Congenital muscular dystrophy with hyperlaxity is a rare, genetic neuromuscular disease characterized by congenital hypotonia, generalized, slowly progressive muscular weakness, and proximal joint contractures with distal joint hypermobility and hyperlaxity. Scoliosis or rigidity of the spine and delayed motor milestones are also frequently reported. Other manifestations include a long myopathic face and, in rare cases, respiratory failure, mild to moderate intellectual deficiency and short stature. Ambulation may be impaired with time.


Congenital muscular dystrophy with integrin alpha-7 deficiency is a rare, genetic, congenital muscular dystrophy due to extracellular matrix protein anomaly characterized by early motor development delay and muscle weakness with mild elevation of serum creatine kinase, that may be followed by progressive disease course with predominantly proximal muscle weakness and atrophy, motor development regress, scoliosis and respiratory insufficiency.


Congenital muscular dystrophy with intellectual disability and severe epilepsy

A rare, fatal, inborn error of metabolism disorder characterized by respiratory distress and severe hypotonia at birth, severe global developmental delay, early-onset intractable seizures, myopathic facies with craniofacial dysmorphism (trigonocephaly/progressive microcephaly, low anterior hairline, arched eyebrows, hypotelorism, strabismus, small nose, prominent philtrum, thin upper lip, high-arched palate, micrognathia, malocclusion), severe, congenital flexion joint contractures and elevated serum creatine kinase levels. Scoliosis, optic atrophy, mild hepatomegaly, and hypoplastic genitalia may also be associated.


Congenital muscular dystrophy with intellectual disability

A rare, genetic, congenital muscular dystrophy due to dystroglycanopathy disorder characterized by a wide phenotypic spectrum which includes hypotonia and muscular weakness present at birth or early infancy and delayed or arrested motor development, associated with mild to severe intellectual disability and variable brain abnormalities on neuroimaging studies. Feeding difficulties, joint and spinal deformities, respiratory insufficiency, and ocular anomalies (e.g. strabismus, retinal dystrophy, oculomotor apraxia) may be associated. Decreased or absent alpha-dystroglycan on immunohistochemical muscle staining and elevated serum creatine kinase are observed.


Congenital muscular dystrophy without intellectual disability

A rare, genetic, congenital muscular dystrophy due to dystroglycanopathy characterized by a wide phenotypic spectrum which includes hypotonia and muscular weakness present at birth or early infancy, delayed or arrested motor development, and normal intellectual abilities with normal (or only mild abnormalities) neuroimaging studies. Feeding difficulties, joint and spinal deformities, and respiratory insufficiency may be associated. Decreased alpha-dystroglycan on immunohistochemical muscle staining and elevated serum creatine kinase are observed.


Congenital muscular dystrophy, Fukuyama type

A rare congenital progressive muscular dystrophy often characterized by brain malformation (cobblestone lissencephaly), dystrophic changes in skeletal muscle, severe intellectual deficit, epilepsy and motor impairment.

Summary:
Epidemiology
The disease has a high prevalence in the Japanese population due to an ancestral mutation, and is extremely uncommon elsewhere. The prevalence of Fukuyama type muscular dystrophy (FCMD) in Japan is estimated at 1/25,000-50,000 live births.
Clinical description
Disease onset typically occurs in early infancy. Initial symptoms include a poor suck, weak cry, floppiness and developmental delay. Symmetrical generalized muscle weakness and hypotonia are present. With time, patients develop retractile phenotype and show contractures of the hips, knees and interphalangeal joints. Later features include myopathic facial appearance, pseudohypertrophy of the calves and forearms, and ophthalmologic abnormalities (visual impairment and retinal dysplasia). Progressive cardiac involvement, respiratory failure and swallowing and feeding disturbances (leading to recurrent aspiration pneumonia and death) occur in infants with severe FCMD and in patients over ten years of age. Seizures (generalized tonic-clonic convulsions, complex partial seizures and partial seizures with secondary generalization, infantile spasms, tonic seizures and myoclonic seizures) occur in over 50% of affected individuals (median age of seizure onset 1-3 years of age). All patients with the Japanese ancestral mutation show severe intellectual deficit and the intelligence quotient (IQ) is usually between 30 and 60.
Etiology
It is caused by mutations in the fukutin gene (FKTN; 9q31-q33). Of note, FKTN variants are responsible for a clinical spectrum ranging from CMD without brain involvement to isolated, dilated cardiomyopathy.
Diagnostic methods
The diagnosis is based on the clinical picture, characteristic neuroimaging and electromyography findings, muscle biopsy results, and molecular genetic testing.
Differential diagnosis
Differential diagnoses include Duchenne and Becker muscular dystrophies, and other muscular dystrophies associating a type II lissencephaly (known as dystroglycanopathies). Brain, cerebellar and ocular abnormalities observed in most FCMD patients are similar to and would be diagnosed out of Japan as MEB syndrome. Therefore, there is an increasing tendency to use the global term MEB/FCMD syndrome.
Antenatal diagnosis
Prenatal diagnosis is possible where 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
Management includes physiotherapy, treatment of orthopedic, respiratory and cardiac complications, respiratory aid, and medical or surgical treatment for nutritional and gastrointestinal problems. Control of seizures requires antiepileptic drugs. Surveillance includes monitoring for respiratory and cardiac function.
Prognosis
Prognosis depends on the severity of complications, mainly neurologic, cardiac or respiratory.

