A rare, congenital, fetal lower urinary tract obstruction (LUTO) anomaly occurring in males and characterized by a posteriorly directed semilunar fold arising from the floor of the anterior urethra and causing urethral obstruction during micturition. The valves may be located anywhere distal to the membranous urethra. Clinical presentation is highly variable, depending on age and degree of urinary obstruction, and includes urinary incontinence, urinary retention, weak urinary stream, post-micturitional dribbling, bulging on the ventral penis, urinary tract infection, and urosepsis.

Summary:
Epidemiology
The exact prevalence is unknown, although it occurs less frequently than posterior urethral valves. This disease affects males only.
Clinical description
Anterior urethral valve (AUV) can be located anywhere distal to the membranous urethra, occurring either in the bulbar urethra (40%), penoscrotal junction (30%), or in the penile urethra (30%), and are occasionally associated with urethral diverticulum. Clinical presentation is highly variable and may occur prenatally with hydronephrosis or a distended bladder, or between birth and adolescence with urinary tract infections or weak urinary stream. Other clinical manifestations include lower urinary tract obstruction, palpable distended bladder, urinary incontinence, renal insufficiency, renal dysplasia, a thickened, trabeculated bladder, and vesicoureteral reflux. After valve ablation, patients typically void spontaneously; however, over 20% of patients have abnormal renal function after treatment, which can range from stable azotemia to end stage renal disease. Complications from surgery include bleeding, incomplete valve resection, urethral stricture or damage to the external sphincter.
Etiology
A genetic cause has not been identified. AUV is postulated to arise either from a tissue growth imbalance during urethral development, incomplete hypospadias, an abortive process during urethral duplication, or faulty union between glandular and urethral tissue.
Diagnostic methods
Diagnosis is with voiding cystourethrogram (VCUG), which typically demonstrates a urethra dilated proximal to the valve and narrowing distal to it. Other findings may include a trabeculated bladder, bladder diverticulum, and urethral diverticulum. On ultrasonography, patients may demonstrate bladder distension and bilateral hydroureteronephrosis.
Differential diagnosis
Differential diagnosis includes posterior urethral valve, prune belly, and urethral atresia.
Antenatal diagnosis
Prenatal ultrasound may identify hydronephrosis, a distended bladder, or periurethral cystic mass which is indicative of the malformation.
Management and treatment
Initial management involves decompression and drainage of the genitourinary system with an indwelling urethral or suprapubic catheter. Definitive surgical treatment is typically with transurethral valve ablation, either with laser, electrocautery or cold knife urethrotomy. However, this may be deferred in favor of a primary vesicostomy in premature infants, or infants with low birth weight and high creatine levels. Due to the risk of developing renal insufficiency and other complications, all patients should be followed up with serial renal and bladder ultrasound. In severe cases with large urethral diverticulum, formal urethral reconstruction is needed, with excision of diverticulum and tubularization of urethra around a catheter.
Prognosis
Delayed treatment can lead to renal insufficiency and is potentially life threatening. Typically, valve ablation results in a good functional outcome, although there is a risk of complications and continued renal or bladder dysfunction.

                            Last update:
                            September 2020

                            - Expert reviewer(s):
                            Pr Yazan RAWASHDEH | EUROGEN*

                                * European Reference Network


Anti-glomerular basement membrane disease

A rare, fulminant small vessel vasculitis that affects the capillary beds of the kidneys and lungs and characterized by the presence of anti-glomerular basement membrane (GBM) and, in its full-blown form, anti-alveolar basement membrane (ABM) antibodies. Consequently, it may manifest as a rapidly progressive, isolated glomerulonephritis (anti-GBM nephritis) or as a pulmonary-renal syndrome with severe lung hemorrhage.

Summary:
Epidemiology
The incidence of the disease is estimated to be approximately 0.6-1.8 cases per million per year in both Asian and European Caucasian (more frequently affected) populations. Men and women seem equally affected. The disorder is responsible for 1-5% of all cases of glomerulonephritis and is the cause in up to 10-15% of patients with rapidly progressive crescentic glomerulonephritis.
Clinical description
Anti-GBM disease onset is bimodal, occurring mainly in the third and the seventh decades of life. The majority of patients (80-90%) will present with features of rapidly progressive glomerulonephritis. 40 to 60% will have concurrent lung hemorrhage, and a small minority of patients may present with isolated pulmonary disease. Features of lung involvement may include cough, shortness of breath, hemoptysis, chest pain and hypoxia. Anemia is often encountered and fatal respiratory failure may occur in more severe cases. Nephritis mainly presents with a rapidly progressive course. Rarely, renal function may be preserved for several months, despite severe pulmonary hemorrhage. Systemic features (i.e. malaise, fatigue, mild fever, pallor, weight loss) have been reported.
Etiology
Anti-GBM disease is considered to be a vasculitis affecting glomerular capillaries, pulmonary capillaries, or both, with deposition of anti-basement membrane antibodies against the non-collagenous domain 1 of the alpha 3 chain of type IV collagen (alpha3(IV)NC1). The production of anti-GBM autoantibodies usually precedes the development of clinical manifestations by months. About one-third of the patients will also develop anti-neutrophilic cytoplasmic antibodies (ANCA). Autoreactive T cells may play a role in its pathogenesis and a strong correlation between the condition and HLA-DRB1*1501 and DRB1*1502 has been reported in Caucasian populations.
Diagnostic methods
Diagnosis is based on the detection of anti-GBM antibodies either in serum or deposited in tissue, along with pathologic features of crescentic GN, with or without evidence of alveolar hemorrhage. Histologic examination on biopsy may show extensive formation of crescents (extra-capillary cell proliferation), GBM destruction, interstitial inflammation and tissue necrosis.
Differential diagnosis
Differential diagnosis includes systemic vasculitis (e.g. Wegener's granulomatosis (GPA), microscopic polyarteritis (MPA), systemic lupus erythematosus, Churg-Strauss syndrome (EGPA)) and other vasculitides (e.g. Behçets disease, cryoglobulinemia). Idiopathic progressive glomerulonephritis, severe pneumonia, pulmonary edema with acute renal failure, and renal vein thrombosis with pulmonary embolism should also be considered.
Management and treatment
Standard therapy consists in plasma exchange combined with high doses of glucocorticoids and cyclophosphamide. Recently, several reports of rituximab use have been reported, either as an adjuvant to standard therapy or as a substitute for cyclophosphamide. Dialysis may be required in severe cases, as well as medications that regulate fluid and electrolyte balance and blood pressure. Renal transplantation is not recommended as long as circulating autoantibodies are detected. Sustained remission in the absence of clinical signs of recurrence should be confirmed every 6 months.
Prognosis
If untreated, anti-GBM disease prognosis is poor. Alveolar hemorrhage is the main cause of early death in the disorder. The severity and prognosis of renal disease are correlated with levels of circulating anti-GBM. Relapses are rare.

                            Last update:
                            November 2020

                            - Expert reviewer(s):
                            Pr Dario ROCCATELLO | ERKNet*

                                * European Reference Network


A rare, acquired, subepidermal autoimmune bullous disease characterized by polymorphic cutaneous lesions (blisters, urticarial lesions or scars/milia) associated with imunoglubulin G deposition in the basement membrane zone. Lesions are frequently localized on extremities, trunk, palmoplantar and cephalic areas as well as mucous membranes.

Summary:
Epidemiology
Approximately 115 cases been reported in the literature to date. A male predominant of about 2:1 is observed.
Clinical description
The disease predominantly affects elderly people (mean age 66 years, range 28-91). Cutaneous lesions are polymorphic, but typically include itchy erythematous lesions and tense blisters, vesicles, and erosions on trunk and extremities, with possibly predominant palmoplantar involvement. In some cases, patients can have annularly arranged lesions. Usually, lesions heal without scarring, and milia formation has only been reported in few cases. About half of the patients have mucosal involvement affecting either oral or anogenital mucosa, or both. In Japanese patients, coexisting (mostly preexisting) psoriasis may be present (30% of cases).
Etiology
The exact etiology is unknown, but may be related to laminin gamma-1, consistent with the identified characteristics of the p200 protein (an acidic non-collagenous N-linked glycoprotein localized within the lower lamina lucida outside of hemidesmosomes).
Diagnostic methods
Diagnosis is based on the combination of the clinical features and direct immunofluorescence microscopy showing linear deposits of IgG and/or C3 at the dermal-epidermal junction in an n-serrated pattern and is confirmed by detection of a 200-kDa band by immunoblotting of patients' serum on human dermal extracts. About 90% of patients' sera are positive for anti-laminin-gamma 1 reactivity on ELISA or immunoblotting.
Differential diagnosis
Differential diagnosis includes bullous pemphigoid, epidermolysis bullosa acquisita, mucous membrane pemphigoid, IgA linear bullous dermatosis, pemphigus herpetiform, and pemphigus.
Management and treatment
The treatment may follow that of bullous pemphigoid. Super-potent topical corticosteroids may be applied on the whole-body surface or tapering doses of prednisolone 0.5 mg/kg/day, frequently associated with dapsone. Doxycycline, azathioprine and ciclosporine can also be used.
Prognosis
Prognosis is variable. Most patients achieve complete remission on therapy. The use of systemic corticosteroid treatment may contribute to higher mortality rate in the older patients.

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Dr Marion CASTEL | ERN-Skin* - Pr Pascal JOLY | ERN-Skin*

                                * European Reference Network


A rare systemic autoimmune disease characterized by hypercoagulability with vascular thrombosis and, in women, pregnancy morbidity (miscarriages, severe pre-eclampsia, placental insufficiency) in the presence of serum antiphospholipid antibodies, such as lupus anticoagulant, anticardiolipin antibodies, and anti-beta2-glycoprotein 1 antibodies.


A rare idiopathic inflammatory myopathy (IIM) characterized principally by myositis, generally symmetrical arthritis and interstitial lung disease (ILD) in association with serum autoantibodies to aminoacyl-transfer RNA synthetases (anti-ARS). More variable features include arthralgia, Raynaud phenomenon, heliotrophic rash, distal esophageal dysmotility and mechanic's hands.

