A rare inherited bleeding disorder due to reduced activity of factor II (FII, prothrombin) and characterized by mucocutaneous and soft tissue bleeding symptoms.

Summary:
Epidemiology
Factor II deficiency is the most rare coagulation factor deficiency. Prevalence of homozygous forms is estimated at 1/2,000,000. Both sexes are equally affected.
Clinical description
Congenital FII deficiency can manifest at any age, with severe forms of the disease manifesting early in life. Common clinical signs include epistaxis, menorrhagia, oral cavity bleedings, mucosal bleeding, soft tissue bleeding, hemarthrosis, easy bruising, and prolonged bleeding after tooth extraction, trauma or surgery. Severe forms may present intracranial hemorrhage. The severity of the bleeding manifestations correlates with the FII levels. Thromboembolic manifestations have been described in case of dysprothrombinemia.
Etiology
Inherited FII deficiency is caused by mutations in the F2 gene (11p11-q12) encoding prothrombin.
Diagnostic methods
Diagnosis is based on prolonged prothrombin and activated partial thromboplastin times (PT, aPTT) and on low FII coagulant activity measured using a PT based assay. Molecular testing is available, but is unnecessary for diagnosis.
Differential diagnosis
Differential diagnoses include deficiencies of factors V, VII, X, VIII, IX, XI, XIII or acquired deficiencies in FII (lupus anticoagulant).
Antenatal diagnosis
Prenatal diagnosis is available for the most severe forms.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.
Management and treatment
Prothrombin Complex Concentrates (PCCs) or fresh frozen plasma (if PCCs are not available) are usually used to treat hemorrhagic episodes.
Prognosis
Prognosis is good with early diagnosis and adequate treatment.

                            Last update:
                            October 2020

                            - Expert reviewer(s):
                            Pr Jenny GOUDEMAND


Congenital factor V deficiency is an inherited bleeding disorder due to reduced plasma levels of factor V (FV) and characterized by mild to severe bleeding symptoms.

Summary:
Epidemiology
Prevalence of homozygous forms is estimated at 1/1,000,000. Both sexes are equally affected.
Clinical description
Congenital FV deficiency can manifest at any age, with the most severe forms manifesting early in life. Common clinical signs include epistaxis, bruising, mucosal bleeding, soft tissue bleeding, and hemarthrosis. Excessive and prolonged bleeding during or following surgery, delivery or trauma are frequent. Women may present with menorrhagia. In severe forms of the disease, there can be a risk of intracranial, pulmonary or gastrointestinal bleedings. The severity of the bleeding manifestations correlates with the FV levels.
Etiology
Congenital FV deficiency is caused by mutations in the F5 gene (1q23) controlling the production of plasma FV.
Diagnostic methods
Diagnosis is based on prolonged prothrombin and activated partial thromboplastin times (PT, aPTT) and on low FV levels measured using a PT based assay. The bleeding time (BT) may be prolonged. Molecular testing is available, but unnecessary for diagnosis.
Differential diagnosis
Differential diagnoses include factor VIII deficiency, and combined deficiency of factor V and factor VIII (see these terms).
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Fresh frozen plasma (FFP) is the only treatment as FV concentrates are not available. In acute cases of severe bleeding, the addition of platelet concentrates may be helpful.
Prognosis
Prognosis is good with early diagnosis and adequate treatment.

                            Last update:
                            October 2009

                            - Expert reviewer(s):
                            Pr Jenny GOUDEMAND


A rare, genetic, congenital vitamin K-dependant coagulation factor deficiency disorder characterized by decreased levels or absence of coagulation factor VII (FVII), resulting in bleeding diathesis of variable severity.

Summary:
Epidemiology
European point prevalence appears to be close to 1/300,000, but may be markedly higher in countries where consanguineous marriage is frequent.
Clinical description
Clinical expression of this disorder is highly variable and no consistent relationship has been found between the severity of the hemorrhagic syndrome and the residual levels of FVII activity. The clinical picture can be very severe, with early occurrence of intracerebral hemorrhages or repeated hemarthroses, or, in contrast, may be moderate with cutaneous/mucosal hemorrhages (epistaxis, menorrhagia) or hemorrhages provoked by surgery or trauma. Finally, numerous subjects are completely asymptomatic despite a very low FVII level.
Etiology
FVII deficiency is caused by mutations in the F7 gene (13q34) coding for FVII. Typically, only homozygotes or compound heterozygotes develop a hemorrhagic syndrome; heterozygotes are usually asymptomatic. More than 250 mutations and six common variants are known to be associated with increased or decreased FVII plasma levels. Large genomic rearrangements have been reported in the literature and in the different locus-specific databases but they are rare. Genetic rearrangements have also been demonstrated, resulting in total or partial deletion of the F7 gene. The proximity and implication with the F10 gene (13q34) might also be the cause of combined deficits.
Diagnostic methods
Diagnosis is suspected with isolated prothrombin time and further confirmed by chronometric assays revealing a FVII activity level below that of pooled normal plasma (with values usually being between 70 and 140%). The deficiency is usually symptomatic only for values below 30%.
Differential diagnosis
Differential diagnoses include hepatocellular insufficiency, hypoavitaminosis K, acquired FVII deficiency associated with severe sepsis and, more rarely, the presence of autoantibodies against FVII.
Antenatal diagnosis
Due to the marked heterogeneity of the phenotypes (including asymptomatic individuals), access to prenatal diagnosis depends on the clinical repercussions of the disease in the family being considered. Only the existence of a first child with the very severe form may lead the medical team to propose prenatal diagnosis at the time of a subsequent pregnancy.
Genetic counseling
The disease is transmitted in an autosomal recessive manner. Due to the wide phenotypic heterogeneity of the disorder, with many asymptomatic patients, genetic counseling tends to differ depending on the clinical features specific to a family.
Management and treatment
At present, the main treatment consists of recombinant activated FVII (eptacog alfa). Concentrated prothrombinic or plasmatic Factor VII may be used as a second choice and frozen plasma as a last resort. However, indications remain difficult to establish prior to surgery in subjects with few or no symptoms. In 2008, recombinant coagulation factor VIIa (rFVIIa) got an Orphan designation in the USA.
Prognosis
Congenital FVII deficiency usually has good prognosis. Nevertheless, disease remains very disabling, or even fatal, in patients who cannot benefit from long-term replacement prophylaxis and which present the most severe forms (intracerebral hemorrhage and repeated hemarthroses).

                            Last update:
                            February 2019

                            - Expert reviewer(s):
                            Dr Muriel GIANSILY-BLAIZOT


A rare inherited bleeding disorder with a decreased antigen and/or activity of factor X (FX) and characterized by mild to severe bleeding symptoms.

Summary:
Epidemiology
Prevalence of homozygous forms is estimated at 1/1 000 000. Both sexes are equally affected.
Clinical description
Congenital FX deficiency manifests at any age but in general, severe forms of the disease manifest early in life. Patients may experience severe umbilical cord stump bleeding, recurrent epistaxis, soft-tissue hemorrhages, menorrhagia, easy bruising, intra cranial hemorrhages, hematuria, hemarthroses and excessive bleeding during or following surgery or delivery or trauma.
Etiology
Inherited congenital FX deficiency is caused by mutations in the F10 gene (13q34) controlling the production of plasma FX. The severity of the bleeding manifestations correlates with the FX level.
Diagnostic methods
Diagnosis is based on prolonged prothrombin, activated partial thromboplastin, and Russell viper venom times (PT, aPTT, RVVT), and on reduced levels of FX. Molecular testing is available, but unnecessary for diagnosis.
Differential diagnosis
Differential diagnoses include deficiencies of factors II, V, VII, VIII, IX, XI, XIII or acquired deficiencies in FX (amyloidosis).
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy. Heterozygote patients most often remain asymptomatic.
Management and treatment
Prothrombin Complex Concentrates (PCCs) or fresh frozen plasma (if PCCs are not available) are usually used to treat hemorrhagic episodes. A plasma-derived FX concentrate is now available.
Prognosis
Prognosis is good with early diagnosis and adequate treatment.

                            Last update:
                            October 2020

                            - Expert reviewer(s):
                            Pr Jenny GOUDEMAND


A rare inherited bleeding disorder characterized by reduced levels and/or activity of factor XI (FXI) resulting in moderate bleeding symptoms, usually occurring after trauma or surgery.

Summary:
Epidemiology
Prevalence of homozygous forms is estimated at 1/1,000,000. The disease is more frequent in the Ashkenazy Jewish population where the frequency of partial deficiency is 8%. The disease affects both sexes.
Clinical description
Bleeding may manifest at any age, usually occuring after circumcision, dental extractions, trauma, or surgery (in particular surgery in the otorhinological and urogenital areas). Patients usually do not present spontaneous bleeding but women can present with menorrhagia. Hemorrhages are usually moderate. Undiagnosed and untreated patients can develop significant hematomas after a surgical procedure.
Etiology
Congenital FXI deficiency is caused by mutations in the F11 gene (4q35.2) controlling the production of plasma FXI. Unlike in most factor deficiencies, the severity of the bleeding manifestations is poorly correlated with the FXI level.
Diagnostic methods
Diagnosis is based on a prolonged activated partial thromboplastin time (aPTT), and on reduced levels of FXI. FXI levels are < 20 IU/dL in severe defects and range between 20 and 60 IU/dL in partial deficiencies. Molecular testing is available, but unnecessary for diagnosis.
Differential diagnosis
Differential diagnoses include deficiencies of factors II, V, VII, X, VIII, IX, XIII, combined deficiency of factor V and factor VIII, von Willebrand disease and platelet function disorders.
Genetic counseling
Transmission is mainly autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected, homozygous child at each pregnancy. Heterozygous patients with bleeding symptoms have also been observed, which suggests an autosomal dominant mode of transmission with variable penetrance.
Management and treatment
Patients may require treatment when dental extraction or surgery is planned. Factor XI concentrates or fresh frozen plasma is usually used. Low doses recombinant factor VIIa have been also used. Antifibrinolytics (aminocaproic acid, tranexamic acid) are also helpful as FXI deficiency leads to a hyperfibrinolytic state.
Prognosis
Prognosis is good, as bleeding symptoms are usually moderate.

                            Last update:
                            October 2020

                            - Expert reviewer(s):
                            Pr Jenny GOUDEMAND


A rare, autosomal recessive systemic dysfunction of the hemostatic pathway, that is due to a defect in the coagulation factor XII (FXII or Hageman factor), and is either asymptomatic or characterized by a prolonged activated partial thromboplastin time and an increased risk for thromboembolism. FXII deficiency is strongly associated with primary recurrent abortions.