                            Last update:
                            January 2023

                            - Expert reviewer(s):
                            Pr Enrico BERTINI | EURO-NMD* - Pr Susana QUIJANO-ROY | EURO-NMD*

                                * European Reference Network


Congenital muscular dystrophy-infantile cataract-hypogonadism syndrome is characterized by congenital muscular dystrophy, infantile cataract and hypogonadism. It has been described in seven individuals from an isolated Norwegian village and in one unrelated individual. Transmission appears to be autosomal recessive.


Congenital muscular dystrophy-respiratory failure-skin abnormalities-joint hyperlaxity syndrome

A rare congenital muscular dystrophy characterized by neonatal hypotonia, life-threatening respiratory failure, and feeding difficulties, furthermore by delayed motor development, severe muscle weakness predominantly affecting axial muscles (leading to poor head control, rigid cervical spine, and severe scoliosis), generalized joint laxity with no or mild contractures, as well as dry skin with follicular hyperkeratosis. Serum creatine kinase is normal or slightly elevated. Muscle biopsy shows fiber size variability, rounded fibers with mild increase of endomysial connective tissue and adipose replacement, abundant minicore lesions, increase of centrally located nuclei, angular fibers, and cap lesions.


Congenital muscular dystrophy (CMD) is a heterogeneous group of neuromuscular disorders with onset at birth or infancy characterized by hypotonia, muscle wasting, weakness or delayed motor milestones. The group includes myopathies with abnormalities at different cellular levels: the extracellular matrix (MDC1A, UCMD; see these terms), the dystrophin-associated glycoprotein complex (alphadystroglycanopathies, integrinopathies see these terms), the endoplasmic reticulum (rigid spine syndrome [RSMD1], and the nuclear envelope (LMNA-related CMD; [L-CMD] and Nesprin-1-related CMD; see these terms).

Summary:
Epidemiology
The prevalence of CMDs is not well known but is estimated at about 1-9/100,000 in countries where they are most frequent. Males and females are equally affected.
Clinical description
Orthopaedic and respiratory complications that may be life-threatening often develop in the course of the disease.
Etiology
CMDs have autosomal recessive inheritance with the exception of dominant mutations possible in at least two forms (UCMD may have autosomal dominant or recessive inheritance; L-CMD is due to dominant de novo mutations). At least 15 genes are known to be responsible for this group of disorders.
Diagnostic methods
Diagnosis is often difficult due to the wide clinical, immunohistochemical and genetic heterogeneity. The diagnosis is based on clinical findings, immunochemical staining on muscle biopsy, and molecular genetic testing. Increased creatine kinase (CK) levels, presence of intellectual deficiency and type of distribution of different signs or symptoms are useful markers to distinguish different forms. CMDs due to collagen VI disorders are complex and may need additional studies in skin fibroblasts.
Differential diagnosis
Differential diagnoses include congenital and early onset neuromuscular disorders, mainly congenital myopathies, spinal muscular atrophy and congenital myasthenic syndromes (see these theses terms). Patients with mutations in genes identified in other neighbour muscular disorders such as congenital myopathies may present sometimes as a CMD (including the finding of dystrophic features on muscle biopsy) without specific ultrastructural abnormalities on muscle biopsy.
Antenatal diagnosis
Antenatal diagnosis is feasible through molecular analysis of amniocytes and in some forms coupled with immunohistochemical staining of chorionic villus samples (MDC1A).
Management and treatment
Currently there is no curative therapy, but supportive treatments. Besides global and nutritional management, common restrictive respiratory insufficiency may need mechanical respiratory assistance. Orthopedic complications (joint contractures, spinal deformities) are a main concern and preventive or proactive treatment by regular physical and occupational therapies and trunk and limb orthesis is often useful to reduce the severity and course of the deformities. Surgical interventions in spine (spinal fusion) are used to correct or stabilise the spine if scoliosis develops. Tenotomies are also used to reduce the severity of joint contractures but do not have always a beneficial result. Cardiac and neurological symptoms may be particularly severe in certain forms and require specific treatment. Psychological support is very helpful for patients or families.
Prognosis
The prognosis depends on the type of congenital muscular dystrophy. Respiratory insufficiency and brain pathology are the main causes of mortality.

