent mucosal lesions are those in the upper part of the GI and respiratory tracts. The extensive erosions and ulcerations of the oral mucosa severely hamper feeding, and involvement of the laryngotracheal mucosa, manifesting as hoarseness, dyspnea and stridor, may lead to acute respiratory failure requiring tracheostomy. Other consistent features include nail anomalies with paronychia, several degrees of onychodystrophy and nail shedding. Dental abnormalities, when survival enables their observation, include regularly marked hypoplasia or complete absence of enamel. Frequent ocular lesions comprise corneal blisters, erosions and scarring, and ectropion formation. Failure to thrive is an almost constant finding, and multifactorial anemia is also common.
Etiology
Severe JEB is caused by mutations in one of the three laminin-332 coding genes: LAMA3 (18q11.2), LAMB3 (1q32) and LAMC2 (1q25-q31). In most cases, null mutations are found on both alleles of the causative gene.
Diagnostic methods
In addition to the finding of a cleavage plane located within the lamina lucida of the cutaneous basement membrane zone, a negative immunofluorescence staining for laminin-332 is typical of severe JEB. However, in rare cases the staining is strongly reduced and thus does not enable differentiation of severe JEB from intermediate JEB. In these cases, genetic testing, showing null mutations in one of the three genes encoding laminin-332, is necessary to confirm the diagnosis.
Differential diagnosis
Differential diagnosis includes other types epidermolysis bullosa, in particular congenital autoimmune bullous diseases.
Antenatal diagnosis
Prenatal diagnosis should always be recommended and diseases-causing pathogenic variants should be disclosed in advance.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.
Management and treatment
The approach is multidisciplinary with neonatal pathology units for severely affected patients, antibiotics for pulmonary infections, local antisepsis for slow-healing lesions and advanced dressing for the treatment of ulcers. Nutritional support is mandatory.
Prognosis
Prognosis is poor and the most severe JEB patients die in the first few years of life, with the major causes of death being failure to thrive, respiratory failure, sepsis, and pneumonia. Some rare patients with generalized cutaneous and internal disease reach the age of 10-15 years. In addition, squamous cell carcinomas may arise in a minority of severe JEB patients (4.5% according to data from the U.S. National EB Registry).

                            Last update:
                            June 2021

                            - Expert reviewer(s):
                            Dr Michela BRENA | ERN-Skin* - Dr Sophie GUEZ | ERN-Skin* - Dr Gianluca TADINI | ERN-Skin*

                                * European Reference Network


Severe growth deficiency-strabismus-extensive dermal melanocytosis-intellectual disability syndrome

A rare multiple congenital anomalies/dysmorphic syndrome with intellectual disability characterized by infantile onset of global developmental delay, severe intellectual disability, growth deficiency, microcephaly, strabismus, blue-gray sclerae, and extensive Mongolian spots. Some patients also present with epilepsy. Brain imaging may demonstrate variable abnormalities including cerebral atrophy, thin corpus callosum, ventriculomegaly, or arachnoid cysts.


A severe form of hemophilia A characterized by a large deficiency of factor VIII (biological activity <1 IU/dL) leading to frequent spontaneous hemorrhage and abnormal bleeding as a result of minor injuries, or following trauma, surgery or tooth extraction. It primarily affects males but may also be observed in female carriers of disease-causing mutations.


A severe form of hemophilia B characterized by a large deficiency of factor IX (biological activity <1 IU/dL) leading to frequent spontaneous hemorrhage and abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction. It primarily affects males but may also be observed in female carriers of disease-causing mutations.


Severe hereditary thrombophilia due to congenital protein C deficiency

A rare inherited coagulation disorder characterized by deep venous thrombosis symptoms due to reduced synthesis and/or activity levels of protein C.

Summary:
Epidemiology
Prevalence of severe protein C deficiency (homozygous or compound heterozygous forms) is estimated at 1/ 500,000. Partial deficiencies (heterozygous forms) are much more frequent (1/200-1/500). Men and women are equally affected.
Clinical description
Patients with undetectable protein C levels usually manifest the disease several hours to days after birth, with purpura fulminans (see this term) or massive venous thrombosis. Purpura fulminans is a life-threatening condition involving severe clotting throughout the body and causing necrosis of tissues. Patients with low but detectable protein C levels have milder symptoms generally similar to those of heterozygous individuals. Usually, patients with heterozygous protein C deficiency are asymptomatic until adulthood. Thrombotic episodes are mainly provoked by other risk factors such as surgery, pregnancy or immobilization. Deep vein thrombosis of the lower limbs with or without pulmonary embolism is the most common manifestation of the disease. Cerebral or mesenteric venous thrombosis may also occur.
Etiology
Protein C deficiency is caused by mutations in the PROC (2q13-q14) gene controlling the production of protein C. Transmission is autosomal recessive.
Diagnostic methods
Diagnosis is based on the measurement of protein C levels. Protein C activity levels range from 0 to 30% in case of severe deficiencies and from 30 to 70% in case of partial defects. There are two biological forms of the disease. Type I deficiency is characterized by concordant reduction in protein C activity and antigen. In type II deficiency, protein C activity is reduced but protein C antigen is normal. Molecular testing is available, but is unnecessary for diagnosis.
Differential diagnosis
Differential diagnoses include other inherited thrombophilias including antithrombin and protein S deficiencies (see these terms).
Antenatal diagnosis
Antenatal diagnosis is feasible for families with affected children and is based on the identification of the causal mutation on DNA obtained by chorionic villus sampling.
Management and treatment
Administration of protein C concentrates or fresh frozen plasma is critical for the initial treatment of neonatal purpura fulminans. Surgical procedures may be required for excision of thrombotic lesions. Patients with thromboses are treated with anticoagulant therapy (heparin, warfarin). Attention should be paid to the risk of coumarin-induced skin necrosis. Preventive treatment is indicated in cases with a strong positive family history of thrombotic diseases, during the peripartum period or perioperatively.
Prognosis
Prognosis may be severe in homozygous or compound heterozygous patients. Prognosis is good for heterozygous patients. With adequate treatment and monitoring, the risk of thromboembolic disease is markedly reduced. Mortality may result from pulmonary embolism.