Summary:
Epidemiology
About a quarter of all IIM patients may have antisynthetase syndrome (ASyS), providing a prevalence estimate of 1/25,000-33,000 worldwide. The disorder affects females twice as often as males.
Clinical description
The age of onset is highly variable with a mean of 50 years (range 19 to 82). Myositis, arthritis, ILD are key features of the disease. ILD is one of the clinical hallmarks. Respiratory symptoms (shortness of breath, coughing, dysphagia) are found in 40-60% of patients at disease onset. Respiratory insufficiency may be acute or develop gradually. Some patients develop clinically overt myositis while others have hypomyopathic or even amyopathic forms of the disorder. At onset, 20-70% of patients have muscle weakness of the proximal and axial muscles, and many have myalgia and muscle stiffness, similar to the milder presentations of other idiopathic inflammatory myopathies. Non-specific symptoms of fever, loss of appetite, or weight loss may occur. Rarely reported manifestations include Shawl and V signs (erythema over the back and shoulders or over the anterior neck and chest in a V), and periungual erythema. Pulmonary arterial hypertension is possible but rare. The incidence of malignancies appears to be fairly low.
Etiology
The exact pathophysiology is not known. It is currently thought that the disease starts in the lungs triggered by environmental factors (tobacco exposure, airborne contaminants) and infections, and favored by a genetic predisposition. The non-specific tissue damage activates the innate immune system, leading to release of immunogenic neo-antigens. This, in turn, induces the activation of the adaptive immune system with the production of anti-ARS antibodies, and the spreading of the immune response to targeted tissues (muscle, joint, skin).
Diagnostic methods
The diagnosis is based on the clinical features and is confirmed in the presence of positive serologic testing for anti-ARS antibodies (anti-Jo-1, anti-PL-12, anti-PL-7, anti-OJ, anti-KS, anti- YRS, anti-Zo). ILD is diagnosed by high resolution computed tomography (HRCT) of the lungs. The most frequent patterns are non-specific interstitial pneumonia (70% of the patients) and organizing pneumonia (20% of the patients). Creatine kinase (CK) levels are often significantly elevated. Absence of myositis or ILD does not exclude the diagnosis of ASyS. Diagnosis is considered probable in patients with ILD and/or inflammatory myopathy in the presence of anti-ARS. The features on the muscle biopsy include necrosis and regenerative myofibers, C5b-9 depositions on sarcolemma of non-necrotic myofibers, and sarcolemmal MHC class I overexpression with inflammatory cells infiltrates. These features occur mainly in the perifascicular area.
Differential diagnosis
Differential diagnoses include other inflammatory myopathies and idiopathic isolated ILD such as usual interstitial pneumonia. Joint involvement may also mimic or even overlap with rheumatoid arthritis.
Management and treatment
Whilst there is no consensus on treatment regimens, oral corticosteroids (prednisone) and immunosuppressive agents are the mainstay of treatment. The presence and the severity of ILD is a key point to consider. Depending on the presentation and severity, drug therapy regimens may include azathioprine, methotrexate, cyclophosphamide, cyclosporine, tacrolimus, mycophenolate mofetil, polyvalent immunoglobulins or rituximab. Dermatological symptoms have been treated effectively with hydroxychloroquine. ILD generally responds well to immunosuppressive treatment. Exercise is recommended to improve muscle strength. Response to therapy should be assessed clinically on muscle strength and CK levels. Pulmonary function tests and HRCT imaging are important for ILD follow-up.
Prognosis
The disease is chronic, requiring long-term treatment. Prognosis is guarded in severe cases but may stabilize or improve in other cases. Progression of ILD is the main prognostic factor (with aggravation in 20% of cases despite treatment) and is more likely in patients with non-anti-JO-1 antibodies.

                            Last update:
                            February 2021

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


A rare syndromic craniosynostosis characterized by craniosynostosis with midface hypoplasia, radiohumeral synostosis, femoral bowing and joint contractures.

Summary:
Epidemiology
Antley-Bixler syndrome (ABS) has been described in more than 100 patients. The relative prevalence of the two main etiologies is unknown but cases due to FGFR2 variants seem rarer than those due to POR variants.
Clinical description
Children present with characteristic facial features, including a large domed forehead, flat nose, and midface hypoplasia with proptosis and dysplastic ears. The types of craniosynostosis may include trigonocephaly (due to early metopic synostosis) or brachycephhaly but also severe pansynostosis with cloverleaf skull. Characteristic skeletal features include the radio-humeral synostosis, femora bowing (with possible fractures). Arachnodactyly and/or camptodactyly, choanal atresia and cleft palate have also been reported. A diverse range of malformations (cardiac, renal, anal or vertebral) are often associated. Urogenital anomalies with sexual ambiguity due to impaired steroidogenesis can occur. Intellectual development is variable.
Etiology
Two genetically distinct forms are observed: type 1 Antley-Bixler syndrome is associated with heterozygous mutations in the FGFR2 gene (10q26) without impairment of steroidogenesis, whereas type 2 Antley-Bixler is associated with homozygous mutations in the POR gene (7q11.2), encoding cytochrome P450 oxidoreductase (POR), which plays a direct role in steroidogenesis. Type 2 Antley-Bixler can thus be accompanied by sexual ambiguity, but this is not a compulsory finding.
Diagnostic methods
The diagnosis is usually suspected by imaging features and confirmed by molecular screening: next generation sequencing panels, whole exome sequencing and whole genome sequencing.
Differential diagnosis
A similar clinical picture is observed due to in utero environmental exposure to 1) fluconazole, a lanosterol 14 alpha-demethylase inhibitor and 2) methotrexate. A similar phenotype has been reported associated with biallelic CYP26B1 variants.
Antenatal diagnosis
ABS may be evoked in case of syndromic craniosynostosis including radio-humeral synostosis, femora bowing, choanal atresia and other visceral malformations.
Genetic counseling
Inheritance depends on the gene involved. ABS due to FGFR2 is autosomal dominant, and most cases are de novo. Affected families should be informed that it is associated with a low recurrence risk (the residual risk is due to germinal mosaicism risk, estimated to approximately 1%). ABS due to POR variants is an autosomal recessive disorder. 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
Treatment is symptomatic, and includes early neurosurgical as well as pulmonary and orthopedic management. This disorder is associated with a high risk of pediatric complications.
Prognosis
The prognosis is poor with the majority of reported patients dying during infancy due to respiratory and medullary complications.

                            Last update:
                            April 2021

                            - Expert reviewer(s):
                            Dr Geneviève BAUJAT | ITHACA*

                                * European Reference Network


Aortic arch anomaly-facial dysmorphism-intellectual disability syndrome

A developmental anomaly characterized at birth by the presence of right-sided aortic arch, craniofacial dysmorphism (microcephaly, asymmetric, facial bones, broad forehead, borderline hypertelorism, nasal septum deviation, large nasal cavity, large, posteriorly rotated ears, and microstomia with downturned corners), and intellectual disability. These features were observed in 4 members of one family, involving 2 successive generations, suggesting an autosomal dominant mode of transmission. There have been no further descriptions in the literature since 1968.


A rare heart defect characterized by complete lack of anatomical continuity between the transverse aortic arch and the descending thoracic aorta. AAI should be distinguished anatomically from atresia of the aortic arch where continuity between these segments is achieved by an imperforate fibrous strand of various lengths.


A congenital, extracardiac channel which connects the ascending aorta above the sinotubular junction to the cavity of the left, or (less commonly) right ventricle.

Summary:
Epidemiology
The exact incidence is unknown, estimates ranging from 0.5% of fetal cardiac malformations to less than 0.1% of congenitally malformed hearts in clinico-pathological series. Approximately 130 cases have been reported in the literature, about twice as many cases in males as in females.
Clinical description
Associated defects, usually involving the proximal coronary arteries, or the aortic or pulmonary valves, are present in nearly half the cases. Occasional patients present with an asymptomatic heart murmur and cardiac enlargement, but most suffer heart failure in the first year of life.
Etiology
The etiology of aorto-ventricular tunnel is uncertain. It appears to result from a combination of maldevelopment of the cushions which give rise to the pulmonary and aortic roots, and abnormal separation of these structures.
Diagnostic methods
Echocardiography is the diagnostic investigation of choice. Antenatal diagnosis by fetal echocardiography is reliable after 18 weeks gestation.
Differential diagnosis
Aorto-ventricular tunnel must be distinguished from other lesions which cause rapid run-off of blood from the aorta and produce cardiac failure.
Management and treatment
Optimal management of symptomatic aorto-ventricular tunnel consists of diagnosis by echocardiography, complimented with cardiac catheterization as needed to elucidate coronary arterial origins or associated defects, and prompt surgical repair. Observation of the exceedingly rare, asymptomatic patient with a small tunnel may be justified by occasional spontaneous closure. All patients require life-long follow-up for recurrence of the tunnel, aortic valve incompetence, left ventricular function, and aneurysmal enlargement of the ascending aorta.

                            Last update:
                            October 2007

                            - Expert reviewer(s):
                            Dr Roxane MCKAY


A frequent form of acrocephalosyndactyly, a group of inherited congenital malformation disorders, characterized by craniosynostosis, midface hypoplasia, and finger and toe anomalies and/or syndactyly.

Summary:
Epidemiology
The estimated incidence of Apert syndrome is reported to be 1/100,000 to 1/160,000 live births.
Clinical description
Patients generally have extensive structural and functional impairments related to cranial and limb deformities. Craniosynostosis can lead to acrobrachycephaly or turribrachycephaly with delayed closure of fontanels and a possible impact on brain growth and neurological development. Macrocephaly is also found. Limb malformations mainly consist of soft tissue and bony syndactyly of fingers and toes (involving variable numbers of digits), occasional rhizomelic shortening, and elbow ankylosis, with functional impairments and restriction of mobility. Facial findings include midface hypoplasia that is generally moderate to severe with hypoplasia of the maxilla, shallow orbits, strabismus, hypertelorism, down-slanting palpebral fissures, and proptosis, as well as depressed nasal bridge and deviated nasal septum. Dental findings include delayed eruption, impaction, crowding, thick gingival swelling, and missing teeth, along with a high risk of caries. Unilateral and bilateral posterior crossbites are frequent. Common associated complications include chronic otitis media, hearing loss, and increased ocular pressure that can cause blindness. Moderate to severe intellectual disability and variable developmental delay are also common in AS (more than 50% of cases). Some patients are also reported to have agenesis of the corpus callosum, ventriculomegaly, hydrocephalus, fused cervical vertebrae (usually C5-C6), and occasionally, cardiac and gastrointestinal defects, radiohumeral synostosis, or cleft velum (see this term).
Etiology
A mutation in the FGFR2 gene (10q25.3-10q26) involved in cell signaling during embryonic development is causative in Apert syndrome. Advanced paternal age has been associated with de novo mutations, which are found in most cases.
Diagnostic methods
Diagnosis is based on the clinical findings at birth. Some cases may be identified prenatally. The diagnosis can be confirmed by molecular genetic testing.
Differential diagnosis
The differential diagnosis includes other syndromic craniosynostosis syndromes, such as Pfeiffer, Crouzon, Saethre-Chotzen, Muenke, and Jackson-Weiss syndromes (see these terms).
Antenatal diagnosis
Prenatal MRI or molecular genetic testing can be used to diagnose suspected cases.
Genetic counseling
A mutation in the FGFR2 gene (10q25.3-10q26) involved in cell signaling during embryonic development is causative in Apert syndrome. Advanced paternal age has been associated with de novo mutations, which are found in most cases.
Management and treatment
A multidisciplinary approach to care is necessary with life-long monitoring. Treatment primarily involves craniosynostosis release, followed by surgical advancement or distraction for midface hypoplasia, and reparative or cosmetic treatment of other malformations. Successful treatment can improve aesthetics and functional performance (breathing, mastication, oral and ocular health). In patients with mitten-glove syndactyly, surgical separation of the digits generally provides little functional improvement. The psychosocial aspects of the syndrome should also be taken into account.
Prognosis
The prognosis is guarded. Many individuals have life-threatening complications, including airway and central nervous system compromise. Others can do relatively well with proper medical and surgical management, but intellectual limitations are still very common. Life expectancy varies among patients with AS due to variable clinical severity and treatment success.