                            Last update:
                            September 2009

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


Congenital myasthenic syndrome (CMS) is a group of genetic disorders of impaired neuromuscular transmission at the motor endplate characterized by fatigable muscle weakness.


Congenital myopathy with excess of thin filaments

A rare, genetic, congenital myopathy disorder characterized by variable degrees of muscular weakness, frequently associated with severe nemaline myopathy-like disease (including neonatal hypotonia, lack of spontaneous movements, feeding and swallowing difficulties, frequent respiratory infections, respiratory insufficiency, early death), and histopathologic findings of large, densely packed, subsarcolemmal accumulations of thin, actin-immunopositive filaments (with or without intranuclear nemaline rods) on muscle biopsy.


Congenital myopathy with internal nuclei and atypical cores is a rare genetic skeletal muscle disease characterized by neonatal hypotonia, distal more than proximal muscle weakness, progressive exercise intolerance with prominent myalgias, and mild-to-moderate overall motor impairment with preserved ambulation. Face, extraocular, cardiac, and respiratory muscles are unaffected. Mild cognitive impairment is also noted in most patients.


Congenital myopathy with myasthenic-like onset is a rare, genetic, non-dystrophic myopathy characterized by fatigable muscle weakness associated with congenital myopathy. Patients present with axial hypotonia, myopathic facies with fatigable ptosis, feeding difficulties, delayed gross motor development and proximal limb weakness with a RYR1-related typical pattern of muscle involvement (i.e. severe involvement of the soleus muscle and sparring of the rectus femoris, sartorius, gracilis and semitendinous muscles). Scoliosis and frequent respiratory tract infections are additional observed features.


Congenital myopathy with reduced type 2 muscle fibers

A rare congenital myopathy characterized by neonatal onset of severe muscle weakness with selective atrophy/hypotrophy or absence of type II myofibers. Patients present at birth with hypotonia and respiratory failure, as well as mild facial and severe axial and proximal upper and lower limb weakness with areflexia and mild contractures. Eye movements and cardiac function are normal.


A rare congenital muscular dystrophy characterized by early onset of hypotonia, delayed motor development, and variably progressive generalized muscle weakness. Predominant involvement of pelvic and neck flexor muscles has been reported, as well as early involvement of hamstrings and medial gastrocnemius visible on muscle MRI. Serum creatine kinase levels are markedly elevated (in some cases already from early childhood). Muscle biopsy shows absence of dysferlin.


Congenital nephrotic syndrome, Finnish type

A rare congenital nephrotic syndrome characterized by massive protein loss and marked edema manifesting in utero or during the first 3 months of life.

Summary:
Epidemiology
This type of nephrotic syndrome is more frequent in Finland with a prevalence of 1/8,200 births. The disease is observed in various ethnic groups worldwide but the prevalence is unknown.
Clinical description
Affected children show massive proteinuria and edema starting in utero (fetal hydrops). Children usually have low birth weight and are born prematurely; the weight of the placenta constitutes more than 25% of the birth weight. Severe nephrotic syndrome develops soon after birth; typical features include hypoalbuminemia, hyperlipidemia, hypothyreosis, abdominal distension and edema with associated failure to thrive, increased susceptibility to thromboembolic events and severe infections. Histologically, microcystic dilatations of the tubules are seen whereas glomeruli are only slightly modified initially, with variable mesangial cell hypercellularity and/or endocapillary hypercellularity. Electron microscopy shows glomerular effacement of the podocytes.
Etiology
The disease is caused by recessive mutations in the NPHS1 gene (19q13). NPHS1 encodes for Nephrin, a zipper-like protein, which is essential for the porous structure of the glomerular slit diaphragm. To date more than 200 NPHS1 mutations have been detected but two of them have a particular high frequency in affected Finnish children, one is a two base pair deletion in exon 2 resulting in a truncated protein (Fin-major) and the other is a nonsense mutation in exon 26 (Fin minor). These two mutations are observed in 94% of Finnish patients but are quite rare outside Finland.
Diagnostic methods
The diagnosis is suspected on clinical grounds and confirmed by genetic analysis.
Differential diagnosis
Differential diagnoses include other forms of early onset nephrotic syndrome, including Denys Drash syndrome, Pierson syndrome, Galloway Mowat syndrome, Schimke immuno-osseous dysplasia and congenital membranous nephropathy due to maternal anti-neutral endopeptidase alloimmunization.
Antenatal diagnosis
Antenatal proteinuria results in an up to 10-fold increase in alpha-fetoprotein concentrations as early as in the 15th week of gestation, with a parallel but smaller rise in the maternal serum level. However, heterozygous mutations in the NPHS1 gene can also lead to increased levels of alpha-fetoprotein, leading to misdiagnosis. Reliable antenatal diagnosis is achieved by gene analysis on a trophoblastic sample.
Genetic counseling
The pattern of disease transmission is autosomal recessive. The risk of recurrence in siblings of an affected individual is 25%.
Management and treatment
The nephrotic syndrome does not respond to any immunosuppressive therapy and treatment is largely symptomatic, comprising frequent albumin infusions, protein-rich diet, anti-proteinuric pharmacotherapy with RAS (renin-angiotensin system) inhibitors and indomethacin, anticoagulation, thyroid hormone supplementation and aggressive treatment of infections. In case of failure to thrive despite these measures, uni- or bilateral nephrectomy may be necessary to stop the massive protein loss.
Prognosis
With adequate supportive care, most children survive long-term but develop end-stage kidney disease requiring renal replacement therapy within the first 2-3 years of life. Five-year patient and graft survival after transplantation is around 90%, similar as in infants with other causes of end-stage kidney disease. Post-transplant disease recurrence is limited to patients who are homozygous for the Fin major mutation, who have a 30% risk to develop de novo glomerulonephritis due to circulating anti-nephrin antibodies.