Congenital factor XIII deficiency is an inherited bleeding disorder due to reduced levels and activity of factor XIII (FXIII) and characterized by hemorrhagic diathesis frequently associated with spontaneous abortions and defective wound healing. Factor XIII deficiency is one of the most rare coagulation factor deficiencies.

Summary:
Epidemiology
Prevalence of homozygous forms is estimated at around 1/2,000,000. Both sexes are equally affected.
Clinical description
Congenital FXIII deficiency can manifest at any age, but diagnosis is often made during infancy. Umbilical stump bleeding manifests in up to 80% of patients. Other common signs include intracranial hemorrhage (25-30%), soft tissue bleeding, bruising, hemarthroses (20%), and recurrent spontaneous abortions. In most cases, hemorrhages are delayed (12-36hr) after trauma or surgery. Patients may have poor wound healing. Acquired forms of the disease have also been reported in association with hepatic failure, inflammatory bowel disease (see this term), and myeloid leukemia.
Etiology
Congenital FXIII deficiency is usually caused by mutations in the F13A1 gene (6p24.2-p23) encoding the catalytic A subunit, but mutations have also been found in the F13B gene (1q31-q32.1) encoding the B subunit. Transmission is autosomal recessive. The phenotype is less severe when the F13B gene is mutated.
Diagnostic methods
Diagnosis is based on quantitative FXIII activity measurement and antigen assays. Common clotting assays such as activated Partial Thromboplastin Time (aPTT) and Prothrombin Time (PT) are normal and cannot be used for the screening. The clot solubility test may also be used (clot is stable for more than 24 hours in case of FXIII deficiency). Molecular testing is available, but unnecessary for diagnosis.
Differential diagnosis
Differential diagnoses mainly include the other congenital coagulation factor deficiencies: fibrinogen, factors II, V, VII, X, XI, VIII, IX (see these terms).
Antenatal diagnosis
Antenatal diagnosis is possible if the causal mutations have previously been identified in the family.
Management and treatment
Factor XIII concentrates or fresh frozen plasma (when FXIII concentrates are not available) is usually used for the treatment of bleedings. Prophylactic therapy with FXIII concentrate should be indicated to prevent recurrent bleedings such as intracranial hemorrhage.
Prognosis
Intracranial hemorrhage can be life threatening, but prognosis is favorable if adequate treatment is provided.

                            Last update:
                            October 2009

                            - Expert reviewer(s):
                            Pr Jenny GOUDEMAND


Congenital fiber-type disproportion myopathy

A rare genetic, congenital, non-dystrophic myopathy characterized by neonatal or infantile-onset hypotonia and mild to severe generalized muscle weakness.

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
Disease onset is typically at birth or within the first year of life. Limb weakness may be greatest in the limb girdle and proximal limb muscles, but weakness is never solely distal. Facial weakness is often present, resulting in a long face, high-arched palate, and tented upper lip. Ophthalmoplegia and bulbar weakness can be seen. Tendon reflexes are often decreased or absent. Approximately 30% of patients have mild to severe respiratory involvement and feeding difficulties. Contractures (ankles, fingers, hips, elbows, knees) and spinal deformities (scoliosis, kyphoscoliosis, lordosis) occur in approximately 25% of affected children. Congenital hip dislocation and talipes equinovarus may also be present. In rare cases, cardiac involvement, cognitive impairment and cryptorchidism may occur. Ophthalmoplegia, ptosis, and facial and/or bulbar weakness with severe limb/respiratory weakness predict a poor prognosis. Histologically, there is a characteristic (but not specific) reduction in the caliber of type 1 muscle fibers. Type 1 muscle fibers are predominant compared to type 2 fibers, which are either normal or hypertrophied.
Etiology
Causative mutations have been identified more frequently in 4 genes, ACTA1 (1q42.13), RYR1 (19q13.2), TPM3 (1q21.3), and SELENON (1p36.11).
Diagnostic methods
Diagnosis is based on a combination of clinical presentation and morphologic features observed on skeletal muscle histology. Molecular testing is clinically available for the causative genes.
Differential diagnosis
Differential diagnoses include other congenital myopathies (X-linked myotubular myopathy, multiminicore disease, nemaline myopathy) and neuromuscular disorders (congenital muscular dystrophy, Emery-Dreifuss muscular dystrophy).
Antenatal diagnosis
Once the pathogenic variant(s) have been identified in the affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for CFTD are possible.
Genetic counseling
For the majority of cases the pattern of inheritance is either autosomal recessive or autosomal dominant. The risk to siblings of inheriting the disease is therefore 50% in autosomal dominant forms and 25% in autosomal recessive forms. X-linked inheritance has been reported in one family, with a 50% risk of male siblings of an affected individual inheriting the disease; variable penetrance is seen in female carriers. The causative gene has not been identified.
Management and treatment
Management is directed towards treating the muscular weakness and contractures (through physical and occupational therapy, exercise, stretching), respiratory problems (breathing exercises, chest physiotherapy, ventilatory support), feeding difficulties (gavage or gastrostomy feedings). Regular orthopedic monitoring is needed and corrective surgery may be necessary.
Prognosis
Over time, the disease becomes static in more than 90% of patients or even shows improvement and, rarely, is slowly progressive.

                            Last update:
                            May 2019

                            - Expert reviewer(s):
                            Dr Luciano MERLINI


Rare inherited coagulation disorders characterized by bleeding symptoms ranging from mild to severe resulting from reduced quantity and/or quality of circulating fibrinogen. Afibrinogenemia (complete absence of fibrinogen) and hypofibrinogenemia (reduced plasma fibrinogen concentration) correspond to quantitative anomalies of fibrinogen while dysfibrinogenemia corresponds to a functional anomaly of fibrinogen. Hypo- and dysfibrinogenemia may be frequently combined (hypodysfibrinogenemia).

Summary:
Epidemiology
Prevalence of afibrinogenemia is estimated at 1/1,000,000. Hypo- and dysfibrinogenemia are more frequent. Both sexes are equally affected. Fibrinogen deficiency can be discovered at any age but afibrinogenemia usually manifests early in childhood, often in the neonatal period.
Clinical description
Common manifestations of afibrinogenemia include umbilical cord bleeding, epistaxis, hemarthrosis, gastrointestinal bleeding, menorrhagia, traumatic and surgical bleeding and, rarely, intracranial hemorrhage. Recurrent spontaneous abortions may occur in women affected with afibrinogenemia. Hypofibrinogenemia is characterized by fewer and milder bleeding episodes following trauma or surgery. Most of patients with dysfibrinogenemia are asymptomatic (60%). The others may have bleeding symptoms (28%) or even thrombosis (20%).
Etiology
Congenital deficiencies of fibrinogen are caused by mutations in the FGA, FGB, or FGG genes. Afibrinogenemia is autosomal recessive; hypofibrinogenemia and dysfibrinogenemia are mainly autosomal dominant.
Diagnostic methods
Diagnosis is based on prolonged activated partial thromboplastin time (aPTT), prothrombin time (PT), thrombin and reptilase times and on fibrinogen levels measured by functional (Clauss) and immunological assays.
Differential diagnosis
Differential diagnoses include the other congenital clotting factor deficiencies (Factors II, V, VII, X, XI, VIII, IX and XIII; see these terms) and acquired fibrinogen deficiency (consumptive coagulopathy, hepatic failure). In case of thrombosis, differential diagnosis also includes congenital or acquired thrombophilia (antithrombin deficiency, protein C or S deficiency, Factor V Leiden mutation, lupus anticoagulant (see these terms) and FII Leiden mutation).
Antenatal diagnosis
Antenatal diagnosis of afibrinogenemia is possible if the causal mutations have already been identified in the family.
Management and treatment
Fibrinogen concentrates are usually used for the treatment of hemorrhages. Fresh frozen plasma is used when fibrinogen concentrates are not available. Recurrent spontaneous abortions can be prevented by routine prophylaxis based on administration of fibrinogen concentrates early in pregnancy.
Prognosis
Although life-threatening intracranial hemorrhage may occur, prognosis of afibrinogenemia is good with early diagnosis and adequate treatment. Prognosis of hypo- or dysfibrinogenemia is usually good.

                            Last update:
                            October 2009

                            - Expert reviewer(s):
                            Pr Jenny GOUDEMAND


Congenital fibrosis of extraocular muscles

A rare syndromic disorder with strabismus characterized by congenital non-progressive ophthalmoplegia affecting the oculomotor and/or trochlear nucleus/nerve and their innervated muscles. Patients present with abnormal resting position of the eyes (in most cases infraducted and exotropic), limitation of vertical and horizontal gaze, impaired binocular vision, amblyopia, unilateral or bilateral blepharoptosis, and compensatory abnormal head posture. Extraocular manifestations include intellectual disability, peripheral neuropathy, and skeletal abnormalities, among others.


Congenital generalized hypercontractile muscle stiffness syndrome

A rare defect of tropomyosin characterized by decreased fetal movements and generalized muscle stiffness at birth. Additional features include joint contractures, short stature, kyphosis, dysmorphic features, temperature dysregulation, and variably severe respiratory involvement with hypoxemia. Muscle biopsy shows mild myopathic features.


Congenital generalized hypertrichosis, Ambras type is an extremely rare type of hypertrichosis lanuginosa congenita, a congenital skin disease, that is characterized by the presence of vellus-type hair on the entire body, especially on the face, ears and shoulders, with the exception of palms, soles, and mucous membranes. Facial and dental anomalies can also be observed, such as triangular, coarse face, bulbous nasal tip, long palpebral fissures, delayed tooth eruption and absence of teeth.


A rare autosomal recessive form of lipodystrophy characterized by the association of generalized lipoatrophy with acromegaloid features, muscle hypertrophy, insulin resistance, hypertriglyceridemia, and liver steatosis.