                            Last update:
                            October 2014

                            - Expert reviewer(s):
                            Dr Austin HAMM  - Dr Nathaniel ROBIN


An extremely rare congenital limb malformation syndrome, described in only 3 patients to date,characterized by the association of hypoplasia or aplasia of the hand and foot phalanges, hemivertebrae and various urogenital and/or intestinal abnormalities (i.e. dysgenesis of the urogenital tract and rectum). There have been no further descriptions in the literature since 1991.


An extremely rare malformation syndrome characterized by the association of partial distal aphalangia with syndactyly, duplication of metatarsal IV, microcephaly, and mild intellectual disability.


Aphonia-deafness-retinal dystrophy-bifid halluces-intellectual disability syndrome

A rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by moderate to severe intellectual disability, congenital aphonia, hearing loss, optic atrophy, retinal dystrophy, broad thumbs and duplicated halluces. Facial dysmorphism (incl. thick eyebrows, ptosis, long, downslanting palpebral fissures, microstomia, low-set, posteriorly rotated ears) and genital abnormalities are also associated.


Aplasia cutis congenita-intestinal lymphangiectasia syndrome

An extremely rare association syndrome, described in only two brothers to date (one of which died at 2 months of age), characterized by aplasia cutis congenita of the vertex and generalized edema (as well as hypoproteinemia and lymphopenia) due to intestinal lymphangiectasia. There have been no further descriptions in the literature since 1985.


A rare skin disorder characterized by localized absence of skin that is usually located on the scalp but can occur anywhere on the body including the face, trunk and extremities. Aplasia cutis congenita (ACC) may occasionally be associated with other anomalies.

Summary:
Epidemiology
Worldwide ACC prevalence is approximately 1/10,000 live births.
Clinical description
ACC is noticed immediately at birth and usually presents as a solitary lesion on or near the vertex. There may also be multiple lesions occurring on the scalp or elsewhere. The individual lesion can vary from a superficial, circular or oval, well-demarcated defect or atrophic scar with alopecia to a weeping or granulating ulcer extending to the bone (non-membranous ACC). The lesions can range from few millimeters to more than 10 cm in diameter. Some defects can have a membranous covering that can be filled with fluid, giving it a bullous appearance (membranous ACC). A tuft of long, dark colored hair (hair collar sign) may be present around the membranous lesion suggesting cranial dysraphism. Membranous ACC is not associated with non-neuroectodermal anomalies. The common Frieden classification subdivides ACC into 9 groups based on cause, localization and associated malformations.
Etiology
Etiology is manifold; genetic factors (including causal mutations in the genes BMS1 (10q11.21) and DLL4 (15q15.1), identified in a few families), teratogens, amniotic adhesion, vascular anomalies, pharmacological agents (e.g. thyreostatics as methimazole, valproic acid, benzodiazepines, heparin) and drugs (cocaine), intrauterine trauma and herpes virus infections have all been implicated. Membranous ACC of the scalp has been proposed to be due to incomplete closure of ectodermal fusion lines whereas non-membranous ACC rather appears to have vascular causes.
Diagnostic methods
Newborns with ACC have to be thoroughly examined for associated anomalies. Extensive cases of ACC necessitate immediate MRI to evaluate any accompanying bone and intracranial malformations. Histologic examination of healed ACC lesions shows scar-like tissue devoid of skin appendages and elastic fibres. Membranous ACC may reveal heterotopic brain tissue.
Differential diagnosis
Differential diagnoses include traumatic lesions, localized scalp infections, dermoid cyst (facial, cervical, nasal or involving the central nervous system), isolated encephalocele, meningocele and nodular neuronal heterotopia. As the child grows and scarring occurs, sebaceous nevus, nevus psiloliparus, localized scleroderma and other types of cicatricial alopecia should be considered. Hypertrophic scars can be mistaken for scalp tumors. ACC can occur in association with inherited epidermolysis bullosa and with epidermal and organoid nevi (didymosis aplasticosebacea). It may also form part of numerous syndromes including: chromosomal abnormalities (mainly trisomy 13), Adams-Oliver syndromes, Johanson-Blizzard, SCALP syndrome, focal facial dermal dysplasia, oculocerebrocutaneous syndrome, scalp-ear-nipple syndrome, Toriello-Lacassie-Droste syndrome, aplasia cutis congenita-intestinal lymphangiectasia syndrome, aplasia cutis-myopia syndrome, cutis verticis gyrata-thyroid aplasia-intellectual disability syndrome, and others.
Antenatal diagnosis
Prenatal diagnosis is limited to ACC types with transmittable genetic origin.
Genetic counseling
Most reported cases of nonsyndromic ACC are sporadic, but autosomal dominant inheritance has been reported in familial cases (including the BSM1 and DLL4 pathogenic variants).
Management and treatment
Biopsy, drainage or excision of lesions should not be undertaken without prior imaging. Treatment of ACC usually involves a conservative approach (gentle cleansing, topical antiseptics, hydrocolloidal dressings) allowing the lesions to heal by secondary intention when possible. Repair using skin flaps and grafts is only recommended for larger defects, such as those extending down to the dura mater, to prevent hemorrhage and infection.
Prognosis
Less severe cases usually resolve within weeks to months, but alopecia persists. Underlying or associated defects may significantly affect mortality and morbidity.

                            Last update:
                            November 2019

                            - Expert reviewer(s):
                            Pr Henning HAMM


A rare disorder characterised by the association of aplasia cutis congenita with high myopia, congenital nystagmus and cone-rod dysfunction. It has been described in two siblings (brother and sister). Transmission is autosomal dominant.


A rare autosomal dominant disorder characterized by aplasia, atresia or hypoplasia of the lacrimal and salivary glands leading to varying features since infancy such as recurrent eye infections, irritable eyes, epiphora, xerostomia, dental caries, dental erosion and oral inflammation.


A developmental disorder affecting premature infants, likely secondary to an immaturity of respiratory control resulting in idiopathic pauses in breathing often associated with reduced heart rate and arterial blood oxygen levels. It may be exacerbated by concurrent neonatal diseases.


A rare lipoprotein metabolism disorder characterized biochemically by complete absence of apolipoprotein AI and extremely low plasma high density lipoprotein (HDL) cholesterol, and clinically by corneal opacities and xanthomas complicated with premature coronary heart disease (CHD).

Summary:
Epidemiology
Prevalence of Apo A-I deficiency is unknown. The disease has been described in about 30 families.
Clinical description
Although extremely low plasma HDL cholesterol may be detected in any patient fortuitously from birth, the age of symptom onset and the clinical presentation varies greatly. While some patients remain asymptomatic until advanced adulthood, others may present from adolescence with a combination of the following symptoms: blurred vision due to corneal opacities or cataract, tubero-eruptive, tendinous, palmar and/or planar xanthomas, xanthelasmas, and premature CHD (e.g. myocardial infarction) and carotid atherosclerosis. Less often, Apo A-I deficiency may manifest with neurosensory signs (e.g. cerebellar ataxia, neurosensory hearing loss, proliferative retinopathy) or other multi-organ manifestations of secondary amyloidosis (e.g. hepatomegaly, nephropathy, cardiomyopathy), all potentially progressing into end-stage organ failure (liver, renal or cardiac failure).
Etiology
The disease is due to various deletions and mutations of the APOA1 gene (11q23-q24), encoding the apo A-I protein, a major constituent of HDL, that lead to decreased apo A-I production, impaired function or increased apo A-I catabolism. The clinical picture depends on the type of mutation. Mutations severely impairing Apo A-I expression (i.e. nonsense or frameshift point mutations, genomic rearrangements), result in premature CHD. Missense mutations associated with detectable plasma apoA-I and very low HDL cholesterol, result in milder cardiovascular symptoms and, occasionally, in systemic or neurological amyloidosis, or are associated with healthy patients with no signs of atherosclerosis.
Diagnostic methods
Diagnosis is based on biochemical analysis of plasma Apo A-I and HDL cholesterol levels showing extremely low HDL cholesterol levels and very low to undetectable Apo A-I (inferior to 5 mg/dL). Low HDL cholesterol levels are associated with normal VLDL and LDL cholesterol levels, and normal or decreased triglyceride levels. Histological examination of skin lesions reveals numerous foam cells. Diagnosis is confirmed by genetic testing.
Differential diagnosis
The differential diagnosis includes Tangier disease, LCAT deficiency (see these terms) and secondary causes of extremely low HDL cholesterol levels that include medications (androgenic steroids, paradoxical response to fibrates) and malignancies.
Antenatal diagnosis
Antenatal diagnosis is usually not performed, but is possible in families with severe systemic or neurological amyloidosis.
Genetic counseling
Transmission is autosomal dominant. Genetic counseling should be offered to the affected families informing them of the 50% risk the offspring has of inheriting the disease-causing mutation and therefore being affected with the disorder.
Management and treatment
To date, there is no curative therapy. In case of carotid atherosclerosis or cardiovascular complications, a low-fat diet balanced in anti-oxidants (e.g. Mediterranean type) may be combined with statins (HMGCoA reductase inhibitors) that lower LDL cholesterol levels below 70 mg/dL. Oral anti-oxidants, or infused synthetic HDL-mimetics or reconstituted HDL, are being investigated as potential anti-atherosclerotic therapies. Regular cardiovascular monitoring should be offered to Apo AI deficient patients with extremely low HDL cholesterol (<20 mg/dL) because of the increased risk (Odds Ratio x2-3) of coronary artery disease. In cases exhibiting signs of amyloidosis, long-term follow-up of target organ function should be proposed.
Prognosis
Prognosis depends on the occurrence of premature CHD and end-stage organ failure in cases with signs of amyloidosis.