                            Last update:
                            June 2019

                            - Expert reviewer(s):
                            Pr Franz SCHAEFER | ERKNet*

                                * European Reference Network


A rare, genetic, primary immunodeficiency disorder characterized by severe congenital neutropenia, bone marrow fibrosis and neutrophil dysfunction which is refractory to granulocyte colony-stimulating factor, manifesting with life-threatening infections and/or deep-seated abscesses, hepato-/splenomegaly, thrombocytopenia, hypergammaglobulinemia, anemia with reticulocytosis and nephromegaly. Other reported features include osteosclerosis and neurological abnormalities (e.g. developmental delay, cortical blindness, hearing loss, thin corpus callosum or dysrhythmia on EEG).


A rare ophthalmic disorder with cranial nerve involvement characterized by partial or complete ptosis and ophthalmoplegia with impaired ability to elevate, depress, or adduct the eyeball, causing strabismus and amblyopia. The pupils can also be dilated. The condition is typically unilateral and may present with or without aberrant regeneration.


Congenital osteogenesis imperfecta-microcephaly-cataracts syndrome

A rare multiple congenital malformations/dysmorphic syndrome characterized by osteogenesis imperfecta with multiple prenatal bone fractures, joint laxity, severe microcephaly, and bilateral cataracts. Additional reported manifestations include dysmorphic facial features (such as blue sclerae, hypertelorism, and low-set ears), lissencephaly, hydrocephalus, and cardiac and genital anomalies. The syndrome is lethal in utero or shortly after birth. There have been no further descriptions in the literature since 1978.


A rare pancreatic disease characterized by a most commonly single, unilocular, thin-walled cystic lesion which may be located anywhere within the pancreas (but is more frequently found in the body and tail) and does not communicate with the pancreatic ductal system. Patients may be asymptomatic or present with signs and symptoms of gastrointestinal or biliary obstruction, or pancreatitis. The condition can be isolated or occur in association with other anomalies (such as von Hippel-Lindau disease or polycystic kidney disease).


Congenital panfollicular nevus is a rare, benign, skin tumor disorder characterized by the presence of congenital, large (few centimeters), elevated, well-circumscribed, pink-tan, multinodular, non-ulcerative, bosselated-surface skin lesions located on the neck, scalp or hand and which enlarge with time. Histologically, hamartomatous proliferation containing irregularly arranged, malformed hair follicles in various stages of development, surrounded by fibrous tissue and densely distributed within the dermis is observed.


Congenital partial agenesis of pericardium is a rare, mostly asymptomatic, congenital heart malformation mainly characterized by the partial absence of the left pericardium. It is occasionally associated with chest pain or dyspnea and is usually incidentally diagnosed during surgery or at autopsy. Herniation and strangulation of a portion of the heart through the pericardial foramen may occur, resulting in myocardial acute ischemia and possible sudden death. Right side pericardium involvement is rare.


Congenital partial pulmonary venous return anomaly

A form of congenital pulmonary venous return where one or a few of the pulmonary veins drain into the right atrium or one of its tributaries instead of the left atrium. Some patients can be asymptomatic while others can manifest with non-specific signs such as frequent respiratory infections, fatigue and exertional dyspnea.


A rare congenital limb malformation characterized by permanent and manually irreducible lateral dislocation of the kneecap. It typically presents with flexion contracture of the knee, genu valgus, absent or dysplastic trochlear groove of the femur, external rotation of the tibia, and dysfunction of the extensor mechanism. The defect may be unilateral or bilateral and can occur as an isolated malformation, be associated with other malformations of the lower limb, or be part of a polymalformative syndrome.