Summary:
Clinical description
Presentation is typically in the first months of life with failure to thrive, hepatomegaly, generalized lipoatrophy, prominent musculature, umbilical prominence, acromegaloid features of extremities. Hypertriglyceridemia, insulin resistance, hyperglycemia and liver steatosis can be present in infancy, or diagnosed in late childhood, adolescence or adulthood. Accelerated growth in infancy, virilization of female patients and precocious puberty have been reported in some cases. High blood pressure, hypertrophic cardiomyopathy and bone cysts are frequent complications. Mild intellectual disability can be present, mainly in CGL related to BSCL2. Muscular dystrophy and cardiac arrhythmia are reported in CGL related to CAVIN1.
Etiology
Two main causative genes have been identified: AGPAT2 (9q34), encoding a key enzyme in triglyceride biosynthesis (1-acyl-glycerol-3-phosphate-O-acyltransferase-2), BSCL2 (11q13), encoding the reticulum endoplasmic seipin protein. A few cases of CGL are due to biallelic pathogenic variants in CAV1 (7q31.2) and CAVIN1 (17q21.2), encoding respectively caveolin-1 and cavin-1, which are major components of specialized plasma membrane microdomains called caveolae. Generalized lipodystrophy is described in rare patients with biallelic pathogenic variants in the genes PPARG (3p25.2) or LMNA (1q22), for which heterozygous mutations are associated with familial partial lipodystrophy.
Diagnostic methods
Diagnosis of CGL is based on recognition of the clinical picture and associated metabolic disturbances including low serum leptin levels. The differential diagnosis of each monogenic form of the disease requires genetic testing.
Differential diagnosis
CGL may occur as a feature in other diseases. Differential diagnoses include acquired generalized lipodystrophy (which occurs mainly in the context of auto-immune diseases), monogenic syndromes of insulin resistance, autoinflammatory diseases, partial forms of lipodystrophy and premature ageing syndromes.
Antenatal diagnosis
Prenatal diagnosis can be discussed in families with a known disease causing mutation.
Genetic counseling
Transmission is autosomal recessive. Couples in which each member carries at least one pathogenic variant should be informed that the risk of disease transmission to their offspring is 25%. A positive genetic test in an adult patient may lead to test the carriership of his/her partner.
Management and treatment
Diet should be carefully managed, avoiding overfeeding in patients with CGL who are typically hyperphagic due to leptin deficiency. A low glycemic-index and low fat diet, supplemented with medium chain triglycerides in infants/children, is usually needed to manage insulin resistance, diabetes and hypertriglyceridemia. Exercise should be encouraged in the absence of cardiac complications. Insulin sensitizers (mainly metformin) and lipid-lowering drugs (statins, or fibrates in case of major hypertriglyceridemia) are helpful. Diabetes may require other non-specific treatments, along with insulin. The orphan drug metreleptin is authorized in Europe, as a therapeutic option in addition to diet, for the treatment of metabolic complications of generalized lipodystrophy associated with leptin deficiency, in adults and children above the age of 2 years. Regular metabolic, hepatic and cardiac monitoring is recommended. Ethinylestradiol should be avoided in women with CGL.
Prognosis
Prognosis depends on the presence of associated complications. Complications of diabetes, liver disease, and hypertrophic cardiomyopathy are significant causes of morbidity and early mortality.

                            Last update:
                            December 2020

                            - Expert reviewer(s):
                            Pr Corinne VIGOUROUX


A rare congenital knee dislocation characterized by permanent knee flexion with limited extension. It can be unilateral or bilateral and may occur as an isolated malformation or be part of a syndrome (especially arthrogryposis multiplex congenita).


A rare congenital knee dislocation characterized by hyperextension of the knee greater than 0° associated with limited flexion, with prominence of the femoral condyles in the popliteal fossa and increased transverse skin folds over the anterior surface of the knee. It can be unilateral or bilateral and may occur as an isolated malformation, be associated with other orthopedic abnormalities (like developmental dysplasia of the hip or clubfoot) or be part of a syndrome (e. g. Larsen's syndrome).


A rare, congenital non-syndromic heart malformation characterized by an abnormal shunting between the left ventricle and right atrium. The clinical manifestation varies, depending on the volume of the shunt. Small congenital shunts are usually asymptomatic or associated with dyspnea and fever, whereas larger shunts often present with chest pain, fatigue, weakness, lower extremity edema, and sometimes heart failure and death. Other congenital heart anomalies may be associated.


A rare ophthalmic disorder characterized by an elevated intra-ocular pressure. The clinical presentation frequently associates an increase in the size of the eye, as well as corneal edema.

Summary:
Epidemiology
Congenital glaucoma (CG) is the most common glaucoma of infancy. The birth prevalence is estimated at around 1/45,450 live births in Europe. Males are more commonly affected than females and the disease is bilateral in 70 to 80% cases.
Clinical description
Diagnosis is made in the first year of life in about 80% of cases. The classic triad includes epiphora, blepharospasm and photophobia. Affected children are noted as having red watery eyes, cloudy corneas and ocular enlargement, caused by stretching of the immature eye due to elevated intraocular pressure. Children older than 3 years develop progressive myopia and insidious field loss.
Etiology
Etiology is poorly understood but the obstruction to the aqueous outflow seems to occur at the iridocorneal angle and at the level of the trabeculum. Gene mapping of affected families has identified three chromosomal loci, GLC3A in 2p22.2, GLC3B in 1p36 and GLC3C in 14q24.3-q31.1 of which, the CYP1B1 gene (2p22.2) on GLC3A harbors mutations. Mutations in LTBP2 (14q24.3) and MYOC (1q23-q24) genes have also been identified.
Diagnostic methods
Diagnosis is made by a complete ophthalmologic examination, which reveals a hazy cornea of increased size and presence of Haab's striae, increased intraocular pressure (IOP) (more than 20 mm Hg or asymmetry of more than 5 mm Hg is of concern), deep anterior chamber, abnormally high insertion of iris, poorly developed scleral spur (with gonioscopy), increased cup to disc ratio of the optic nerve head and refraction testing showing myopia and astigmatism. Examination under anesthesia is done if necessary.
Differential diagnosis
The differential diagnoses for red watery eyes include nasolacrimal duct obstruction, conjunctivitis, corneal abrasion and uveitis while those for corneal enlargement include high axial myopia and megalocornea. The differential diagnoses for corneal clouding and edema include congenital corneal dystrophies, birth trauma, keratitis, congenital ocular anomalies or storage diseases while those for optic nerve cupping include physiologic cupping, coloboma of optic papilla, genetic optic atrophy and optic nerve hypoplasia.
Antenatal diagnosis
Prenatal diagnosis can determine the risk of the disease in families with known mutations.
Genetic counseling
Most cases are sporadic, in about 10% of cases autosomal recessive inheritance is seen with variable penetrance. In the case of an autosomal recessive inheritance, genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Congenital glaucoma is primarily managed surgically, with medical therapy playing only an adjunctive role. At first, it is usually practiced angle surgery (such as goniotomy or trabeculotomy), trabeculectomy or deep sclerectomy The choice depends on the severity of the glaucoma and the surgeon's habits Glaucoma drainage devices and diode laser cyclophotocoagulation are used in refractory cases. Amblyopia, corneal scarring and cataract are late complications. Early visual rehabilitation is important to prevent amblyopia. Patients may need regular life-long follow up to monitor IOP.
Prognosis
Prognosis is largely related to the timing of presentation; early diagnosis and prompt surgical treatment significantly influences the visual outcome. Most patients successfully treated in infancy maintain good pressure control with stable optic nerves and fully functional visual fields into adulthood.

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Dr Emmanuel MARCIANO


A form of diffuse hyperinsulinism due to glucokinase hyperactivity and characterized by an excessive/ uncontrolled insulin secretion (inappropriate for the level of glycemia) and recurrent episodes of hypoglycemia induced by fasting and glucose rich meals. The clinical spectrum can range from mild and intermediate cases that respond well to dietary modifications and medical management with diazoxide to severe cases that are unresponsive to diazoxide. The potential development of type 2 diabetes with age is another notable feature.


Congenital heart block (CHB) is a rare disorder of atrioventricular conduction, characterized by absence of conduction of atrial impulses to the ventricles with slower ventricular rhythm (atrioventricular dissociation). CHB can occur in association with immunological evidence of maternal connective disease (autoimmune CHD), fetal structural CHD or can be idiopathic.


Congenital heart defect-round face-developmental delay syndrome

A very rare syndrome described in three sibs of one Japanese family and characterized by congenital heart disease, round face with depressed nasal bridge, small mouth, short stature, and relatively dark skin and typical dermatoglyphic anomalies, and intellectual deficit.


Congenital hereditary endothelial dystrophy type II

Congenital hereditary endothelial dystrophy II (CHED II) is a rare subtype of posterior corneal dystrophy (see this term) characterized by a diffuse ground-glass appearance of the corneas and marked corneal thickening from birth with nystagmus, and blurred vision.

Summary:
Epidemiology
Prevalence of this form of corneal dystrophy is unknown. Most cases have been identified in children of consanguineous parents from Saudi Arabia, India, Pakistan, Myanmar (Burma) and Ireland.
Clinical description
Diffuse ground glass lesions are present from birth and are accompanied by nystagmus. Tearing and photophobia are minimal or absent. The course is relatively stable. Patients also occasionally have sensorineural deafness. The cornea is swollen due to extensive stromal edema.
Etiology
Most cases are caused by homozygous mutations in the SLC4A11 gene. A high degree of mutational heterogeneity has been detected and genetic heterogeneity may exist as no mutations in SLC4A11 or in its promoter region have been detected in some affected families. In CHED II, an increased tendency for the abnormal endothelium to synthesize a homogenous, posterior, non-banded Descemet membrane is observed.
Genetic counseling
Transmission appears to be autosomal recessive.
Management and treatment
Patients with CHED II usually require a penetrating keratoplasty. Procedures for repairing the posterior surface of the cornea, such as a deep lamellar endothelial keratoplasty (DLEK), Descemet stripping endothelial keratoplasty (DSEK), or Descemet stripping automated endothelial keratoplasty (DSAEK) are technically difficult in young children.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Dr Gordon KLINTWORTH


Congenital hereditary facial paralysis-variable hearing loss syndrome is an extremely rare autosomal recessive disorder characterized by bilateral facial palsy with masked facies, sensorineural hearing loss, dysmorphic features (midfacial retrusion, low-set ears), and strabismus.


Congenital herpes simplex virus infection

Congenital herpes virus infection is a group of anomalies that an infant may present as a result of maternal infection and subsequent foetal infection with herpes virus. This virus causes recurrent cutaneous infections in adults, often involving the lips or the genitalia. Herpes infections in other organs, such as the liver or central nervous system, are less frequent.

Summary:
Clinical description
Skin lesions and scars, chorioretinitis, microcephaly, hydrencephaly, and microphthalmia have been described in infants with in utero primary herpes virus infections, but a causal relationship between these manifestations and the infection could not be established. Pregnancy complications including preterm delivery, intrauterine growth retardation, and neonatal infection have been attributed to the herpes virus.
Etiology
There are two types of virus (HSV-1 and HSV-2) and both appear to have the same activity. However, type 1 infections more commonly involve the oral cavity, whereas type 2 infections more commonly involve the genital region. It has been suggested that latent HSV-2 infections occur in as many as 20 to 40% of women. Exposure of the foetus to herpes virus at the time of delivery carries a serious risk of infection for the newborn. This risk may be high during the initial infection of the mother (33 to 50%), but probably does not exceed 3% in cases of reinfection because of the protective effect of maternal antibodies.
Differential diagnosis
It remains difficult to distinguish between cases with a primary infection and those with a previously undetected recurrent infection that has become symptomatic during pregnancy.
Management and treatment
In spite of described cases of serious foetal illness, primary infection with herpes virus during pregnancy is not an indication for therapeutic abortion, and the use of antivirals in the treatment of primary herpes infections during gestation has been recommended. Some authors recommend caesarean delivery for women with first-episode genital herpes lesions at the time of delivery.