                            Last update:
                            December 2013

                            - Expert reviewer(s):
                            Dr Pascale BENLIAN


A rare form of pseudohyperaldosteronism characterized by very early-onset and severe hypertension, associated with low renin levels and hypoaldosteronism.

Summary:
Epidemiology
Prevalence is difficult to estimate and likely varies between populations depending on the level of consanguinity. Less than 100 cases have been reported in the literature so far.
Clinical description
AME is usually diagnosed within the first years of life and is characterized by polyuria and polydipsia, failure to thrive, severe hypertension with low renin and aldosterone levels, profound hypokalemia with metabolic alkalosis, and most often nephrocalcinosis. Stroke has been observed before the age of 10 years in untreated children.
Etiology
AME is caused by homozygous or compound heterozygous loss-of-function mutations or deletions in the HSD11B2 gene (16q22). In all cases, these mutations lead to abolition or a marked decrease in the activity of 11-beta-hydroxysteroid dehydrogenase type 2 (11-beta-HSD2), an enzyme involved in the conversion of cortisol to cortisone.
Diagnostic methods
Diagnosis should be suspected on the basis of the clinical and biochemical characteristics. Detection of a marked increase (10 to 100-fold) in the ratio of cortisol/cortisone (F/E) or of the tetrahydroxylated metabolites (THF+alloTHF/THE) in plasma and urine is a strong indication for diagnosis. However, a milder form of AME (AME2, also caused by mutations in the HSD11B2 gene) has been described with less marked hypertension and only mild abnormalities of cortisol metabolism. The diagnosis can be confirmed by genetic testing.
Differential diagnosis
Differential diagnoses include pseudohyperaldosteronism (particularly Liddle syndrome; see this term), as well as other forms of early-onset childhood hypertension (particularly renal hypertension). Natural licorice consumption can result in a clinical picture that mimics AME, but this phenomenon is only rarely observed in children as it requires either a sustained and chronic, or a high and acute, exposure to cause adverse effects.
Antenatal diagnosis
For families in which the disease-causing mutation has already been identified, prenatal diagnosis may be considered in case of a life-threatening case in a previous child.
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Early diagnosis and treatment is important to prevent end-organ damage (central nervous system, kidney, heart and retina). Two main strategies can be used to treat AME. The first is the blockade of the mineralocorticoid receptor by spironolactone (2-10 mg/kg/day), combined with thiazides to help to normalize blood pressure and reduce hypercalciuria and nephrocalcinosis. The second and complementary strategy, is the administration of exogenous corticoids to block ACTH and suppress the endogenous secretion of cortisol. This strategy has proven efficacy on blood pressure, renin and aldosterone levels but has little effect on urinary cortisol, cortisone and corticosterone concentrations. As the hypertension is severe, nonspecific antihypertensive agents (e.g. calcium antagonists) are also often required.
Prognosis
In the absence of treatment, the prognosis for AME is severe with malignant hypertension, stroke, cardiac and renal insufficiency. However, the prognosis for patients with appropriate treatment appears to be good.

                            Last update:
                            February 2009

                            - Expert reviewer(s):
                            Pr Xavier JEUNEMAITRE


A rare genetic non-syndromic central nervous system malformation characterized by absence of the telencephalon and absent or abnormal diencephalic structures, combined with severe abnormalities of the mesencephalon and cerebellum. Further malformations, for example of the hands and feet, have been described in addition.


A group of rare central nervous system malformations characterized by varying degrees of absence or dysplasia of the derivatives of the prosencephalon (i. e. telencephalon and diencephalon), with an intact cranial vault. The spectrum comprises atelencephaly, the less severe form, in which only the telencephalon is affected, and aprosencephaly, where the diencephalon is also involved. The malformations may occur in an isolated form or in association with other anomalies.


A rare skin disease characterized by transient wrinkling of the skin, edema, formation of whitish papules, pruritus, burning sensation, or pain, on the palms and/or soles in response to contact with water. Duration of exposure and water temperature affect the rate of development and intensity of the lesions. The condition is more common in females than in males and frequently occurs in patients with cystic fibrosis.


Arachnodactyly-abnormal ossification-intellectual disability syndrome

A multiple congenital developmental anomalies syndrome characterized by arachnodactyly of fingers and toes associated with craniofacial dysmorphism (including abnormal cranial ossification, frontal bossing, flat calvaria, shallow deformed orbits resulting in exophtalmos, midface hypoplasia and micrognathia), feeding difficulties in infancy, infantile muscular hypotonia, and developmental delay leading to intellectual disability.


A rare multiple congenital anomalies/dysmorphic syndrome characterized by facial dysmorphism (brachycephaly, long, narrow, triangular face, prominent forehead, hypertelorism, flat philtrum, microstomia, thin lips, hypoplastic maxilla), marfanoid habitus with arachnodactyly, and moderate to severe intellectual disability. Additional features may include clinodactyly, triphalangeal thumbs, hammer-shaped toes, hyperextensible joints, hypotonia, hyperreflexia and underdeveloped musculature. Delayed external genitalia development, as well as seizures and mitral regurgitation have been reported in some cases. There have been no further descriptions in the literature since 1995.


A disorder with extraparenchymal cysts, intra-arachnoidal collections of fluid, the composition of which is close to that of cerebrospinal fluid. They are often asymptomatic.

Summary:
Epidemiology
Studies carried out since the advent of MRI and CT suggest that the prevalence is higher than previously thought, perhaps as high as 1 per 5000. In neurosurgery case series, cysts are more commonly located in the temporo-sylvian fossae. Temporal cysts are significantly more frequent in males than in females (4:1), while cysts in other locations do not show preponderance for a specific gender. A significant predominance of left-sided temporal cysts is found in males (2:1).
Clinical description
Arachnoid cysts may evolve during postnatal life. This malformation may be primitive or may be due to a disturbed flow of cerebrospinal fluid, generated by agenesis of veins.
Etiology
Different mechanisms may explain the increase in volume of the cysts: fluid secretion by cells of the cyst wall, unidirectional valvula or fluid movements secondary to movements of vein walls.
Genetic counseling
Although most diagnosed cases are sporadic, identical arachnoid cysts have been reported in at least three sets of sibs, the parents not being related. In one family, sibs also had microcephaly and intellectual deficit. If mendelian, arachnoid cysts may be an autosomal recessive condition.

                            Last update:
                            April 2005


A chronic inflammation of the arachnoid layer of the meninges, of which adhesive arachnoiditis is the most severe form, characterized by debilitating, intractable neurogenic back and limb pain and a range of other neurological problems.

Summary:
Epidemiology
The prevalence is unknown. About 25,000 cases of arachnoiditis occur each year, mostly in North and South America, Asia and Europe, where spinal operations are more prevalent.
Clinical description
Patients present with chronic, persistent deafferentiation pain in the lower back, limbs and trunk that is increased by activity, hyporeflexia, loss of temperature sensation, numbness, and often widespread allodynia, dysesthesia and hyperpathia. Patients may also experience proprioception alterations (including loss of balance, tinnitus and reduced hearing and vision), motor weakness, muscle cramps, fasciculation, anhidrosis, and bladder, bowel and sexual dysfunction. Arachnoiditis may, in a minority of cases, involve the brain as well as the spinal cord, possibly causing communicating hydrocephalus.
Etiology
Arachnoiditis can be mechanically (localized) or chemically (diffuse) induced, and is often associated with spinal operations (60% of cases), neuroaxial (spinal and epidural) anesthesia (22%), spinal taps (7%), myelography (3%), pain relief procedures and secondary infections. It can also be caused by bacterial and viral spinal infections (7%) and repeated subarachnoid injections of anticancer drugs or antimetabolites. Syringomyelia, cauda equina syndrome, pseudomeningoceles, intrathecal cysts or tethering of the spinal cord and nerve roots (NR) may complicate lumbosacral arachnoiditis. Arachnoiditis occurs as a progression of inflammatory changes. In the early (inflammatory) phase NR are edematous (enhanced), while in the late proliferation stage (adhesive arachnoiditis) NR are clumped and asymmetric. The flow of cerebrospinal fluid from the distal dural sac to the brain is impeded, intrathecal pressure increases and this causes back pain and postural headache. In some cases the scar tissue calcifies (arachnoiditis ossificans).
Diagnostic methods
Diagnosis is based on patient history, clinical presentation and a causative event, and can be confirmed by MRI with contrast. When MRI is not possible, myelogram followed by CT scan is indicated. The adhesions generally occur on the dorsal segments, are arranged peripherally, and have been described as looking `like the bark of a tree' when viewed by myelography.
Differential diagnosis
Differential diagnoses include intra-spinal hematoma or dislodged disc fragment if the condition presents immediately after surgery, and Failed Back Surgery Syndrome (FBSS). Some patients are diagnosed with fibromyalgia (see this term), but these symptoms are likely to occur as a secondary feature due to the altered spinal dynamics.
Management and treatment
In the early phase, treatment includes large doses of IV methylprednisolone for five days, preferably within three months of the causative injury, followed by a protocol directed to control neuropathic pain using a multimodal approach that includes an anti-inflammatory, an anticonvulsant and an antidepressant. Large doses of opiates, that can cause hyperalgesia, hypersensitivity and tachyphylaxis, and lead to dependence, should be discouraged. If necessary, to treat exacerbation ``flare-ups'', IV infusions of NMDA receptors antagonists (including lidocaine, MgSO4, ketamine) can be given.
Prognosis
Once the proliferative stage has begun, arachnoiditis will be permanent and is complicated by the aging process of the spine. Operations, injections or any other invasions of the spine may exacerbate the disease significantly.

                            Last update:
                            March 2010

                            - Expert reviewer(s):
                            Pr Antonio ALDRETE


A rare genetic disease characterized by lipoatrophic diabetes, mild craniofacial dysmorphism (such as pronounced antitragal incisura and mandibular prognathism), ectodermal dysplasia (generalized hypotrichosis and dental and nail abnormalities), hypoplasia or aplasia of the breasts, and urogenital/renal anomalies. Additional reported manifestations include skeletal abnormalities and hepatosplenomegaly.


A disorder that caused by the Junin virus (JUNV), is an acute viral hemorrhagic disease characterized by initial fever and malaise followed by gastrointestinal symptoms and in some cases hemorrhagic and neurological manifestations.