Congenital patent ductus arteriosus aneurysm

A rare, congenital, arterial duct anomaly characterized by a saccular dilatation of the ductus arteriosus. It is often asymptomatic or presents shortly after birth with respiratory distress, stridor, cyanosis and/or weak cry. Complications, such as rupture, thromboembolism, infection, airway erosion and/or compression of the adjacent thoracic structures, can develop. Spontaneous resolution has been reported.


Congenital pericardium anomaly comprises a group of rare congenital cardiac malformations characterized by the complete (Congenital complete agenesis of pericardium) or partial absence of the pericardium (Congenital partial agenesis of pericardium), or by the presence of pericardial cysts (Pleuropericardial cyst) (see these terms).


Congenital plasminogen activator inhibitor type 1 deficiency

A rare hemorrhagic disorder due to a constitutional haemostatic factors defect characterized by premature lysis of hemostatic clots and a moderate bleeding tendency.

Summary:
Epidemiology
Congenital plasminogen activator inhibitor type 1 (PAI-1) prevalence and incidence remain unknown. Both partial and total PAI-1 deficiencies are extremely rare disorders. In the Amish community (Indiana, USA), eighteen homozygous patients with clinical symptoms and more than 100 heterozygous patients without bleeding symptoms have been reported to date. Additional cases have been reported from North America, Europe and Asia.
Clinical description
Clinical signs of congenital PAI-1 deficiency may appear in early childhood. Spontaneous bleeding is rarely observed, whereas easy bruising or moderate hemorrhage localized to the joints (knees, elbows), nose and gingiva are usually triggered by mild trauma. Menstrual bleeding may be severe, and prolonged bleeding after surgery is common. Hemorrhage is less frequent and less severe (or absent) in heterozygous individuals (partial deficiency) and clinical manifestations, if any, may appear late in life after a traumatic or surgical event.
Etiology
Affected patients carry one (heterozygote) or two (homozygote) alleles with a mutation in the SERPINE1 gene (7q22.1), resulting in partial or total antigenic PAI-1 deficiency. PAI-1 is the physiological inhibitor of tissue-type plasminogen activator (t-PA), the main source of intravascular fibrinolysis. PAI-1 deficiency is a quantitative defect; however, in some patients the protein is present but functionally inactive.
Diagnostic methods
The diagnosis is based on antigenic (ELISA) and functional (plasminogen activator inhibition test) assays of PAI-1. A genotype analysis may be necessary in family studies. Molecular genetic testing confirms the diagnosis.
Differential diagnosis
Differential diagnosis includes acquired PAI-1 deficiency and alpha2-antiplasmin deficiency.
Genetic counseling
Heterozygotes are asymptomatic carriers. Carrier testing must be performed for relatives of affected patients with the SERPINE1 genetic variant.
Management and treatment
Prompt diagnosis is essential since hemorrhages can be safely and efficiently treated with fibrinolysis inhibitors (epsilon amino-caproic acid or tranexamic acid), avoiding the use of blood and derivatives. Menstruation and pregnancy require special consideration with regard to diagnosis and treatment with antifibrinolytics.
Prognosis
The prognosis is generally good as bleeding can be prevented and controlled with antifibrinolytic treatment.

                            Last update:
                            August 2019

                            - Expert reviewer(s):
                            Dr Eduardo ANGLES-CANO  - Pr Aurora DE LA PEÑA


Congenital portosystemic shunt is a rare, congenital anomaly of the great veins characterized by an abnormal communication between one or more veins of the portal and the caval systems, resulting in complete or partial diversion of the portal blood away from the liver to the systemic circulation. Clinical manifestations include liver atrophy, hypergalactosemia without uridine diphosphate enzyme deficiency, hyperammonemia, encephalopathy (resulting in learning disabilities, extreme fatigability and seizures), pulmonary hypertension, hypoxemia from hepatopulmonary syndrome and benign or malignant tumours.


A rare genetic coagulation disorder characterized by the usually incidental laboratory finding of a prolonged activated partial thromboplastin time (aPTT) but normal prothrombin time, due to a deficiency of normal prekallikrein or the presence of nonfunctional prekallikrein. Most patients remain clinically asymptomatic, although an association with cardiovascular conditions (hypertension, myocardial infarction, other coronary artery diseases, and ischemic strokes) and venous thrombosis, as well as rare cases with increased bleeding tendency have been reported.


A rare developmental defect during embryogenesis characterised by an absence of the lens. CPAK can be associated with variable secondary ocular defects.