                            Last update:
                            November 2009

                            - Expert reviewer(s):
                            Pr Jenny GOUDEMAND


Severe hereditary thrombophilia due to congenital protein S deficiency

An inherited coagulation disorder characterized by recurrent venous thrombosis symptoms due to reduced synthesis and/or activity levels of protein S.

Summary:
Epidemiology
Prevalence of partial protein S deficiency (heterozygous individuals) is estimated at 0.16-0.21% in the general population. Prevalence of severe protein S deficiency (homozygous or compound heterozygous individuals) is unknown but is probably comparable to that of severe protein C deficiency which is estimated at 1/500,000. Men and women are equally affected.
Clinical description
In severe protein S deficiency, the disease manifests several hours to days after birth, with purpura fulminans (see this term) or massive venous thrombosis. Purpura fulminans is a life-threatening condition involving severe clotting throughout the body and causing necrosis of tissues. Severe retinopathy of prematurity (ROP) (see this term) may also occur. Heterozygous patients are usually asymptomatic until adulthood. Thrombotic episodes are mainly provoked by other risk factors such as surgery, pregnancy or immobilization. Deep vein thrombosis of the lower limbs with or without pulmonary embolism is the most common manifestation of the disease. Arterial thrombosis may also occur.
Etiology
Protein S deficiency is caused by mutations in the PROS1 gene (3q11-q11.2).
Diagnostic methods
Diagnosis is based on the measurement of protein S antigen levels (total protein S or free protein S) and anticoagulant activity. There are three biological forms. Type I and type III are quantitative deficiencies with low free antigen levels (with normal total protein S levels in type III and decreased total protein S levels in type I deficiency). Type II is a qualitative deficiency with normal total and free protein S levels. Molecular testing is available, but is unnecessary for diagnosis.
Differential diagnosis
Differential diagnoses include other inherited thrombophilias including antithrombin and protein C deficiencies (see these terms).
Antenatal diagnosis
Antenatal diagnosis is feasible for families with affected children and is based on the identification of the causal mutation on DNA obtained by chorionic villus sampling.
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Administration of fresh frozen plasma may be required for the initial treatment of neonatal purpura fulminans. Surgical procedures may be required for excision of thrombotic lesions. Patients with thromboses are treated with anticoagulant therapy (heparin, wafarin). Attention should be paid to the risk of coumarin-induced skin necrosis. Preventive treatment is indicated in cases with strong positive family history of thrombotic diseases, during the peripartum period or perioperatively.
Prognosis
Prognosis is severe in homozygous or compound heterozygous patients. Prognosis is good for heterozygous patients. With adequate treatment and monitoring, the risk of thromboembolic disease is markedly reduced. Mortality may result from pulmonary embolism.

                            Last update:
                            November 2009

                            - Expert reviewer(s):
                            Pr Jenny GOUDEMAND


Severe hypotonia-psychomotor developmental delay-strabismus-cardiac septal defect syndrome is a rare, genetic, non-dystrophic congenital myopathy disorder characterized by a neonatal-onset of severe generalized hypotonia associated with mild psychomotor delay, congenital strabismus with abducens nerve palsy, and atrial and/or ventricular septal defects. Cryptorchidism is commonly reported in male patients and muscle biopsy typically reveals increased variability in muscle fiber size.


Severe-immune mediated enteropathy describes a variety of intestinal disorders that can range from a serious, early-onset systemic disease (IPEX; see this term) to a mild isolated gastrointestinal disease. In children it manifests with severe diarrhea and dehydration in the presence of characteristic antibodies (anti-enterocyte and anti-goblet cell) and in adults with chronic diarrhea, malabsorption and weight loss.


Severe intellectual disability and progressive spastic paraplegia

A rare complex hereditary spastic paraplegia characterized by an early onset hypotonia that progresses to spasticity, global developmental delay, severe intellectual disability and speech impairment, microcephaly, short stature and dysmorphic features. Patients often become non-ambulatory, and some develop seizures and stereotypic laughter.