Central diabetes insipidus (CDI) is a hypothalamus-pituitary disease characterized by polyuria and polydipsia due to a vasopressin (AVP) deficiency. It can be inherited or acquired (hereditary CDI and acquired CDI; see these terms).

Summary:
Epidemiology
CDI is a rare disease with a reported prevalence of 1/25,000.
Clinical description
Idiopathic CDI onset can occur at any age but most often in 10-20 year olds. In the familial form, disease onset can be as early as the neonatal period. The symptoms characteristic of CDI are polyuria and polydipsia, usually associated with weight loss. Nocturia is common and in children often presents as enuresis. Polyuria is characterized by a urine volume in excess of 150 ml/kg/24h at birth, 100-110 ml/kg/24h until the age of 2 years, and 40-50 ml/kg/24h in older children and adults. Water deprivation leads to rapid dehydration. In children, additional symptoms of CDI can include lethargy, irritability, growth retardation, weight loss, fever, vomiting or diarrhea. In secondary CDI, further manifestations may be present resulting from the secondary cause.
Etiology
Acquired CDI, especially in children and young adults, is caused by destruction or degeneration of the neurons that originate in the supraoptic and paraventricular nuclei of the hypothalamus. The known causes of these lesions include germinoma, craniopharyngioma, Langerhans cell histiocytosis, sarcoidosis (see these terms), local inflammatory, autoimmune or vascular diseases and trauma from surgery or accident. Midline cerebral and cranial malformations are another possible cause of CDI. Between 20 and 50 % of cases are considered idiopathic. Autoimmunity may play a role in the pathogenesis of CDI. Genetic defects in AVP synthesis inherited as autosomal dominant, autosomal recessive or X-linked recessive traits are the underlying cause in less than 10% of CDI.
Diagnostic methods
Diagnosis of CDI is based on the demonstration of plasma hyperosmolality (> 300 mosm/l) associated with urine hypoosmolality (< 300 mosm/l or urine/plasma osmolality ratio < 1) and polyuria. A water deprivation test and blood test is needed to differentiate CDI from nephrogenic diabetes insipidus (NDI; see this term). The administration of desmopressin will help to make a differential diagnosis between CDI and NDI. Once the diagnosis of CDI has been established, other investigations are mandatory, including tumor markers, skeletal survey and especially brain neuroimaging.
Differential diagnosis
The main differential diagnosis is NDI as the disorders share the same manifestations. Recently, the dosage of aquaporin 2 (AQP2) has been used in the differential diagnosis of CDI as the failure to increase AQP2 excretion after desmopressin administration indicates a nephrogenic form of diabetes insipidus. Wolfram syndrome (see this term) is another differential diagnosis.
Genetic counseling
Genetic counseling is required in the very rare cases of familial CDI.
Management and treatment
Immediate water intake and drug therapy is the course of treatment for CDI to correct water and electrolyte levels. Desmopressin is the most commonly used antidiuretic drug and can be given parenterally, orally or intranasally. Daily requirements are 100-1200 micrograms in 3 divided doses given orally, approximately 2-40 micrograms intranasally or 0.1-1 micrograms parenterally with maximum plasma concentrations being reached in 40-55 minutes. Follow-up is necessary to monitor electrolyte levels and determine the success of a chosen treatment. In early infancy, fluids alone can be a management strategy. Acquired CDI can be transient if the underlying causes of CDI are removed and the pituitary stalk is intact.
Prognosis
There is no cure for idiopathic CDI but it is a manageable disease with no effect on life expectancy. In cases of secondary CDI, inadequate treatment of the underlying disease can lead to death.

                            Last update:
                            July 2012

                            - Expert reviewer(s):
                            Dr Stefano GHIRARDELLO


Arginine vasopressin resistance-intracranial calcification-short stature-facial dysmorphism syndrome

A rare, genetic, renal tubular disease characterised by nephrogenic diabetes insipidus, intracerebral calcifications, intellectual disability, short stature and facial dysmorphism. There have been no further descriptions in the literature since 1990.


A rare, genetic renal tubular disease that is characterized by polyuria with polydipsia, recurrent bouts of fever, constipation, and acute hypernatremic dehydration after birth that may cause neurological sequelae.

Summary:
Epidemiology
To date, over 350 families have been reported with genetic mutations, for which over 90% involve the gene AVPR2.
Clinical description
The disease typically presents in the first year of life. Typical features of NDI are failure to thrive associated with, feeding difficulties, vomiting, constipation, fever, and irritability. Hypernatremia occurs where management is lacking for urinary water losses. Acquired NDI is more common in adulthood, presenting with polyuria/polydipsia. Affected adults typically drink and void between 10-12 litres per day. Polyuria may exceed 10 liters in children.
Etiology
The disease results from the failure of the renal tubules to respond to antidiuretic hormone. In most cases, the disease is caused by mutations in the gene located on Xq28 coding for the V2 receptor of antidiuretic hormone. In cases of autosomal recessive or dominant transmission, NDI is caused by mutations in the AQP2 gene (12q13) that codes for aquaporin-2. Aquaporin-2 is involved in the transportation of water in the renal tubules. Acquired NDI is mainly caused by drugs with lithium therapy used in psychiatric diseases such as bipolar disorder.
Diagnostic methods
A diagnosis of diabetes insipidus (DI) is easily established by the presence of inappropriately dilute urine in the context of hypernatraemic dehydration. If DI is suspected based on history, yet plasma sodium concentration and osmolality are normal, a water deprivation test can help confirm the diagnosis. Once the diagnosis of DI is established, a desmopressin test (DDAVP) can distinguish between central and nephrogenic DI. In congenital NDI, the diagnosis can be confirmed by genetic testing.
Differential diagnosis
The main differential diagnosis is central diabetes insipidus. There are also forms of secondary inherited forms of NDI, associated with other inherited diseases, such as Bartter syndrome, cystinosis and distal Renal Tubular Acidosis (dRTA). These patients have a clinical phenotype of NDI, but associated with other features of the underlying disorder, such as hypokalaemic alkalosis (Bartter syndrome) or acidosis (cystinosis, dRTA).
Antenatal diagnosis
Mutation analysis of amniotic cells or chorionic villi is possible in families with a known genetic cause of NDI, but is associated with a small risk of fetal injury or loss. As the osmotic load of breast milk or formulas is low, most cases of NDI present during the weaning period and genetic testing on a blood sample obtained from the umbilical cord at birth is usually sufficient to establish an early diagnosis and thus prevent dehydration episodes.
Genetic counseling
In most cases, the disease is X-linked recessive, but it can also be autosomal recessive or dominant. Genetic counseling should be offered to affected families.
Management and treatment
Abnormal urine concentration does not respond to antidiuretic hormone treatment. Treatment is prophylactic with prevention of hypernatremic dehydration events by minimizing urinary losses. Patients should receive a low salt diet with limited potassium and protein intake. Thiazide diuretics (e.g. hydrochlorothiazide) and prostaglandin synthesis inhibitors (e.g. indomethacin, ibuprofen or celecoxib) can further help reduce urine output. Careful dietetic counselling is recommended to ensure adequate caloric and protein intake, as well as normal growth in children.
Prognosis
Mental impairment associated with intracranial calcifications has been previously reported, but is no longer seen in patients with adequate medical treatment. One report highlights an increased prevalence of attention deficit/hyperactivity disorder in patients with NDI, but it is unclear if this reflects an intrinsic aspect of the disorder, or the constant craving for water and the frequent need for voiding. Dilation of the urinary tract has been reported in patients with NDI, especially in those with voiding abnormalities and can lead to serious bladder and/or kidney function impairment.

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Pr Detlef BÖCKENHAUER | ERKNet*

                                * European Reference Network


A rare autosomal recessive amino acid metabolism disorder characterized clinically by variable degrees of hyperammonemia, developing from about 3 years of age, and leading to progressive loss of developmental milestones and spasticity in the absence of treatment.


A rare, genetic disorder of urea cycle metabolism typically characterized by either a severe, neonatal-onset form that manifests with hyperammonemia accompanied with vomiting, hypothermia, lethargy and poor feeding in the first few days of life, or late-onset forms that manifest with stress- or infection-induced episodic hyperammonemia or, in some, behavioral abnormalities and/or learning disabilities, or chronic liver disease. Patients often manifest liver dysfunction.

Summary:
Epidemiology
The prevalence at birth of argininosuccinic aciduria (ASA) ranges between 1/70,000-218,000 worldwide.
Clinical description
ASA can have a variable clinical picture with either a neonatal-onset or a late-onset (at any age outside the newborn period). Neonates with severe neonatal-onset ASA usually appear normal during the first 24-48 hours after birth but within a few days present with severe hyperammonemia manifesting with lethargy, somnolence, refusal to feed, vomiting, tachypnea and respiratory alkalosis. If untreated, worsening lethargy, seizures, coma and death may occur. Late-onset ASA is usually triggered by an acute infection, stress or after high protein intake. A presentation of late-onset cognitive impairment or learning disabilities in the absence of hyperammonemic episodes has also been reported. Some patients can be clinically asymptomatic despite showing clear biochemical signs of the disease. Long-term complications associated with both forms of ASA include chronic hepatomegaly, liver dysfunction (fibrosis or cirrhosis), neurocognitive deficits (i.e. cognitive impairment, seizures, and developmental delay), brittle hair (i.e. trichorrhexis nodosa), hypokalemia and arterial hypertension.
Etiology
ASA is caused by mutations in the ASL gene (7q11.21) that encodes the enzyme argininosuccinate lyase. This enzyme catalyzes the conversion of argininosuccinic acid into arginine and fumarate during the fourth step of the urea cycle. Defects in this step of the urea cycle lead to an accumulation of plasma ammonia, argininosuccinic acid, citrulline, and urinary orotic acid, and to a plasma arginine deficiency.
Diagnostic methods
Diagnosis is based mainly on clinical findings and laboratory test results. Plasma concentrations of ammonia (>150 µmol/L) and citrulline (200-300 µmol/L) are elevated. Elevated levels of argininosuccinic acid (5-110 µmol/L) in the plasma or urine are diagnostic. Molecular genetic testing confirms diagnosis. Newborn screening for ASA is available in the U.S. and parts of Australia, and is considered in several European countries.
Differential diagnosis
Differential diagnoses include other urea cycle disorders such as carbamoyl-phosphate synthetase 1 deficiency, ornithine transcarbamylase deficiency, citrullinemia type I and arginase deficiency, although neither of these exhibits the classical marker argininosuccinic acid.
Antenatal diagnosis
Prenatal diagnosis is possible in families with a known disease causing mutation on both alleles.
Genetic counseling
ASA is inherited in an autosomal recessive manner; where both parents are unaffected carriers, the risk of disease transmission is 25%.
Management and treatment
During an acute hyperammonemic episode, oral proteins must be avoided (for 24-48 hours' maximum) and intravenous (I.V.) lipids, glucose and insulin (if needed) should be given to promote anabolism. I.V. nitrogen scavenging therapy (with sodium benzoate and/or sodium phenylacetate/phenylbutyrate) should normalize ammonia levels, but if unsuccessful or in case of severe hyperammonemic encephalopathy, hemodialysis is recommended. Long-term management involves dietary protein restriction as well as arginine supplementation; in those with frequent episodes of metabolic decompensation or with hyperammonemia even when following a protein-restricted diet, daily oral nitrogen scavenging therapy (sodium benzoate and/or sodium or glycerol phenylbutyrate) may be successful. Orthotopic liver transplantation offers long-term relief of hyperammonemia but does not seem to sufficiently correct neurological complications. Arterial hypertension can be treated by restoring nitric oxide deficiency.
Prognosis
With early diagnosis and treatment, hyperammonemic episodes can be avoided but long-term complications (neurocognitive impairment, hepatic disease and arterial hypertension) are frequent and have a negative effect on life-expectancy and quality of life.