Summary:
Epidemiology
Congenital primary aphakia (CPAK) prevalance is unknown.
Clinical description
CPAK is a congenital eye defect presenting at birth with no lens formation, resulting from a failure of lens induction from the surface ectoderm and aborted lens development. CPAK is often associated with other ocular anomalies, including aplasia/dysplasia of the anterior segment of the eye, microphthalmia, glaucoma.
Etiology
CPAK is caused by variants in the FOXE3 gene. Most cases are autosomal recessive. It is important to note that both dominant and recessive variants in FOXE3 are associated with a variable mixed phenotype of developmental eye disorders including anterior segment dysgenesis, microphthalmia, Peters anomaly, sclerocornea, early-onset cataract, glaucoma and ocular coloboma.
Diagnostic methods
Molecular diagnosis can be made through genetic testing, for example whole exome/genome sequencing and can be validated by bi-directional Sanger sequencing. Clinical diagnosis can be made based on clinical examination and confirmed with ultrasound. Anterior segment ultrasound biomicroscopy may aid detection of co-existent anterior segment dysgenesis. Due to the association of CPAK and the rubella virus, a TORCH complex evalutation is also recommended.
Antenatal diagnosis
Transabdominal ultrasound at 23 weeks gestation has detected CPAK.
Genetic counseling
Genetic testing for FOXE3 variants will provide a molecular diagnosis. This yields information regarding carrier status and provide choices that would not otherwise be available to facilitate decision making for the patient and their family. Genetic testing is essential for defining inheritance patterns, carrier status and enabling effective genetic counselling with consequent implications for prenatal or pre-implantation genetic diagnosis.
Management and treatment
CPAK should be managed by specialists with expertise in the condition. Supportive measures for those with sight impairment include involvement of social services. Regular follow-up will be required to monitor progression of associated anterior segment dysgenesis and glaucoma with medical and surgical interventions where needed. Intraocular surgery is not advised unless steps are taken to avoid inflammatory membrane formation and subsequent retinal detachment. Regular refraction to reduce/prevent amblyopia. Genetic counselling should be offered to the family.
Prognosis
Early diagnosis will enable prompt supportive treatment.

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Dr Mariya MOOSAJEE  -  Hajrah SARKAR


A rare primary lymphedema characterized by bilateral, painless lower limb swelling present at birth. Prominent veins around the ankles and on the dorsa of the feet, dysplastic and upslanting toenails due to edema of the nailbed, and subtle dysmorphic facial features (such as high forehead, hypertelorism, depressed nasal bridge, mild bilateral ear dysplasia, and short neck) have also been described. The degree of lymphatic impairment is milder than in the otherwise clinically similar Milroy disease, as evidenced by slightly less severe lymphedema and significantly more uptake of tracers on lymphoscintigraphy.


A rare non-syndromic urogenital tract malformation characterized by a dilated ureter and normal bladder and bladder outlet. It may be obstructed, refluxing or unobstructed and not refluxing.

Summary:
Epidemiology
Prevalence is unknown, but primary megaureter (PM) is the second most common cause of neonatal hydronephrosis. The male to female ratio is nearly 4:1. The left side is more often affected than right (1.6-4.5 times). The incidence of obstructed megaureter is 1/10,000.
Clinical description
About half of cases are asymptomatic (most of these unobstructed nonrefluxing) and discovered on routine antenatal ultrasound. PM is usually diagnosed in children but may present in adults. Symptomatic PM presents with urinary tract infections (UTI), hydronephrosis, fever and abdominal and flank pain. Microscopic hematuria is frequent, may occur without infection and may indicate calculus formation. Patients rarely present with signs of renal failure. Bilateral PM occurs in ~20% of cases and is more likely in children presenting < 1 year old. In unilateral PM, the contra-lateral kidney is absent or dysplastic in 10-15% of patients. ''Obstructed PM'' is the term used when ureteral dilatation due to restricted urinary outflow will cause progressive renal deterioration if untreated.
Etiology
The cause is unknown. It may be due to high fetal urine outflow, changes in the ureter pre-/postnatal or transient anatomical obstructions that improve with postnatal development, such as ureteral folds. Refluxing PM is due to short or absent intravesical ureter, congenital paraureteric diverticulum or other derangement of the vesico-ureteric junction. Obstructed PM occurs when the aperistaltic juxtavesical segment is unable to transport urine at acceptable rates. The cause may be excessive collagen deposition, hypertrophy of ureter muscle, thick periureteral tissues or a circumferential segment devoid of muscle. PM is not known to be hereditary but families with multiple affected members were described.
Diagnostic methods
Diagnosis is based on clinical presentation and confirmed by US. Reflux is diagnosed using voiding cystourethrography. Diuretic renography evaluates urine transport dysfunction. Doppler US, MRI and pressure flow studies have been suggested to determine obstruction.
Differential diagnosis
Differential diagnoses include causes of secondary megaureter: polyuria (diabetes insipidus), infection, bladder outlet obstruction, neuropathic bladder, infravesical obstruction or extrinsic lesions.
Antenatal diagnosis
Scanning starts at 16-18 weeks of gestation and is repeated depending on the clinical findings. The 28th week is the most sensitive for UT evaluation. Attention must be paid to laterality and grade of dilatation, bladder volume and dynamic of emptying, sex, other malformations, amount of amniotic fluid and echogenicity of the kidneys.
Genetic counseling
At the moment, there is no evidence of genetic cause. Congenital PM can co-occur with other syndromic malformations for which genetic counseling may be indicated (e.g. prune belly, megacystis, Hirschsprung disease, Down syndrome, etc.).
Management and treatment
Antibiotic prophylaxis is started routinely in prenatally detected cases. For refluxing PM, medical management is appropriate during infancy and is continued depending on grade of vesicoureteral reflux and symptoms (UTI and/or renal scars). Surgery is recommended for persistent high-grade reflux in older children. There is no consensus about timing/type of correction; endoscopic subureteric injections of bulking agents or surgical ureteric reimplantation are possible. Nonrefluxing unobstructed PM usually does not require surgery; regular follow-up with antibiotic prophylaxis results in reduction of UT dilation and no deterioration of renal function in 85% of cases. For obstructed PM, surgery is only indicated in cases of significant impairment to urine flow, persistent pain, pyelonephritis, calculi or a decrease in renal function. Temporary endoscopic stenting (with/without previous balloon dilatation) or surgical reimplantation are the preferred options.
Prognosis
PM often resolve spontaneously within the first two years of life, with the maturation of the UT.