                            Last update:
                            March 2006

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


Congenital high-molecular-weight kininogen deficiency

A rare genetic hematologic disease characterized by abnormal surface-mediated activation of fibrinolysis due to the deficiency of high-molecular-weight kininogen in plasma. Activated partial thromboplastin time (aPTT) may be prolonged. Clinically, patients are typically asymptomatic and do not show increased bleeding or thrombotic tendency.


Congenital Horner syndrome is a rare neurological disorder characterized by relative pupillary miosis and blepharoptosis, evident at birth, caused by interruption of the oculosympathetic innervation at any point along the neural pathway from the hypothalamus to the orbit. Often additional symptoms, such as enophthalmos, facial anhidrosis, iris heterochromia, conjunctival congestion, transient hypotonia and/or pupillary dilation lag, may be present. Association with birth trauma, neoplasms or vascular malformations has been reported.


A rare central nervous system malformation characterized by abnormally enlarged cerebral ventricles due to impaired cerebrospinal fluid circulation. It arises in utero and can be either acquired or inherited. The severity of the resulting brain damage depends on the duration and extent of ventriculomegaly.


Congenital hyperinsulinism due to HNF4A deficiency

A form of diazoxide-sensitive diffuse congenital hyperinsulinism due to HNF4A deficiency and, characterized by macrosomia, transient or persistent hyperinsulinemic hypoglycemia (HH), responsiveness to diazoxide and a propensity to develop maturity-onset diabetes of the young subtype 1 (MODY).


Congenital hypothyroidism due to developmental anomaly

Thyroid dysgenesis is a type of primary congenital hypothyroidism (see this term), a permanent thyroid hormone deficiency that is present from birth.

Summary:
Epidemiology
Prevalence is estimated at about 1/4,700. Thyroid dysgenesis causes 85% of permanent congenital hypothyroidism (see this term) in iodine-sufficient countries. Thyroid dysgenesis occurs in three major forms: thyroid ectopy, athyreosis and thyroid hypoplasia (see these terms). Thyroid ectopy causes two-thirds of thyroid dysgenesis while athyreosis and thyroid hypoplasia account for the other third. Thyroid ectopy is twice as common in females as in males.
Clinical description
Clinical manifestations of thyroid dysgenesis are often subtle or not present at birth, probably as a result of trans-placental passage of some maternal thyroid hormone or due to some residual infant thyroid hormone production. Goiter is always absent. More specific symptoms and signs do not develop until several months of age. Common clinical features and signs include decreased activity and increased sleep, feeding difficulty and constipation, prolonged jaundice, myxedematous facies, large fontanels (especially posterior), macroglossia, a distended abdomen with umbilical hernia, and hypotonia. Slow linear growth and developmental delay are usually apparent by 4-6 months of age. Without treatment thyroid dysgenesis results in severe intellectual deficit and short stature. Thyroid ectopy refers to an ectopic location of the thyroid gland, while thyroid athyreosis refers to the complete absence of thyroid tissue and thyroid hypoplasia refers to underdevelopment of the thyroid. Thyroid dysgenesis may also occur as thyroid hemiagenesis (see this term), where half of the gland is missing. In the majority of cases thyroid hemiagenesis is asymptomatic.
Etiology
Around 2% of cases have been shown to be familial and may be caused by mutations in the FOXE1,  NKX2-1, NKX2-5 or PAX8 genes (9q22, 14q13, 5q34 and 2q12-q14). Mutations that result in complete inactivation of the TSHR gene (14q31) can present with athyreosis or thyroid hypoplasia.
Diagnostic methods
In countries with newborn screening programs (with either a primary thyroxine (T4)-follow-up TSH or primary TSH test), infants are diagnosed after detection by screening tests. Diagnosis should be confirmed by elevated serum TSH level and low T4 or free T4 level. The type of thyroid dysgenesis can be determined using thyroid radionuclide uptake and scan and thyroid ultrasonography. Genetic testing can also be used.
Differential diagnosis
Differential diagnoses include other forms of congenital hypothyroidism (see this term), which can be excluded by evidence on imaging studies of the absence or underdevelopment of the thyroid gland.
Antenatal diagnosis
Genetic counseling and antenatal diagnosis can be offered in families where a genetic defect has been identified.
Genetic counseling
Thyroid dysgenesis is generally thought to be sporadic. However, recent evidence points to the possibility of a genetic component.
Management and treatment
It is not necessary to know the underlying etiology when initiating hormone treatment. Levothyroxine is the treatment of choice; the recommended starting dose is 10-15mcg/kg/day. The immediate goals of treatment are to raise the serum T4 above 130 nmol/L (10 ug/dL) as rapidly as possible; with these starting doses, serum TSH usually normalizes in 2-4 weeks. Frequent laboratory monitoring in infancy is essential to ensure optimal neurocognitive outcome. Serum TSH and T4 or free T4 should be measured every 1-2 months in the first 6 months of life, every 3 months between 6 months and 3 years of age, and 4 weeks after any dose change.
Prognosis
The prognosis of infants started on treatment early is excellent, with IQs similar to sibling or classmate controls. Lower neurocognitive outcomes may occur in those infants started after more than 30 days of age, on lower l-thyroxine doses than currently recommended, and in those infants with more severe hypothyroidism.

                            Last update:
                            August 2010

                            - Expert reviewer(s):
                            Dr Stephen LAFRANCHI  - Dr Maynika RASTOGI


Congenital hypothyroidism due to maternal intake of antithyroid drugs

A rare congenital hypothyroidism disorder characterized by transient, primary, fetal or neonatal hypothyroidism resulting from transplacental transfer of antithyroid drugs due to maternal intake. Patients may present fetal or neonatal goiter, hoarse cry, reduced tendon reflexes, feeding difficulty, constipation, prolonged jaundice and/or respiratory distress. Elevated levels of T4 and thyroid stimulating hormone usually normalize without treatment within 3 weeks of birth.


Congenital hypothyroidism due to transplacental passage of TSH-binding inhibitory antibodies

Congenital hypothyroidism due to transplacental passage of maternal thyroid-stimulating hormone (TSH)-binding inhibitory antibodies is a type of transient congenital hypothyroidism (see this term), a thyroid hormone deficiency that is not permanent.

Summary:
Epidemiology
Prevalence is estimated to be 1/100,000.
Clinical description
Patients may present with symptoms similar to those of permanent CH (see this term) or they may be asymptomatic.
Etiology
It is caused by the transfer of maternal TSH blocking antibodies, which can block the TSH receptor in the neonatal thyroid resulting in hypothyroidism in the infant. The effect can last up to 3-6 months after birth as maternal antibody levels fall.
Management and treatment
Treatment with l-thyroxine is usually required during this period.

                            Last update:
                            August 2010

                            - Expert reviewer(s):
                            Dr Stephen LAFRANCHI  - Dr Maynika RASTOGI


Congenital hypothyroidism (CH) is defined as a thyroid hormone deficiency present from birth.

Summary:
Epidemiology
It occurs in approximately 1/2,000 to 1/4,000 newborns and is more common in Asian, Native American, and Hispanic infants.
Clinical description
The clinical manifestations are often subtle or not present at birth, probably as a result of trans-placental passage of some maternal thyroid hormone and the fact that many infants have some thyroid production of their own. More specific symptoms often do not develop until several months of age. Common clinical features include decreased activity and increased sleep, feeding difficulty and constipation, prolonged jaundice, myxedematous facies, large fontanels (especially posterior), macroglossia, a distended abdomen with umbilical hernia, and hypotonia. Slow linear growth and developmental delay are usually apparent by 4-6 months of age. Without treatment CH results in severe intellectual deficit and short stature.
Etiology
CH can be divided into permanent (with primary, secondary, or peripheral causes) or transient forms (see these terms). Causes of primary CH include thyroid dysgenesis (85% of cases) and inborn errors of thyroid hormone biosynthesis (dyshormonogenesis, 10-15% of cases) (see these terms). The cause of thyroid dysgenesis remains unknown in the vast majority of cases. Secondary or central CH results from thyroid-stimulating hormone (TSH) deficiency and is usually associated with congenital hypopituitarism. Peripheral CH results from defects in thyroid hormone transport, metabolism, or action as in Allan-Herndon-Dudley syndrome or as a result of peripheral resistance to thyroid hormones (see these terms). CH may also occur as part of a syndrome, for example in the Pendred and Bamforth-Lazarus syndromes (see these terms). Transient CH most commonly occurs in preterm infants born in areas of endemic iodine deficiency. In Western countries, transient hypothyroidism is more likely to be associated with exposure to excess iodine, or with maternal thyroid blocking antibodies.
Diagnostic methods
In countries with newborn screening programs (with either a primary thyroxine (T4)-follow-up TSH or primary TSH test), infants are diagnosed after detection by screening tests finding an elevated serum TSH level and low T4 or free T4 level. Other diagnostic tests (thyroid radionuclide uptake and scan, thyroid sonography, or serum thyroglobulin determination) may help pinpoint the underlying etiology and separate transient from permanent cases.
Genetic counseling
If a familial form of CH is discovered, this will guide genetic counseling. Thyroid dysgenesis is usually a sporadic disorder; thyroid dyshormonogenesis is autosomal recessive, with a recurrence risk of 25%.
Management and treatment
Etiological diagnosis is not necessary when initiating thyroid hormone treatment. Levothyroxine is the treatment of choice; the recommended starting dose is 10-15 mcg/kg/day. The immediate goals of treatment are to raise the serum T4 above 130 nmol/L (10 ug/dL) as rapidly as possible; with these starting doses, serum TSH usually normalizes in 2-4 weeks. Frequent laboratory monitoring in infancy is essential to ensure optimal neurocognitive outcome. Serum TSH and T4 or free T4 should be measured every 1-2 months in the first 6 months of life, every 3 months between 6 months and 3 years of age, and 4 weeks after any dose change.
Prognosis
The prognosis of infants started on treatment early is excellent, with IQs similar to sibling or classmate controls. Lower neurocognitive outcomes may occur in those infants started after more than 30 days of age, on lower l-thyroxine doses than currently recommended, and in those infants with more severe hypothyroidism.

                            Last update:
                            August 2010

                            - Expert reviewer(s):
                            Dr Stephen LAFRANCHI  - Dr Maynika RASTOGI


A rare autosomal recessive congenital ichthyosis (ARCI) characterized by generalised scaling accompanied by a more or less severe erythroderma, without blister formation.