                            Last update:
                            November 2019

                            - Expert reviewer(s):
                            Pr Johannes HÄBERLE


A rare dermatosis, which can be either localized or generalized, that occurs after prolonged contact and absorption of silver containing compounds over a period of years and that is characterized by irreversible blue-gray to gray-black staining of skin, fingernails and/or mucous membranes, most evident on sun exposed areas of the skin. Silver exposure is usually occupational but may also occur through dental amalgams, the ingestion of colloidal silver, acupuncture needles, orthopedic implants and topical medications (such as silver sulfadiazine).


A central nervous system malformation characterized by caudal displacement of the cerebellar tonsils exceeding 5mm below the foramen magnum with or without syringomyelia. Symptoms vary in onset and severity and include suboccipital headache, neck pain, vertigo, tinnitus, ocular symptoms (diplopia, blurred vision, photofobia, nystagmus), lower cranial nerve signs, cerebellar ataxia, and spasticity. Some affected individuals can be asymptomatic.


A rare disorder that disrupts the synthesis of estradiol, resulting in hirsutism of mothers during gestation of an affected child; pseudohermaphroditism and virilization in women; and tall stature, osteoporosis and obesity in men.

Summary:
Epidemiology
Fewer than 20 cases have been reported to date.
Clinical description
Affected female newborns present with different degrees of ambiguous genitalia, virilization and non-palpable gonads, in one case female genitalia were present. Female internal genitalia differentiation is unaffected. Ovarian cystic follicles may appear in childhood, even at birth, or adolescence when patients manifest primary amenorrhea and no pubertal growth spurt. Breasts remain hypoplastic after initial development during puberty, while pubic hairs develop in a normal fashion. Males may present with cryptorchidism, but are generally asymptomatic until after puberty when patients present with bone pain and tall stature. The pubertal growth spurt is absent, but linear growth continues due to incomplete epiphyseal closure and progressive genu valgum, eunuchoid proportion of the skeleton and osteoporosis manifest. For these reasons the diagnosis is often overlooked in men. Metabolic co-morbidities may manifest as obesity, steatohepatitis, insulin resistance with acanthosis nigricans and dyslipidemia. Fertility is partially or completely disrupted in male patients.
Etiology
Aromatase (CYP19A1, 15q21.1), or cytochrome P450, synthesizes estradiol from androgens. Several null mutations have been identified, placental expression of aromatase converts androgens to estradiol; excess androgens affect both the mother and fetal development. One reported case of a promoter region mutation exclusively inhibited placental expression.
Diagnostic methods
Females are generally diagnosed at birth. Male patients are usually diagnosed during adulthood due to continuing linear growth in height and unfused epiphyses are revealed by hand radiographs. Measurement of serum estradiol, testosterone and luteinizing hormone may be followed by genetic testing.
Differential diagnosis
In female patients, differential diagnosis includes congenital adrenal hyperplasia; in male patients, estrogen resistance syndrome 46,XY difference of sex development due to isolated 17, 20 lyase deficiency, congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency and congenital hypogonadotropic hypogonadism.
Antenatal diagnosis
During the third trimester of gestation, mothers exhibit severe acne, deep voice and in some cases clitoral enlargement and hirsutism, symptoms resolve spontaneously post-partum. Genetic testing is recommended in these cases.
Genetic counseling
Genetic testing is recommended for families who have had one affected child, transmission is autosomal recessive.
Management and treatment
Female patients are candidates for surgical modification of genitalia depending on the degree of ambiguity and must be monitored for ovarian cysts. Upon puberty, daily treatment with estrogen must be administered (0.625 mg/twice weekly increasing to daily) and may be supplemented with progesterone-like hormone and monthly treatments of gonadotrophin-releasing hormone antagonists. Adult men should be treated immediately upon diagnosis: daily transdermal administration of up to 50 µg of estradiol (serum estradiol at 40 pg/ml) for 6-9 months to complete skeletal maturation. Upon epiphyseal closure, estradiol replacement may be reduced to 25 µg daily. Hypocaloric diet should be complemented with calcium, vitamin D and physical activity. Dyslipidemia, glucose intolerance or insulin resistance must be treated symptomatically.
Prognosis
Lifetime hormone replacement therapy is obligatory. In male patients with late diagnosis, skeletal defects remain even after successful hormonal treatment and may require surgical correction. Furthermore, adiposity and fertility defects are not alleviated by estradiol treatment.

                            Last update:
                            April 2013

                            - Expert reviewer(s):
                            Dr Cesare CARANI  - Dr Vincenzo ROCHIRA


A rare, genetic endocrine disease characterized by increased levels of estrogen due to elevated extraglandular aromatase activity. Males present with heterosexual precocious puberty which manifests with pre- or peripubertal onset of gynecomastia, premature growth spurt, accelerated bone maturation resulting in decreased adult stature, and may present mild hypogonadotropic hypogonadism. Female patients may have isosexual precocious puberty or not have any manifestations at all.


Aromatic L-amino acid decarboxylase deficiency

A rare, severe, genetic neurometabolic disorder associated with clinical manifestations related to impaired synthesis of dopamine, noradrenaline, adrenaline and serotonin. Clinical manifestations are typically characterized by early-onset muscular hypotonia, movement disorders (oculogyric crisis, dystonia), developmental delay, ptosis and non-motor symptoms (sleep disturbance, irritability, excessive sweating, and nasal congestion).

Summary:
Epidemiology
The global incidence of aromatic L-amino acid decarboxylase deficiency (AADC) deficiency is unknown. Since the initial description more than 150 patients have been described in the medical literature.
Clinical description
AADC deficiency typically presents in infancy with muscular hypotonia, oculogyric crises, and developmental delay. Thermoregulation disturbances, autonomic dysfunction, sleep disorders, dystonia, nasal congestion, feeding problems and intellectual disability are additional disease features. Age of onset of initial symptoms ranges from neonatal period to 12 months (mean 2-3 months). The majority of published patients have severe phenotype with profound motor developmental impairment while some present mild to moderate phenotype with ability to walk independently and having functional independence in daily activities. It has been suggested that symptoms can evolve with age.
Etiology
Aromatic L-amino acid decarboxylase (AADC), coded by the DDC gene (7p12.2-p12.1), is the final enzyme in the biosynthesis of the monoamine neurotransmitters serotonin and dopamine; dopamine is the precursor for norepinephrine and epinephrine. Subsequently, AADC enzyme deficiency results in a severe combined deficiency of serotonin, dopamine, norepinephrine and epinephrine.
Diagnostic methods
The diagnosis is established by determination of biogenic amines in cerebrospinal fluid (CSF), enzyme activity essay in plasma and mutational analysis. Additionally, measurement of 3-O-methyldopa (3-OMD) in dried blood spot in new born screening programs is proposed and already implemented in some programs.
Differential diagnosis
AADC deficiency can show clinical symptoms overlapping with other primary disorders of biogenic amines or tetrahydrobiopterin (BH4) metabolism that should be differentiated via biochemical investigation of the CSF in the first step. PNPO (pyridoxamine 5'-phosphate oxidase) deficiency can show a similar biochemical pattern in CSF but presents with a different clinical picture.
Antenatal diagnosis
A biochemical prenatal diagnosis of AADC deficiency might be possible by measuring 3-OMD, 5-HTP and L-Dopa in amniotic fluid or fetal plasma but if both disease-causing genetic variants are known, the most reliable method of prenatal diagnostic approach is genetic analysis of chorionic villi or amniotic fluid cells. This option should be offered to carriers of mutations of AADC deficiency, especially in case of a known index patient.
Genetic counseling
The pattern of inheritance is autosomal recessive; where both parents are unaffected carriers, there is a 25% risk of transmitting the disease to offspring. Genetic counseling about inheritance, risk of reoccurrence and disease is very important for affected families.
Management and treatment
The treatment of AADC deficiency is challenging since symptoms are refractory particularly in severe cases. A complex treatment regimen including dopamine agonists, monoamine oxidase inhibitors, pyridoxine phosphate, anticholinergic and antiepileptic drugs are required. Various supportive therapeutic approaches (physiotherapy, speech therapy) are recommended. In clinical trials, gene therapy has demonstrated clinical improvement (reduced frequency of oculogyric crises, weight recovery, and improvement in the ability to sit, walk, and talk over a five-year period). The treatment is pending approval in Europe.
Prognosis
The prognosis mainly depends on the disease severity. There is no clear genotype-phenotype correlation but some mutations are associated with severe phenotype. It has been described that there is a significant childhood mortality risk for patients with severe disease course.

                            Last update:
                            July 2020

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


A malformation disorder characterized by complete or incomplete absence of nose (arrhinia), choanal atresia, microphthalmia, anophthalmia and cleft or high palate.


A rare association syndrome, reported in several members of two families to date, characterized by arterial dissection, occurring at an early age and presenting with a range of manifestations depending on the vascular territory involved (ex. headache, dysphasia, hemiparesis), in association with cystic medial necrosis and multiple lentigines (brown and black in color and mainly affecting the skin of the trunk and extremities).


A form of thoracic outlet syndrome that presents as unilateral upper extremity ischemia.