                            Last update:
                            June 2023

                            - Expert reviewer(s):
                            Pr Marco CASTAGNETTI  - Dr Giovanni MOSIELLO | EUROGEN*

                                * European Reference Network


Congenital progressive bone marrow failure-B-cell immunodeficiency-skeletal dysplasia syndrome

A rare multiple congenital anomalies/dysmorphic syndrome characterized by early-onset progressive bone marrow failure with anemia, leukopenia, mild thrombopenia, and myelodysplastic features, as well as non-hematologic manifestations, such as developmental delay, cataracts, facial dysmorphism, short stature, and skeletal anomalies. Immunodeficiency primarily affects B-cells and may lead to increased susceptibility to infections. Additional reported features include dry skin and eczema, cardiac anomalies, hearing loss, and reduction of cerebral volume on brain imaging.


Congenital pseudoarthrosis of the clavicle

A rare dysostosis of genetic origin characterized by a painless mass over the clavicle which is due to the failure of the union process of the ossification nuclei of the clavicle.

Summary:
Epidemiology
Currently, the reported incidence in UK is 1/17,500 livebirths and over 400 cases are described in literature. The condition is most likely underdiagnosed. No gender prevalence was observed.
Clinical description
The condition is a typically monolateral painless bulge in the mid-portion of the clavicle, which involves the right side in over 90% of cases. Association with cervicothoracic abnormalities (e.g. cervical ribs) is uncommon (<5%). Association with dextrocardia, in case of involvement of the left clavicle, is unproven.
Etiology
Etiology is unknown. Familial inheritance or syndromic association is sporadic (<3%).
Diagnostic methods
Diagnosis is usually made during the first years of life by clinical examination and confirmed by plain radiographs.
Differential diagnosis
Differential diagnosis includes obstetric fracture, post-traumatic nonunion, cleidocranial dysostosis and neurofibromatosis.
Antenatal diagnosis
No case of prenatal diagnosis is reported.
Genetic counseling
Genetic counseling is mainly recommended to rule out other similar conditions (cleidocranial dysostosis or neurofibromatosis).
Management and treatment
Surgical repair is recommended in case of pain and functional impairment; other indications include cosmetic issues. The most used surgical procedure consists of open debridement, refreshing of bone ends, fixation with pin or plate and autologous bone graft from iliac crest. The rate of successful union is close to 90%.
Prognosis
The condition is benign. Patients may remain asymptomatic during their entire life. The shoulder's range of movement is usually unimpaired, with no associated pain. In most cases it represents only an esthetic issue. Nevertheless, symptoms may have an apparent slight increase with age, although sufficient information regarding the natural history of the pathology during the adulthood is lacking, especially in untreated patients.

                            Last update:
                            December 2022

                            - Expert reviewer(s):
                            Dr Alessandro DEPAOLI  - Dr Giovanni TRISOLINO  - Dr Paola ZARANTONELLO


A rare bone development disorder characterized by abnormal bowing and subsequent non-healing fracture of the femur resulting in the formation of a false joint (pseudoarthrosis), which is already present at birth. The affected bone is shortened and angulated at the site of the pseudoarthrosis. Congenital hip dysplasia and absence of the patella have been reported in association.