Summary:
Epidemiology
Prevalence ranges between 1/200,000 and 1/1,000,000 individuals.
Clinical description
Congenital ichthyosiform erythroderma (CIE) is a generalized skin disease in which a more or less pronounced erythroderma predominates. A collodion membrane may sometimes be present at birth and will change into ichthyosiform erythroderma after a few days. In addition to the erythroderma, there is usually a generalized, fine, white or grey scaling. The phenotypic expression is very variable and depends on the patient's affected gene and environment. Patients with CIE are particularly prone to severe itching and intolerance to heat. Additional complications (especially for patients who presented with a collodion membrane at birth), can be observed such as ectropion and associated ocular complications (keratitis, corneal scarring), eclabium, palmoplantar keratoderma, nail dystrophy and alopecia. Failure to thrive and short stature may occur, as well as hearing impairment due to the accumulation of scales in the external ear.
Etiology
CIE is a part of the autosomal recessive congenital ichthyosis (ARCI) spectrum of disorders and mostly caused by mutations in known ARCI-related genes (ABCA12, ALOX12B, ALOXE3, CYP4F22, NIPAL4, TGM1, PNPLA1). Pathophysiologically, defects in epidermal lipids and differentiation cause disturbance of the epidermal barrier, resulting in increased transepidermal water loss (TEWL). Erythema and disease severity highly correlate with IL-17 expression in patients with ichthyosis.
Diagnostic methods
The diagnosis is based on the clinical picture and confirmed by genetic testing, mainly using next-generation sequencing (NGS) such as multi-gene panel sequencing or whole-exome sequencing (WES).
Differential diagnosis
Differential diagnosis includes other forms of neonatal erythroderma, especially syndromic ichthyoses (e.g. Netherton syndrome, KID syndrome), congenital reticular ichthyosiform erythroderma (CRIE) caused by specific mutations in the KRT10 or KRT1 gene, various congenital immunodeficiencies (e.g. hyper-IgE syndrome), and atopic dermatitis.
Antenatal diagnosis
A prenatal diagnosis (after amniocentesis or chorionic villus sampling) based on molecular genetic methods is possible if the pathogenic variant in the affected gene has previously been identified in a family member.
Genetic counseling
CIE is part of the autosomal recessive congenital ichthyosis (ARCI) spectrum of disorders. At-risk couples (both individuals are carriers of a disease-causing mutation) should be offered genetic counseling informing them that there is a 25% risk of having an affected child with each pregnancy.
Management and treatment
Management is based on daily applications of emollients. Keratolytics can be used but are often not tolerated. Oral retinoids and vitamin A analogues are indicated for hyperkeratosis rather than erythroderma, and are known to exacerbate skin inflammation and pruritus. In addition, these drugs can only be used in a limited way because of their known side effects (teratogenicity, hypertriglyceridaemia, hyperostosis). Topical anti-inflammatory drugs (i.e. steroids and calcineurin inhibitors) are less effective and have the disadvantage of being systemically absorbed. Recombinant human monoclonal anti-IL-17 (secukinumab), anti-IL-12/IL-23 (ustekinumab), and anti-IL-4/IL-13 (dupilumab) antibodies are undergoing clinical trials and have shown promising results.
Prognosis
The prognosis depends on the underlying genetic defect. There is an increased risk of sepsis during the neonatal period. In some patients, the condition may improve with age. Additional diseases or systemic infections can severely worsen the skin condition. Depending on the severity of the skin phenotype, the quality of life can be severely impacted.

                            Last update:
                            March 2023

                            - Expert reviewer(s):
                            Pr Judith FISCHER | ERN-Skin*

                                * European Reference Network


Congenital ichthyosis-intellectual disability-spastic quadriplegia syndrome

A rare autosomal ichthyosis syndrome with prominent neurologic signs characterized by the association of congenital ichthyosis with global developmental delay, intellectual disability, infantile-onset seizures, and spastic tetraplegia. Brain imaging may show delayed myelination and cerebral atrophy. Marked intrafamilial variability has been reported.


A rare autosomal ichthyosis syndrome with prominent neurologic signs characterized by the association of congenital ichthyosis with severe developmental delay, microcephaly, spastic tetraplegia, sensorineural hearing impairment, athetosis, and myoclonus. Marked epileptic discharges with occurrence of tonic spasms have also been reported. Cerebral MRI shows diffuse cortical atrophy. There have been no further descriptions in the literature since 1995.


Congenital infiltrating lipomatosis of the face

A rare PIK3CA-related overgrowth syndrome characterized by congenital non-hereditary facial overgrowth due to post-zygotic activating mutations in the PIK3CA gene. It is unilateral and involves hypertrophy of both the soft and hard tissue structures on the affected side of the face, including hypertrophy of the facial bones, macroglossia, and proliferation of the parotid gland. Early eruption of the teeth is common.


Congenital insensitivity to pain with severe intellectual disability is a rare autosomal recessive hereditary sensory and autonomic neuropathy characterized by the complete absence of pain perception from birth, an unresponsiveness to soft touch, severe non-progressive cognitive delay, and normal motor movement/behavior and strength. Affected cases retained hot and cold perception.


Congenital insensitivity to pain-anosmia-neuropathic arthropathy

A rare genetic peripheral neuropathy characterized by complete congenital insensitivity to painful stimuli, commonly associated with neuropathic arthropathy. In addition, patients are typically anosmic.


Congenital insensitivity to pain-hyperhidrosis-absence of cutaneous sensory innervation

A rare hereditary sensory and autonomic neuropathy characterized by congenital insensitivity to pain, general hypesthesia, diminished temperature sensitivity, and hyperhidrosis. Motor function is preserved. Skin biopsy reveals lack of cutaneous innervation except for sensory and autonomic innervation of blood vessels and sweat glands.


Congenital intrauterine infection-like syndrome is characterised by the presence of microcephaly and intracranial calcifications at birth accompanied by neurological delay, seizures and a clinical course similar to that seen in patients after intrauterine infection with Toxoplasma gondii, Rubella, Cytomegalovirus, Herpes simplex (so-called TORCH syndrome), or other agents, despite repeated tests revealing the absence of any known infectious agent.

Summary:
Epidemiology
More than 30 cases have been described in the literature so far.
Clinical description
The clinical presentation of the reported cases is rather heterogeneous with variable manifestations including intrauterine growth retardation, hepatosplenomegaly, hyperbilirubinaemia, cerebellar hypoplasia or atrophy, and congenital cataract. Affected individuals with associated thrombocytopaenia have also been reported but it has been suggested that these patients may have a distinct subtype.
Etiology
The cause remains unknown.
Diagnostic methods
Diagnosis relies on the clinical picture and requires exclusion of intrauterine infections.
Differential diagnosis
Congenital intrauterine infection-like syndrome shows considerable clinical overlap with Aicardi-Goutieres syndrome (AGS, see this term). The two syndromes were reported to differ by the presence of cerebrospinal fluid anomalies (CSF leucocytosis and elevated IFN-alpha levels) in AGS and hepatic dysfunction, congenital microcephaly and thrombocytopaenia in congenital intrauterine infection-like syndrome. However, as the clinical manifestations of both syndromes show significant variability, it has been suggested that AGS and congenital intrauterine infection-like syndrome represent different presentations of the same disease. The differential diagnosis should also include other syndromes characterised by microcephaly and intracranial calcification such as Cockayne syndrome, COFS syndrome (which is usely considered as the neonatal form of Cockayne syndrome) and Hoyeraal-Hreidarsson syndrome (the neonatal presentation of dyskeratosis congenita syndrome; see these terms), some cases of mitochondrial encephalomyopathy, and pseudohypoarathyroidism. Ancient cases may have been reported as ``Fahr disease'', an outdated, causally heterogeneous clinical entity that encompasses several entities with intracranial calcifications.
Genetic counseling
Several familial cases, compatible with an autosomal recessive pattern of inheritance, have been described.
Management and treatment
Treatment is symptomatic only.
Prognosis
The prognosis is variable but can be severe with several of the reported patients dying within the first year of life.

                            Last update:
                            May 2008

                            - Expert reviewer(s):
                            Pr Alain VERLOES


Congenital intrinsic factor deficiency (IFD) is a rare disorder of vitamin B12 (cobalamin) absorption that is characterized by megaloblastic anemia and neurological abnormalities.

Summary:
Epidemiology
The incidence and prevalence of IFD are unknown. Fewer than 100 cases have been reported in the literature and fewer than 50 cases have been confirmed molecularly.
Clinical description
The disease usually manifests before the age of 5 but patients in their 10th and 30th decade of life have also been reported. It manifests with failure to thrive and symptoms of anemia (e.g. asthenia, weakness, headache, infections). If untreated, neurological damage may occur such as peripheral neuropathy, subacute combined degeneration of the spinal cord and/or ataxia. Neurological symptoms may include muscular weakness and abnormal gait.
Etiology
Patients have bi-allelic mutations in the GIF gene on chromosome 11 encoding the gastric Intrinsic Factor (IF), a protein necessary for the absorption of vitamin B12. GIF mutations lead to impaired IF synthesis and thus vitamin B12 (cobalamin) malabsorption and deficiency.
Diagnostic methods
Diagnosis depends on blood tests that show low serum levels of cobalamin and megaloblastic anemia (decreased red blood cell count and increased mean corpuscular volume). Nowadays, measurement of transcobalamin-bound cobalamin (holo-transcobalamin) in serum is preferred to measurement of total serum cobalamin. As cobalamin deficiency affects enterocyte function, thereby enhancing cobalamin malabsorption, it is recommended to treat first with cobalamin in order to reestablish proper enterocyte function before performing any diagnostic malabsorption testing. Acid secretion is usually present but patients may show low or absent IF amounts in the gastric juice. Urine tests show increased amounts of methylmalonic acid (MMA) and total homocysteine (tHcy). There are no auto-antibodies directed against the gastric parietal cells antigen H+/K+ ATPase (anti-GPC) and intrinsic factor (anti-IFA). Commercial genetic testing is not yet available.
Differential diagnosis
Differential diagnosis includes Imerslund-Gräsbeck syndrome, transcobalamin II deficiency, cblF defect, and acquired pernicious anemia (see these terms), which is caused by autoimmunity or Helicobacter infection.
Antenatal diagnosis
Antenatal diagnosis is not available.
Genetic counseling
Both sporadic cases and familial cases with autosomal recessive transmission have been reported.
Management and treatment
The standardized treatment consists of weekly to monthly intramuscular injections of vitamin B12. Hydroxocobalamin injections are preferred over cyanocobalamin as the latter may cause muscular pain and have ophthalmo-neurological side effects. Oral vitamin B12 supplementation may be ineffective and not recommended.
Prognosis
Prognosis is good. Without treatment, neurological and hematopoietic complications can occur that can also be fatal.