Summary:
Epidemiology
Determination of incidence is difficult due to the lack of a confirmatory test for TOS. ATOS accounts for less than 1% of all cases of TOS.
Clinical description
ATOS occurs spontaneously in patients of all ages and presents with upper extremity ischemia (pain, pallor, anesthesia, coldness, claudication). Rarely subclavian thrombi embolize retrograde causing stroke.
Etiology
Symptoms of ATOS are caused by subclavian artery compression (often by a cervical rib), or emboli. Subclavian artery compression in the neck results in poststenotic dilation, aneurysm formation, turbulent flow and thrombus formation.
Diagnostic methods
Diagnosis is based on a history of upper extremity ischemia and diminished distal pulses or decreased systolic blood pressure in the affected limb. A cervical rib or long cervical transverse process is identified in over 90% of patients. Subclavian stenosis, occlusion or aneurysm on dynamic ultrasonography, magnetic resonance angiography or arteriography supports the diagnosis. Provocative physical exam maneuvers such as the Roos (test is positive when patient is unable to maintain the position of opening and closing hands while arms are in an elevated position for 3 minutes) and Adson's (test is positif if radial pulse disappears while turning the head with extended neck following deep inspiration) tests can also be helpful.
Differential diagnosis
Differential diagnoses include venous and neurogenic TOS (see these terms), peripheral artery disease and other disorders leading to arterial compromise, such as external compression by a tumor. Venous TOS can be ruled out with venous ultrasound or magnetic resonance venography. True neurogenic TOS presents as a lower trunk brachial plexopathy. Patients with PAD have atherosclerotic risk factors. Other external causes of compression can be ruled out with the appropriate cross sectional imaging.
Management and treatment
Acute arterial ischemia is treated with thrombolysis or embolectomy. Surgical decompression is indicated in symptomatic patients. Arterial reconstruction may be necessary. Physical therapy is generally not helpful.
Prognosis
Arterial occlusion is limb threatening, but most patients recover full function when treated appropriately. In 91% of cases, ATOS decompression results in complete resolution of symptoms.

                            Last update:
                            May 2013

                            - Expert reviewer(s):
                            Dr Joseph FEINBERG  - Dr Paul SCHOLTEN


A rare autosomal recessive connective tissue disorder characterized by tortuosity and elongation of the large and medium-sized arteries and a propensity towards aneurysm formation, vascular dissection, and stenosis of the pulmonary arteries.

Summary:
Epidemiology
Approximately 100 patients have been described in the literature so far. The male to female ratio is 1:1.
Clinical description
The clinical manifestations are variable, depending on the arteries affected. Onset usually occurs in infancy or early childhood. The cardiovascular anomalies may lead to right ventricular hypertension, acute respiratory symptoms, ventricular hypertrophy and cardiac failure. Patients are prone to aneurysm formation, dissection and ischemic events. Other typical manifestations include facial dysmorphism (features variably include an long face, hypertelorism, downslanting palpebral fissures, beaked nose, sagging cheeks, a high palate, and micrognathia), soft and hyperextensible skin, cutis laxa, hernias (inguinal, diaphragmatic, or hiatal), skeletal abnormalities, joint hypermobility, congenital contractures, keratoconus and generalized hypotonia.
Etiology
The disease is caused by loss-of-function mutations in the SLC2A10 gene (20q13.12), encoding the glucose/dehydroascorbic acid transporter 10 (GLUT10). So far, 35 SLC2A10 pathogenic variants have been reported in approximately 80 families. The exact role of GLUT10 in the pathogenesis of the disorder remains to be fully clarified. Previous evidences revealed that the deficiency of GLUT10 perturbs the canonical transforming growth factor beta (TGFbeta) pathway, activates a non-canonical alphavbeta3 integrin-TGF beta receptor II signaling and causes the disorganization of different extracellular matrix proteins (i.e. collagens, elastin, fibronectin, decorin), which are essential for the structural integrity of several connective tissues including blood vessels wall. Moreover, as GLUT10 acts as an intracellular transporter of dehydroascorbic acid, the shortage of ascorbate might impair collagen and elastin crosslinking in the endoplasmic reticulum, redox homeostasis in the mitochondria and global and gene-specific methylation/hydroxymethylation affecting the epigenetic regulation in the nucleus.
Diagnostic methods
Diagnosis requires further examination by echocardiography (ECG), angiography, and magnetic resonance angiography (MRA) and/or CT scan. Histology shows disruption of elastic fibers of the medial layer of the arterial wall. Detection of mutations in the SLC2A10 gene allows confirmation of the clinical diagnosis, and allows adapted genetic counseling and prognostic information to be provided to the patients.
Differential diagnosis
The differential diagnosis should include Loeys-Dietz syndrome, Ehlers-Danlos syndromes (particularly the vascular-like classical Ehlers-Danlos syndrome), Marfan syndrome, occipital horn syndrome, and autosomal recessive cutis laxa (particularly the EFEMP2-, FBLN5-, and LTBP4-related Cutis laxa.
Antenatal diagnosis
Prenatal diagnosis may be suspected by echocardiography and ultrasonography, and can be confirmed by prenatal molecular diagnosis performed on chorionic villi or amniocytes. Pregnancy requires intensive monitoring of both mother and fetus, cesarean delivery, and multidisciplinary postpartum care.
Genetic counseling
The pattern of inheritance is autosomal recessive. The risk of inheriting the disease is 25% where both parents are unaffected carriers.
Management and treatment
All patients require regular follow-up (periodic EGC, and MRA and/or CT scan) and may benefit from surgical interventions (aortic root replacement for aortic aneurysms and pulmonary artery reconstruction).
Prognosis
The prognosis can be severe and the first few years of life, usually before 5 years of age, might be critical for potentially life-threatening events. The main causes of premature death are respiratory insufficiency due to pulmonary artery stenosis, and heart failure due to either right ventricular hypertension and hypertrophy, myocarditis, and organ failure due to ischemic events.

                            Last update:
                            November 2019

                            - Expert reviewer(s):
                            Pr Marina COLOMBI


A form of Ehlers-Danlos syndrome (EDS) characterized by congenital bilateral hip dislocation, severe generalized joint hypermobility with recurrent joint dislocations and subluxations, hyperextensible and/or fragile skin.

Summary:
Epidemiology
The exact prevalence is unknown. It is one of the rare types of EDS.
Clinical description
Patients affected by arthrochalasia Ehlers-Danlos syndrome (aEDS) present at birth with severe hypermobility of both small and large joints with easy dislocation on manipulation, in combination with muscular hypotonia. Congenital bilateral hip dislocation is present in virtually all cases, and congenital foot deformities (clubfoot, flat foot and skew foot) and other congenital joint subluxations/luxations are common. Skin is hyperextensible and described as hyperelastic/redundant, leading sometimes to a criss-cross crease patterning of the palms and soles. Easy bruising and atrophic scarring may also be present, but are not severe. Hypotonia improves with age but, in combination with foot deformities and instable knees, leads to a delay in acquisition of gross motor milestones. Craniofacial dysmorphism is usually mild and may include large fontanelle, frontal bossing, hypertelorism, blue sclera, depressed nasal bridge, midface hypoplasia, and micrognathia. Throughout life, patients suffer recurrent partial or total joint dislocations of upper and lower limb joints and develop persistent foot, hand and spinal deformities. Some patients may also display bone fragility, manifested with fractures, Wormian bones on cranial radiographs, and osteopenia. Dentinogenesis imperfecta has been reported only in few individuals.
Etiology
aEDS is caused by heterozygous mutations that lead to partial or total loss of exon 6 in the COL1A1 (17q21.33) or COL1A2 (7q21.3) genes. The mutations lead to the partial or complete loss of the N-telopeptide of the procollagen type I alpha1 and alpha2 chains, respectively, and result in accumulation of abnormally processed type I collagen, the principal component of ligaments, tendons, dermis, bone and dentin.
Diagnostic methods
Clinical diagnosis is confirmed by the biochemical study of collagen I produced in vitro by cultured skin fibroblasts, or by molecular analysis revealing pathogenic variants in the COL1A1 or COL1A2 genes.
Differential diagnosis
Differential diagnosis includes Larsen syndrome, classical EDS (cEDS), dermatosparaxis EDS (dEDS), kyphoscoliotic EDS (kEDS) and musculocontractural EDS (mcEDS), Loeys-Dietz syndrome and autosomal recessive cutis laxa type 2B.
Antenatal diagnosis
Prenatal testing by molecular or biochemical analyses of a chorionic villus biopsy is possible if a pathogenic mutation has been identified in the family or, if parental mosaicism is suspected. Joint dislocations can be observed on prenatal ultrasound examination (in the third trimester of pregnancy).
Genetic counseling
The pattern of inheritance is autosomal dominant. Genetic counseling can inform parents of an affected child of the 50% risk of disease recurrence among future offspring. Clinically mild or unrecognized parental mosaicism has to be taken into account. Specific heterozygous mutations in COL1A1, c.472-1G>A and c.472-2A>T, have been associated with dentinogenesis imperfecta.
Management and treatment
Management of orthopedic problems is the center of care for patients with aEDS, with the goal being to achieve stable ambulation. A complete skeletal survey is recommended at diagnosis. Open reductions with an iliac osteotomy, with or without femoral osteotomy, are favorable to treat congenital hip dislocations. Orthotic management and early intervention are recommended to assist standing, walking and activities of daily living.
Prognosis
Extensive management seems to be effective, since only few patients described in the literature, mainly those with mutations in COL1A1, are wheelchair bound or unable to walk independently. aEDS patients are at increased risk of premature osteoarthritis.

                            Last update:
                            February 2020

                            - Expert reviewer(s):
                            Dr Cecilia GIUNTA  - Pr Beat STEINMANN


An extremely rare type of arthrogryposis multiplex congenita characterized by the combination of multiple joint contractures with movement limitation, microstomia with a whistling appearance of the mouth that may cause feeding, swallowing, and speech difficulties, a distinctive expressionless facies, severe developmental delay, central and autonomous nervous system dysfunction (excessive salivation, temperature instability, myoclonic epileptic fits, bradycardia), occasionally Pierre-Robin sequence, and lethality generally occurring during the first months of life. Arthrogryposis multiplex congenita-whistling face syndrome has been suggested to be a fetal akinesia deformation sequence.


A group of disorders characterized by congenital limb contractures manifesting as limitation of movement of multiple limb joints at birth that is usually non-progressive and may include muscle weakness and fibrosis. This disorder is always associated with decreased intrauterine fetal movement which leads secondarily to the contractures.