                            Last update:
                            September 2011

                            - Expert reviewer(s):
                            Dr Stephan TANNER


A rare endocrine disease characterized by neonatal hypoglycemia, prolonged cholestatic jaundice, and seizures. Typical are low plasma ACTH and cortisol levels in the absence of structural pituitary defects, and sometimes low partial growth hormone deficiency is associated.


A rare endocrine disease characterized by an excessive or uncontrolled insulin secretion and recurrent episodes of hypoglycemia that can result in neurological sequelae if left untreated. There are two forms according to the response to first line treatment: diazoxide-sensitive and diazoxide-resistant hyperinsulinism; and three histopathological forms: focal, diffuse and atypical forms. Focal forms are only observed in early-onset cases of diazoxide unresponsive patients.

Summary:
Epidemiology
Isolated Congenital hyperinsulinism (CHI) is the most frequent cause of severe and persistent hypoglycemia in the neonatal period and early infancy. The average birth prevalence is 1/27,000 worldwide, but it may be as high as 1/2,500 in communities with substantial consanguinity.
Clinical description
CHI can present from birth through early adulthood according to the severity of hypoglycemia. Neonatal onset is the most frequent; newborns, often macrosomic, present with poor feeding, intolerance to fasting and persistent hypoglycemia. Hypoglycemic episodes range from mild (lethargy, hypotonia and irritability) to severe (apnea, seizures or coma) that lead to neurologic sequelae. Patients who present later have recurrent, typical hypoglycemia (pallor, profuse sweating and tachycardia).
Etiology
Nine genes are associated to CHI; the most common variants involve ABCC8 (11p15.1) and KCNJ11 (11p15.1), the genes encoding the ATP-sensitive potassium channel in pancreatic beta cell.
Diagnostic methods
Detectable serum insulin/C-peptide, low ketone bodies and suppressed fatty acids during hypoglycemic episodes are diagnostic of hyperinsulinemic hypoglycemia. Requirement of continuous glucose above the physiological rate of liver glucose production is pathognomonic of hyperinsulinism (HI). Later onset CHI may require provocative testing. The congenital (genetic) form should be established via family history consistent with HI or monogenic diabetes, abnormal biochemical features (hyperammonemia in association with GDH variants, or high plasma C4-OH and urine 3OH-glutarate with HADH variants), and genetic testing. Lastly, in cases unresponsive to diazoxide urgent genetic testing for ABCC8 / KCNJ11 variants and, when necessary, 18F-DOPA-Positron emission tomography (PET) imaging is indicated in order to differentiate the focal and diffuse forms.
Differential diagnosis
Differential diagnosis include all the other causes of recurrent hypoglycemia: for HI observed from birth these include transient neonatal HI as well as syndromic CHI (more than 30 syndromes feature HI at birth, the most frequent are Beckwith-Wiedemann, Kabuki and Turner syndrome); later in life, these may include insulinoma, post bariatric surgery HI, drug-induced HI, and auto-immune syndromes (HI due to anti-insulin antibodies) etc.
Antenatal diagnosis
Antenatal genetic testing is possible when the molecular etiology has been identified in a proband.
Genetic counseling
The disorder can be autosomal dominant or recessive, and thus genetic counseling will depend on the variants responsible (de novo, germline or somatic mutations). Genetic testing may be offered to affected families when the molecular etiology has been identified in a proband.
Management and treatment
Normoglycemia must be rapidly recovered and maintained to prevent irreversible brain damage, especially in neonates. At birth, severe hypoglycemia might require continuous glucose infusion and glucagon injection. Diazoxide is the first line of medical therapy and octreotide is added as an adjunct in diazoxide unresponsive patients. Partial pancreatic resection is curative for focal HI. For patients with diffuse disease, a conservative treatment is proposed when safely possible; for patients resistant to diet and medical management, near-total pancreatectomy may be necessary.
Prognosis
For neonatal-onset CHI, the main concern is the cognitive outcome, which might be impaired in up to 30 to 50% of patients, especially in those who suffered from prolonged and severe hypoglycemia. The spontaneous evolution of glycemia varies: in children the disease severity reduces with time, and sometimes might even resolve, while in others it persists through adulthood. When resolved, a life-long follow-up is advised due to a risk of diabetes. In cases of subtotal pancreatectomy, glucose intolerance and diabetes mellitus requiring insulin is inevitable, occurring within 15 years after the surgery.

                            Last update:
                            June 2022

                            - Expert reviewer(s):
                            Dr Jean-Baptiste ARNOUX | MetabERN* - Dr Cécile SAINT-MARTIN

                                * European Reference Network


A rare congenital limb malformation characterized by either hyperextension of the knee greater than 0° associated with limited flexion (congenital genu recurvatum) or permanent knee flexion with limited extension (congenital genu flexum). It can be unilateral or bilateral and may occur as an isolated malformation, be associated with other orthopedic abnormalities (like developmental dysplasia of the hip or clubfoot), or be part of a syndrome (e. g. Larsen's syndrome, arthrogryposis multiplex congenita).


Congenital labioscrotal agenesis-cerebellar malformation-corneal dystrophy-facial dysmorphism syndrome

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay, intellectual disability, absent scrotum or labia majora, absent or underdeveloped nipples and a tuft of hair extruding from the lactiferous ducts, bilateral corneal opacities, and dysmorphic craniofacial features (microcephaly, short forehead, and ear abnormalities, among others). Patients also show horizontal nystagmus and ataxic gait. Brain MRI reveals small cerebellar hemispheres and vermis and a small pons.


Congenital lactase deficiency is a rare severe gastrointestinal disorder in newborns primarily reported in Finland and characterized clinically by watery diarrhea on feeding with breast-milk or lactose-containing formula.


Congenital lactic acidosis, Saguenay-Lac-Saint-Jean type

A rare degenerative mitochondrial disease characterized by chronic metabolic acidosis, hypotonia, facial dysmorphism and delayed development.

Summary:
Epidemiology
The French Canadian form of Leigh syndrome was first described in Saguenay-Lac-Saint-Jean (SLSJ) (Quebec, Canada) where its prevalence at birth is estimated to be 1/2,000. The prevalence of the gene mutation underlying the disorder, estimated to be 1/23 inhabitants, is due to a triple founder effect characterizing the settlement pattern of SLSJ. Patients were identified in all Quebec and elsewhere in the world (China, Italia and Great Britain for example).
Clinical description
Facial dysmorphism is characterized by a prominent forehead, wide nasal bridge, hypertelorism, broad anterior fontanelle, midfacial hypoplasia, broad midline, synophrys, and anarched form of the eyebrows, along with mild hirsutism. There are three forms of the disease corresponding to varying degrees of severity: a neonatal form, a classic form and a so-called "survivor" form. The neonatal form is characterized by fulminant acidotic states. The classic form can occur from birth with severe lactic acidosis, or manifest between 14-24 months by ataxic gait. This form is associated with episodes of lactic acidosis that can be triggered by physical exertion, emotional stress, infection or a heavy meal, and/or metabolic crises. Patients who survived several episodes, called "survivors", cross a critical threshold and show less severe symptoms: hypotonia, asthenia, developmental delay (language acquisition and walking) and, in older patients, truncal ataxia, and a characteristic wide-based gait.
Etiology
The disease is caused by mutations in the LRPPRC gene (2p21), the most frequent being A354V mutation. In Quebec where the disease is more frequent, only one patient has been identified as a heterozygous carrier of the A354V mutation and the C1277Xdel8 deletion. Other mutations in LRPPRC have been described in different populations (including Italy, Great Britain and Turkey) but with lower frequency. LRPPRC codes for the leucine-rich pentatricopeptide repeat-containing protein and appears to be involved in the transport and stability of mature mitochondrial mRNA. Biochemically, the cytochrome C oxidase enzyme (COX) involved in the respiratory chain was found to be deficient in all patients, but other proteins in the respiratory chain may also be.
Diagnostic methods
The main diagnostic method is identification of a causal mutation. In situations where genetic testing is impossible, clinical diagnosis is based on determination of lactate levels in the blood and cerebrospinal fluid and determination of COX activity in fibroblasts from liver and skin biopsies, which were the strategies employed before the causal mutations were discovered.
Differential diagnosis
Differential diagnosis includes other forms of Leigh syndrome and other possible causes of metabolic acidosis such as MELAS syndrome, glucose-6-phosphate dehydrogenase (G6PD) deficiency, pyruvate dehydrogenase deficiency, and pyruvate carboxylase deficiency.
Antenatal diagnosis
Since the discovery of the underlying mutation, prenatal diagnosis is offered to couples that have had an affected child. A carrier test for future parents, including this disease, has also been implanted for all of Quebec's population. Moreover, private companies are now including single-nucleotide polymorphisms (SNPs) of LRPPRC in their genetic diagnosis panel for metabolic diseases, for which the quarter of these SNPs have unknown biological impact.
Genetic counseling
The disease follows a monogenic autosomal recessive pattern of inheritance. Genetic counseling is proposed to couples at risk through identification of heterozygous carriers.
Management and treatment
There is no specific treatment for this disease but lifestyle changes can upgrade the quality of life of patients. A diet with a balanced intake of proteins, carbohydrates and lipids, spread evenly over the day, is recommended in order to reduce the high energy demands of digestion. Rest and strict compliance with sleeping needs are also beneficial. It is recommended to prevent infections with adequate vaccination and to visit a doctor promptly if the condition of the patient is deteriorating or in case of an infection. Avoidance of tobacco or vaping products and exposition to cigarette smoke and carbon monoxide (from cars or wood heating) is also recommended.
Prognosis
In the neonatal form, the prognosis is very poor. In other patients, life expectancy was often <5 years due to severe episodes of acidosis. Currently, 80% of the patients with this disease present the so-called ''survivor'' form and exceed the age of 5. Clinical comprehension of the symptoms allowed physicians to state guidelines to include in the lifestyle of the patients. Life expectancy of the less severely affected patients can now exceed 20 years of age. The oldest patient with this disease is now 43 years old.

                            Last update:
                            January 2024

                            - Expert reviewer(s):
                            Pr Bhérer CLAUDE  - Pr Catherine LAPRISE  - Dr Charles MORIN


Congenital laryngeal cyst is a rare larynx anomaly characterized by a cyst involving the larynx or supraglottis locations, such as the epiglottis and vallecula. Timing and severity of presentation depend on the size of the cyst and its proximity to the glottis and range from severe prenatal airway obstruction leading to polyhydramnios and pulmonary hypoplasia to postnatal inspiratory stridor associated with muffled cry, hoarseness and cyanotic episodes, and to feeding difficulties and failure to thrive. It can be associated with laryngomalacia.