Arthrogryposis-anterior horn cell disease syndrome

A rare arthrogryposis syndrome characterized by the association of arthrogryposis multiplex congenita and a severe form of motor neuron disease with loss of anterior horn cells in the spinal cord. Patients present with fetal akinesia deformation sequence with multiple contractures and facial anomalies, such as low-set ears, hypoplastic jaw, and short neck, as well as hypotonia and respiratory insufficiency. Some patients may survive into childhood and show developmental delay, markedly decreased muscle bulk, dystonic and involuntary movements, ataxia, and poor speech.


A rare, genetic developmental defect during embryogenesis syndrome characterized by camptodactyly, joint contractures with amyotrophy, and ectodermal anomalies (oligodontia, enamel abnormalities, longitudinally broken nails, hypohidrotic skin with tendency to excessive bruising and scarring after injuries and scratching), as well as growth retardation, kyphoscoliosis, mild facial dysmorphism, and microcephaly. There have been no further descriptions in the literature since 1992.


Arthrogryposis-hyperkeratosis syndrome, lethal form

A rare arthrogryposis syndrome characterized by the association of multiple congenital joint contractures (of the large joints, fingers and toes) and hyperkeratosis (i.e. thick, scaling and fissured skin), with death occurring in early infancy. There have been no further reports in the literature since 1993.


Arthrogryposis-like hand anomaly-sensorineural deafness syndrome

A rare syndrome characterized by an arthrogryposis-like hand anomaly and sensorineural deafness. It has been described in only one family. Male-to-male transmission was observed.


Arthrogryposis-oculomotor limitation-electroretinal anomalies syndrome

An inherited developmental defect syndrome characterized by multiple congenital contractures of limbs, without primary neurologic and/or muscle disease that affects limb function, and ocular anomalies (ptosis, external ophtalmoplegia and/or strabismus). Intelligence is normal.


A rare, multisystem disorder, characterized by neurogenic arthrogryposis multiplex congenita, renal tubular dysfunction and neonatal cholestasis with low serum gamma-glutamyl transferase activity.

Summary:
Epidemiology
The prevalence is unknown but less than 100 patients have been reported in the literature so far.
Clinical description
The phenotype is variable, even within the same family and cases may go undiagnosed as not all the patients present with the three cardinal features. Renal tubular dysfunction ranges from isolated renal tubular acidosis to complete Fanconi syndrome (polyuria, aminoaciduria, glycosuria, phosphaturia and bicarbonate wasting). Hepatic anomalies include variable combinations of cholestasis, intrahepatic biliary duct hypoplasia and lipofuscin deposition. Additional features include severe failure to thrive, platelet dysfunction (which may be responsible for severe bleeding), facial dysmorphism (low set ears, lax skin, a high arched palate, beaked nose and small anterior fontanelle), diarrhea, recurrent febrile illness, cerebral malformations and sensorineural deafness.
Etiology
Mutations in the VPS33B gene (15q26.1), involved in intracellular protein trafficking and membrane fusion, have been found in 75% of ARC families, as well as mutations in the VIPAR gene (C14ORF133), encoding a protein that complexes with VPS33B.
Differential diagnosis
The differential diagnosis should include progressive familial intrahepatic cholestasis disorders, other forms of arthrogryposis multiplex congenita and congenital ichthyosiform dermatoses (see these terms).
Genetic counseling
The syndrome is generally considered to be transmitted as an autosomal recessive trait.
Management and treatment
There is no specific treatment for the disease.
Prognosis
Most patients die within the first year of life despite supportive care for metabolic acidosis and cholestasis and those surviving longer show cirrhosis and severe developmental delay.

                            Last update:
                            June 2010

                            - Expert reviewer(s):
                            Dr Martine LE MERRER


Distal arthrogryposis type 4 is an inherited developmental defect syndrome characterized by multiple congenital contractures of limbs, without primary neurologic and/or muscle disease that affects limb function, and a mild to severe scoliosis. Intelligence is normal.


A rare pneumoconiosis caused by exposure to asbestos particles. Symptoms may appear many years after exposure and include progressive dyspnea on exertion, dry cough, chest pain, tightness, inspiratory crackles, clubbing of the fingers. Later complications include mesothelioma and lung cancers.


A very rare syndrome characterized by a combination of blepharochalasis, double lip, and non-toxic thyroid enlargement (seen in 10-50% of cases), although the occurrence of all three signs at presentation is uncommon. Hypertrophy of the mucosal zone of the lip with persistence of the horizontal sulcus between cutaneous and mucosal zones gives an appearance of double lip, with the upper lip being frequently involved. Blepharochalasis, or episodic edema of eyelid, appears around puberty, is present in 80% of cases, is usually bilateral, and can rarely lead to vision impairment and other ocular complications. Most cases are sporadic, but familial cases (with a possible autosomal dominant inheritance) have also been reported.


A rare autoinflammatory disorder characterized by recurrent attacks of fever and sterile abscesses.

Summary:
Epidemiology
It is a rare disease with approximately 150 patients documented to date, among which 85 cases are in the French aseptic abscess syndrome register.
Clinical description
It affects mainly young adults and is characterized by recurrent attacks of fever and abscess-like collections, most frequently localized in the abdomen. Blood markers of inflammation and polymorphonuclear neutrophil levels are elevated. Aseptic abscesses may be either isolated or associated with an underlying condition (60% of patients) such as inflammatory bowel disease or relapsing polychondritis. The abscesses usually precede the diagnosis of inflammatory bowel disease, possibly by several years. A neutrophilic dermatosis, like pyoderma gangrenosum, may also be observed.
Etiology
The etiology is unknown: all searches for a pathogen, including those using PCR with universal and specific probes, remain negative.
Diagnostic methods
On pathologic examination, aseptic abscesses consist of a core of altered polymorphonuclear leukocytes surrounded by palisading histiocytes and sometimes giant cells.
Differential diagnosis
Aseptic abscess syndrome is a diagnosis of exclusion. The non-exhaustive list of etiologies to be considered and ruled out includes infectious abscesses (primarily pyogenic, as well as Chlamydia, Bartonella, and Tropheryma whipplei), mycobacterial infection, neoplasia (particularly lymphoma), chronic septic granulomatosis, splenic infarction, and inflammatory conditions (such as sarcoidosis, Wegener's disease, or rheumatoid nodules).
Management and treatment
Antibiotics fail to cure the patients, but dramatic improvements are seen with corticosteroids and immunosuppressive drugs, including biologics.
Prognosis
In the short term, once the diagnosis is established, patients undergo a significant transformation following the initiation of treatment, marked by a rapid resolution of fever. In the longer term, aseptic abscess syndrome is characterized by a high frequency of relapses (60% of patients), with the possibility of multiple relapses. Clinicians have at their disposal numerous treatment options, including biologics. Colchicine, typically used in combination with other treatments, has been described as a protective factor against relapse. There has been no recorded death directly related to aseptic abscess syndrome to date.

                            Last update:
                            October 2023

                            - Expert reviewer(s):
                            Pr Marc ANDRÉ  - Pr Olivier AUMAITRE  - Dr Ludovic TREFOND


A rare, acquired uterine disease characterized by intrauterine adhesions associated with a history of curettage or intrauterine surgery and gynecological symptoms (secondary amenorrhea, hypomenorrhea, pelvic pain, infertility or pregnancy loss).

Summary:
Epidemiology
The prevalence in the general population is unknown. In infertile populations the prevalence varies from 2.8% to 46% depending on the subpopulation. The greatest risk factor for the disease is iatrogenic trauma to the endometrium.
Clinical description
The severity of intrauterine adhesions (IUA) in Asherman's syndrome can vary between complete obliteration of the cavity to minimal, marginal adhesions. Frequently, the uterine cavity is decreased in size. The adhesions are composed of fibromuscular connective tissue bands, with or without surrounding superficial epithelium or glandular tissue. Adhesions vary markedly in their density and size and can be accompanied by areas of endometrial sclerosis. The gravid uterus appears highly predisposed to adhesions, but IUA may develop in non-gravid uterus following intrauterine trauma. Clinical manifestations include infertility, menstrual irregularities, and recurrent pregnancy losses. Amenorrhea or hypomenorrhea are the most frequent symptoms and may be accompanied by dysmenorrhea during the anticipated menstrual period; some patients continue to have normal periods. When the adhesions are exclusively located in the lower uterine tract and functioning endometrium persists, this syndrome can cause severe pelvic pain and retrograde menstruation. Recurrence of UIA post-surgery is high.
Etiology
The intrauterine adhesions result from uterine trauma including curettage, hysteroscopic myomectomy or endometrial ablation. Adhesions may also be diagnosed in women with genital tuberculosis.
Diagnostic methods
A history of uterine trauma (typically curettage) associated with menstrual abnormalities/inability to conceive are suggestive of Asherman's syndrome. Hysteroscopy provides definitive diagnosis, and can characterize the site and extent of adhesions as well as assess the endometrium. Magnetic resonance imaging (MRI) can be helpful as a supplementary diagnostic tool, especially when the adhesions involve the endocervix. IUAs are visualized as low signal intensity on T2 weighed-image inside the uterus. Transvaginal ultrasound and hysterosalpingography may be used but have lower diagnostic accuracy.
Differential diagnosis
Differential diagnosis on unenhanced ultrasound is normal intrauterine longitudinal folds, on hysterosalpingography or saline infusion ultrasonography it includes polyps and minor fibroids.
Management and treatment
For prevention of intrauterine adherences, a gentle emptying of the uterine cavity after delivery or abortion is mandatory preferably under ultrasound guidance. Intrauterine adhesions are ideally treated with hysteroscopy. Filmy adhesions may be separated by the tip of the hysteroscope. Dense adhesions are treated with hysteroscopic adhesiolysis with either mechanical, electrical or thermal energy techniques. Treatment in severe cases is difficult, and counselling should be offered regarding the lower rate of success and the higher risk of complications. Prevention of re-adhesion is important, and good results have been achieved with intrauterine devices, uterine balloon stent, Foley's catheter, and anti-adhesion barriers. In severe cases, several approaches may be required. Hormonal treatment (oestradiol, combined oestradiol/progesterone) is used to restore the normal endometrium; however, there is no consensus on timing of the administration or the type of regimen. Patients should be assessed one-two months post-operatively as complete resolution of the adhesions is not always possible with a single procedure. Ultrasound, HSG and hysteroscopy are the most common follow-up methods.
Prognosis
Whilst some women achieve pregnancy, the burden of infertility post-treatment is significant. The prognosis is worse for patients with a sclerotic, atrophic endometrium.

                            Last update:
                            May 2020

                            - Expert reviewer(s):
                            Dr Eva DREISLER