Congenital laryngeal palsy is a rare larynx anomaly characterized by unilateral or bilateral paralysis of the vocal cords as a result of dysfunction of the motor nerve supply to the larynx. Patients typically present at birth (or shortly thereafter) with stridor, weak or breathy cry, dysphonia or aphonia, feeding or aspiration difficulties and, occasionally, respiratory compromise. Neurological disease, masses that cause compression and aberrant vessels are often associated. Most cases resolve spontaneously over 6-12 months.


A rare larynx anomaly characterized by an inward collapse of supraglottic airway during inspiration, which manifests with an inspiratory stridor and might be associated with feeding difficulties, swallowing dysfunction, failure to thrive, and respiratory distress.


A rare congenital non-syndromic heart malformation characterized by a bulging of the left ventricular wall, connected to the left ventricle by a wide neck (with a ratio of the connection to the body of the anomaly >1). The dimensions of aneurysms have been described as small as 0.5 cm in diameter and as big as 8x9 cm in size. Most frequent locations are the left ventricular apex and the perivalvular area. Aneurysms can be a- or dyskinetic or show almost normal contractility. Patients may remain asymptomatic or present with systemic embolization, congestive heart failure, valvular regurgitation, ventricular wall rupture, ventricular tachycardia, or sudden cardiac death.


A rare skin disorder characterized by erythrodermic, peeling skin from birth with no obvious nail or hair-shaft abnormalities and other associated anomalies including diarrhea, failure to thrive and severe hypoalbuminaemia resistant to correction by enteral or intravenous supplementation. An autosomal recessive mode of inheritance is highly probable. The prognosis is poor and infants die in the first months of life. There have been no further descriptions in the literature since 1992.


Congenital lethal myopathy, Compton-North type is a rare, genetic, lethal, non-dystrophic congenital myopathy disorder characterized, antenatally, by fetal akinesia, intrauterine growth restriction and polyhydramnios, and, following birth, by severe neonatal hypotonia, severe generalized skeletal, bulbar and respiratory muscle weakness, multiple flexion contractures, and normal creatine kinase serum levels. Ultrastructurally, loss of integrin alpha7, beta2-syntrophin and alpha-dystrobrevin from the muscle sarcolemma and disruption of sarcomeres with disorganization of the Z band are observed.


Congenital limbs-face contractures-hypotonia-developmental delay syndrome

A rare multiple congenital anomalies/dysmorphic syndrome with intellectual disability characterized by severe congenital contractures of the limbs and face, hypotonia, neonatal respiratory distress, and global developmental delay. Dysmorphic facial features include downslanting palpebral fissures, broad nasal bridge, large nares, long philtrum, and deep nasolabial folds, among others. Limb deformities (camptodactyly, clubfoot), short neck, scoliosis, as well as seizures have also been reported. Brain MRI may show cerebral and cerebellar atrophy in some cases.


Congenital lipoid adrenal hyperplasia due to STAR deficency

A severe form of congenital adrenal hyperplasia (CAH) characterized by severe adrenal insufficiency and sex reversal in males.

Summary:
Epidemiology
The prevalence is unknown but it is extremely rare and is more common in people of Japanese, Korean (where the heterozygous carrier frequency is estimated to be about one in 300 leading to an estimated number of affected newborns of one in every 250,000 to 300,000) and Palestinian ancestry.
Clinical description
It involves both glucocorticoid and mineralocorticoid deficiencies in the adrenal and androgen deficiency in the testis. Age of onset typically occurs in the antenatal period but congenital anomalies are typically seen in the perinatal period. Boys are not virilized and demonstrate a complete girl phenotype with lack of Müllerian structures. The external genitalia of girls are normal. Hypoglycemic seizures, vomiting or symptoms of dehydration are common manifestations in the first few weeks of life and can be life threatening. Acute adrenal insufficiency is an emergency and can occur in some cases. Non-classic lipoid CAH patients typically have an insidious onset of symptoms of adrenal insufficiency beginning as early as two to four years of age. The 46,XY patients have normal-appearing external genitalia, indicating normal intrauterine Leydig cell function leading to normal male external genital development. However, such patients with non-classic lipoid CAH may also have azoospermia and hypergonadotropic hypogonadism.
Etiology
This disease is due to a mutation in the STAR gene, which encodes for a protein that regulates steroid hormone synthesis by mediating cholesterol transfer across the mitochondrial membrane.
Diagnostic methods
Absence of all glucocorticoids, mineralocorticoids and sex steroids is observed. Diagnosis is usually performed during the neonatal period due to glucocorticoid and mineralocorticoid deficiencies. 46,XY are phenotypically female due to impaired testicular steroidogenesis. Biologically, high basal concentrations of ACTH, elevated plasma renin activity, and hypergonadotropic hypergonadism are seen. Milder ''non-classical'' forms have been reported with intermediate phenotypes. Patients may have minimal disorders of mineralocorticoid secretion, with normal electrolytes and mildly elevated plasma renin activity.
Differential diagnosis
Differential diagnosis includes familial glucocorticoid deficiency.
Antenatal diagnosis
Prenatal diagnosis through chorionic villus sampling is possible in case of a familial form, when the pathogenic variant has previously been identified in a family member.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Treatment includes physiological replacement with glucocorticoids, mineralocorticoids, and in the newborn period, salt. Genetic males have female external genitalia and typically undergo orchidectomy and are raised as females. They require estrogen replacement to induce puberty and long term sex steroid administration.
Prognosis
When affected 46,XX patients receive appropriate glucocorticoid and mineralocorticoid replacement therapy and reach the usual age of puberty, they undergo spontaneous breast development and experience cyclical vaginal bleeding. Successful pregnancy has been achieved. Affected 46,XY individuals are unfertile. Uncontrolled CAH may be associated with life-threatening acute adrenal insufficiency and a higher risk for metabolic and cardiovascular comorbidities.

                            Last update:
                            February 2022

                            - Expert reviewer(s):
                            Pr Juliane LEGER | Endo-ERN*

                                * European Reference Network


A respiratory abnormality characterized by respiratory distress due to hyperinflation of one or more affected lobes of the lung.

Summary:
Epidemiology
It is a rare disease with the birth prevalence being 1/20,000 to 1/30,000.
Clinical description
Most cases present in the neonatal period or in early infancy. Patients with less severe manifestations may present in early childhood or rarely in adulthood. Clinical picture can range from asymptomatic or mildly symptomatic to severe respiratory impairment requiring immediate intervention. Symptomatic patients present with asymmetric chest wall expansion, respiratory distress, dyspnea, tachycardia, cyanosis, and failure to thrive. The left upper lobe is most commonly affected (41%) followed by the right middle lobe (34%) and the right upper lobe (21%). CLE can occur in association with cardiac malformations in 15 to 20% cases.
Etiology
About 50% of cases have no identifiable etiology; however an abnormality or absence of cartilaginous rings, intrinsic obstruction caused by redundant mucosa, extrinsic obstruction (vascular or bronchial) or hyperinflation alone might explain the CLE. Polyalveolar lobe has also been reported as a cause of CLE.
Diagnostic methods
Chest X ray and CT scan are the key imaging modalities used for diagnosis. Chest X ray shows hyperlucent affected lobes with mediastinal shift and collapse of ipsilateral unaffected segments. CT scan provides details of affected lobes and vascular involvement. Echocardiography to detect concomitant heart disease can also be performed.
Differential diagnosis
Respiratory distress and radiolucency in chest X rays can lead to a misdiagnosis of tension pneumothorax. Differential diagnoses also include congenital pulmonary airway malformation, pneumonia, bronchiolitis and foreign body aspiration.
Antenatal diagnosis
Prenatal diagnosis can be made with ultrasonography by identifying hyperechoic areas in fetal lung and Magnetic Resonance Imaging identify uniform T2 hyperintensity compared to normal lung.
Management and treatment
Lobectomy of affected lobes is the widely accepted form of management with a satisfactory outcome. Asymptomatic or mildly symptomatic cases can be managed conservatively but follow up is necessary. Thoracoscopic resection has been attempted and seems to have better post operative outcomes.
Prognosis
Asymptomatic cases may regress spontaneously. Prompt diagnosis and surgical intervention usually provide good long term outcome in symptomatic cases. In some cases, CLE can be lethal.

                            Last update:
                            June 2019

                            - Expert reviewer(s):
                            Pr Daniele CATANEO


A rare developmental defect during embryogenesis characterized by muscular hypertrophy, adenoid hyperplasia, or vascular malformation that results in an enlarged, often protruding, tongue. Complications include difficulty in swallowing, breathing and mastication, drooling, dental and skeletal deformities, such as malocclusion, open bite, asymmetry in maxillary and mandibular arches. It may be isolated or associated with genetic syndromes.


Congenital megacalycosis is a rare renal malformation, characterized by non-obstructive dilation of the renal calyces as well as an increased calyceal number (12-20), with a normal renal pelvis, ureter, and bladder. It may be unilateral or bilateral and is usually asymptomatic unless complicated by nephrolithiasis and urinary tract infection.


Congenital membranous nephropathy due to fetomaternal anti-neutral endopeptidase alloimmunization

A rare, congenital glomerular disease due to maternal anti-neutral endopeptidase (NEP) alloimmunization characterized by severe renal failure and nephrotic syndrome at birth, which rapidly improves in the first weeks of life.

Summary:
Epidemiology
The disorder has been described in 15 infants from 5 families originating from Portugal, the Netherlands, Italy, Germany and Morocco.
Clinical description
Presentation is at birth with nephrotic syndrome, acute renal failure (oligoanuria), or both. Very weak and transient proteinuria is also possible. Respiratory distress and hypertension may also be observed during the first days of life. Some degree of dysmorphism with retrognathism, low set ears and large fontanel may be observed in some cases.
Etiology
The disease is caused by the transplacental transfer of nephritogenic anti-NEP Abs (IgG1, IgG4 subtypes) from mothers with truncating mutations of the MME gene (3q25.2; coding for NEP), resulting in a loss of functional of MME. Absence of NEP induces an alloimmunization process, during pregnancy or following an earlier pregnancy, against the NEP antigen inherited by the fetus from the father. The Abs cross the placenta and bind to the NEP expressed on fetal podocytes, ultimately resulting in glomerular damage and proteinuria.
Diagnostic methods
Diagnosis is based on laboratory findings showing an increased serum creatinine concentration as well as the development of nephrotic-range proteinuria and hypoalbuminemia in the infant during the first days of life. Anti-NEP Abs may be detected in the infant's serum during the first couple of weeks after birth but disappear thereafter. Diagnosis of membranous nephropathy relies on the kidney biopsy. In some cases, it shows a severe and unusual form of membranous nephropathy, collapse of a majority of capillary tufts in the glomeruli with thickening of the capillary wall, and distension of Bowman's spaces. Marked tubular atrophy and severe lesions of the interlobular arteries and arterioles may also be observed. Immunofluorescence studies reveal subepithelial deposits of IgG in the glomeruli. Electron microscopy examination shows abundant electron-dense deposits typically containing annular formations on the outer aspect of the glomerular capillary wall and a marked atrophy of the brush border.
Differential diagnosis
The syndrome should be differentiated from other causes of early-onset membranous nephropathy such as congenital infections like syphilis and toxoplasmosis, and neonatal lupus erythematosus.
Antenatal diagnosis
Prenatal diagnosis is suspected from the 34th week of gestation by ultrasonography which may show oligohydramnios and enlarged fetal kidneys. NEP deficiency can be detected in women, using fluorescence-activated cell-sorter analysis, by incubating granulocytes with anti-NEP monoclonal Abs, or Western blotting of the urine with anti-NEP Abs. Dosage of IgG1 and IgG4 subtypes of anti-NEP Abs can be achieved in pregnant women by ELISA.
Genetic counseling
Transmission of NEP deficiency is autosomal recessive. Penetrance of the infant's renal disease is variable and depends on the quantity and quality of the mother's immune response (IgG4 (milder clinical symptoms) or IgG1 subclass antibodies). Mothers do not show any renal manifestations until the age of 40 when they develop peripheral demyelinating neuropathy.
Management and treatment
No cure exists. Management is mainly symptomatic and includes oxygenation ventilation for hypoxemia, administration of calcium-channel blockers and beta-blockers for blood-pressure control, management of nephrosis and renal failure if present. In neonates with severe presentation, i.e. renal failure and/or nephrotic syndrome, an exchange transfusion to eliminate circulating anti-NEP antibodies can be considered. From 4 weeks post-term, if proteinuria is still present, RAAS (renin-angiotensin-aldosterone system) inhibition may be started (usually captopril is the preferred agent, accompanied by gastroprotection). Intravenous polyclonal immunoglobulins and plasma exchanges may be envisaged in NEP-deficient mothers with increasing titers of anti-NEP IgG1 before pregnancy. Anti-CD20 therapy is another option but should be stopped 6 months before pregnancy.
Prognosis
Infants usually show a rapid improvement of renal failure and the nephrotic syndrome, although a severe form requiring prolonged dialysis may also be observed. Persistent albuminuria has been reported in some cases and postponed development of severe chronic renal failure may occur, especially in subsequent offspring of a NEP-deficient mother.

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Dr Hanna DEBIEC  - Pr Pierre RONCO | ERKNet* - Dr Marina VIVARELLI | ERKNet*

                                * European Reference Network


A rare renal tumor characterized by a unilateral, solitary, well demarcated, mesenchymal/myofibroblastic neoplasm occurring in very young children. Histopathologically, three subtypes (classic, cellular, and mixed) can be distinguished. The tumor most commonly involves the renal sinus and is typically discovered as a palpable abdominal mass. Patients may also present with hypertension or hematuria, rarely with hypercalcemia or hyperreninemia. Prenatal presentation, usually with polyhydramnios, is not infrequent. The most important prognostic factor is completeness of surgical resection. Overall, malignant potential is low and clinical outcome favorable.


Congenital microcephaly-severe encephalopathy-progressive cerebral atrophy syndrome

A rare, genetic, neurometabolic disorder characterized by severe, progressive microcephaly, severe to profound global development delay, intellectual disability, seizures (typically tonic and/or myoclonic and frequently intractable), hyperekplexia, and axial hypotonia with appendicular spasticity, as well as hyperreflexia, dyskinetic quadriplegia, and abnormal brain morphology (cerebral atrophy with variable additional features including ventriculomeglay, pons and/or cerebellar hypoplasia, simplified gyral pattern and delayed myelination). Cortical blindness, feeding difficulties and respiratory insufficiency may also be associated.


Congenital microcoria is a rare autosomal dominant ophthalmological disease caused by maldevelopment of the dilator muscle of the pupil that is characterized by small pupils (<2 mm in diameter) from birth, peripheral iris hypopigmentation and transillumination defects leading to errors of refraction (myopia, astigmatism) and sometimes juvenile open angle glaucoma.


Congenital microgastria is a rare malformation where the embryological development of the stomach is interrupted, leading to an abnormally small foregut in newborns and characterized by extreme feeding intolerance and malnutrition along with growth retardation and death if untreated. It is usually associated with multiple congenital anomalies.


Congenital mitral stenosis is a congenital heart malformation comprising a spectrum of morphologically heterogeneous developmental anomalies that result in functional and anatomic obstruction of inflow into the left ventricle. The structure of the mitral valve is affected at the level of the supravalvular ring, annulus, leaflets or subvalvar components and include supra-valvular ring, leaflet fusion (intra-leaflet ring), mitral parachute deformity and papillary muscle abnormalities. It may be isolated or associated with other heart malformations. The clinical presentation depends on the degree of obstruction, the presence of regurgitation, the presence and severity of associated pulmonary hypertension, and the presence of associated heart malformations. It may present with symptoms and signs of low cardiac output and right ventricular failure such as pulmonary infections, failure to thrive, exertional dyspnoea, cough, cyanosis and congestive heart failure.


Congenital muscular alpha-dystroglycanopathy with brain and eye anomalies (MDDGA) is a cobblestone lissencephaly characterized by and considered to be pathognomonic of a continuum of recessive autosomal disorders with brain, ocular and muscular involvement. MDDGA includes Walker-Warburg syndrome, muscle-eye-brain disease, Fukuyama muscular and cerebral dystrophy and muscle eye brain disease with bilateral multicystic leukodystrophy.


Congenital muscular dystrophy due to LMNA mutation

A rare congenital muscular dystrophy characterized by prominent axial hypotonia, predominantly proximal muscle weakness in upper limbs and distal in lower limbs, joint contractures (initially distal, later proximal), spinal rigidity, and progressive respiratory insufficiency, in the presence of moderately elevated serum creatine kinase. Cardiac arrhythmias and sudden death have also been reported.

Summary:
Epidemiology
To date over 100 cases of congenital muscular dystrophy due to LMNA (L-CMD) have been reported in the literature; both genders are equally affected.
Clinical description
The expressivity, severity and progression of the disease are variable but all present a predominant axial and scapula-humeral topography of muscle weakness and atrophy. Motor symptoms appear during the first two years of life and show often a rapid course. In the most severe patients, no head or trunk support are achieved. In milder patients, a more characteristic picture is observed, with a striking loss of head support (dropped-head syndrome), associated with arm weakness but relatively preserved hip and thigh strength in the initial stages. Skeletal manifestations include muscle and joint contractures, spine rigidity, scoliosis and thoracic lordosis. A progressive thoracic stiffness is associated to the respiratory insufficiency favoring recurrent respiratory infections. Severe cases might show swallowing difficulties. Cardiac arrhythmias and sudden death are not uncommon in this group of patients after the first decade or life.
Etiology
The disorder is due to mutations in the LMNA gene (1q22), coding for type A/C lamins, two intermediate filaments that form cytoplasmic and nuclear networks and shape the nuclear envelope. Myoblasts from L-CMD patients show altered nuclear structure, defective mechanosensing responses and abnormal cell differentiation. Milder phenotypes, known as Emery-Dreifus muscular dystrophy, are also associated with LMNA mutations.
Diagnostic methods
Diagnosis mostly relies on clinical observation, typically of early onset axial muscle weakness with distal progression, muscle and joint contractures, dropped-head syndrome, loss of walking and sitting abilities and cardiac arrhythmias in the first or second decade of life. A moderated elevation of serum creatine kinase levels reflects muscle damages. Genetic screening of mutations in the LMNA gene confirms the diagnosis.
Differential diagnosis
Differential diagnosis includes other congenital muscular dystrophies (laminin subunit alpha 2-related CMD, Ullrich CMD due to COL6 gene defects), early onset myopathies that present increased CK levels, joint contractures or spinal stiffness (SEPN1-related myopathies, titinopathies, Pompe disease, mitochondrial myopathy in particular TK2-related), and myasthenic syndromes where loss of head support can also be observed.
Antenatal diagnosis
Reduced fetal movements observed by prenatal ultrasounds should raise suspicions, but is not specific. In families with a proband, prenatal genetic testing may be advised due to the possibility of germinal mosaicism.
Genetic counseling
The disorder is autosomal dominant. Almost all reported cases arise de novo, although germinal mosaicism is a possibility. Genetic counseling should be offered to affected families.
Management and treatment
The evaluation and management of respiratory, gastro-intestinal, orthopedic and cardiac troubles associated with L-CMD require a multidisciplinary approach. Annual cardiac monitoring by Holter-ECG and ultrasound is recommended to detect cardiac arrhythmias and signs of heart failure. Implantable cardiac monitoring might be considered in some cases. BNP (brain natriuretic peptide) may help to detect cardiac insufficiency. Diuretic drugs, beta-blockers, aldosterone antagonists and ACE (angiotensin-converting-enzyme) inhibitors might improve cardiac function. Some patients have been reported to show motor improvement on corticoid treatment but prospective studies are required to confirm these results.
Prognosis
In the first decade, respiratory insufficiency is the main cause of death. Thereafter, cardiac dysfunction and arrhythmias, which are very frequent in young adults and may lead to sudden death, determine the vital prognosis. Embolic complications due to conduction disorders and right heart failure may worsen the poor prognosis. Respiratory insufficiency and recurrent pulmonary infections reduce the lifespan or may lead to permanent ventilation or tracheostomy.

                            Last update:
                            November 2020

                            - Expert reviewer(s):
                            Pr Susana QUIJANO-ROY


Congenital muscular dystrophy type 1B is a rare, genetic neuromuscular disorder characterized by proximal and symmetrical muscle weakness (particularly of neck, sternomastoid, facial and diaphragm muscles), spinal rigidity, joint contractures (Achilles tendon, elbows, hands), generalized muscle hypertrophy and early respiratory failure (usually in the first decade of life). Patients typically present delayed motor milestones and grossly elevated serum creatine kinase levels, and with disease progression, forced expiratory abdominal squeeze and nocturnal hypoventilation.


Congenital muscular dystrophy with cerebellar involvement

A rare, congenital muscular dystrophy due to dystroglycanopathy characterized by proximal muscle weakness with a tendency for muscle hypertrophy and pseudohypertrophy, variable cognitive impairment, microcephaly, cerebellar hypoplasia with or without cysts, and other structural brain anomalies.