Congenital pseudoarthrosis of the fibula

A rare bone development disorder characterized by abnormal bowing of the fibula with subsequent non-healing fractures and formation of a false joint (pseudoarthrosis), and instability and angulation at the pseudoarthrosis site. The defect is typically unilateral and often associated with pseudoarthrosis of the tibia and neurofibromatosis type 1.


Congenital pseudoarthrosis of the radius

A rare bone development disorder characterized by abnormal bowing of the radius and subsequent non-healing fracture with formation of a false joint (pseudoarthrosis), instability and angulation at the pseudoarthrosis site, and shortening of the forearm. Additional signs and symptoms include radial deviation in the wrist joint and limited pronation and supination of the forearm. Neurofibromatosis type 1, osteofibrous dysplasia, and bowing and pseudoarthrosis of the ulna are frequently associated.


A rare bone development disorder characterized by mostly anterolateral bowing of the tibia usually evident at birth, with subsequent non-healing fractures and formation of a false joint (pseudoarthrosis), and instability and angulation at the pseudoarthrosis site. In the vast majority of patients the defect is unilateral, and more than half of the cases are associated with neurofibromatosis type 1.


A rare bone development disorder characterized by abnormal bowing of the ulna and subsequent non-healing fracture with formation of a false joint (pseudoarthrosis), instability and angulation at the pseudoarthrosis site, and shortening of the forearm. Additional signs and symptoms include concomitant bowing of the radius, abnormalities of the humeroulnar joint, and limited pronation or supination of the forearm. Neurofibromatosis type 1 and osteofibrous dysplasia are frequently associated.


Congenital ptosis is characterized by superior eyelid drop present at birth.

Summary:
Epidemiology
Prevalence is unknown.
Etiology
Isolated congenital ptosis is unilateral in 75% of the cases.
Genetic counseling
Two patterns of inheritance have been described in familial cases: autosomal dominant and X-linked.
Management and treatment
A medical or surgical treatment can potentially be proposed, depending on the severity of ptosis.

                            Last update:
                            April 2007


Congenital pulmonary airway malformation type 0

A rare subtype of congenital pulmonary airway malformation characterized by global arrest of lung development with small, solid appearing lungs with a diffusely granular surface, histologically featuring bronchus-like structures with smooth muscle, glands, and numerous cartilage plates, embedded in loose, vascular mesenchymal tissue. The condition presents at birth and is incompatible with life.


Congenital pulmonary airway malformation type 1

A rare subtype of congenital pulmonary airway malformation characterized by a multicystic mass of non-functioning lung tissue with one or more dominant cysts of 2 to 10 cm in diameter, which may be surrounded by smaller cysts. The lesions have intracystic communications, can be connected to the tracheobronchial tree, and are usually unilateral, involving a single lobe. Small lesions may remain asymptomatic, while most cases present with respiratory distress in the neonatal period or in infancy, or with recurrent respiratory infections later in life. Pulmonary hypoplasia and severe fetal hydrops are rare complications. The condition is associated with an increased risk of pulmonary malignancy, such as bronchoalveolar carcinoma.


Congenital pulmonary airway malformation type 2

A rare subtype of congenital pulmonary airway malformation characterized by a multicystic mass of non-functioning lung tissue, consisting of small cysts of less than 2 cm in diameter. The lesions have intracystic communications, can be connected to the tracheobronchial tree, and are usually unilateral, involving a single lobe. The condition often presents with respiratory distress in the neonatal period or in infancy. It is frequently associated with other severe congenital anomalies, such as renal agenesis or dysgenesis, pulmonary sequestration, or cardiac abnormalities.


Congenital pulmonary airway malformation type 3

A rare subtype of congenital pulmonary airway malformation characterized by a multicystic mass of non-functioning lung tissue consisting of numerous microcysts of less than 0.5 cm in diameter. The lesions have intracystic communications, can be connected to the tracheobronchial tree, and are usually unilateral, involving an entire lobe. The condition may be associated with polyhydramnios, fetal hydrops, and stillbirth, or present with severe respiratory distress in the neonatal period.


Congenital pulmonary airway malformation type 4

A rare subtype of congenital pulmonary airway malformation characterized by a multicystic mass of non-functioning lung tissue, with peripheral, large, thin-walled, often multiloculated cysts, which may be 8 cm in diameter. The lesions have intracystic communications, can be connected to the tracheobronchial tree, and are usually unilateral, involving a single lobe. Patients present with respiratory distress or respiratory infections in the neonatal period or in infancy. The condition is often associated with tension pneumothorax, signs of mediastinal shift, and malignant transformation to pleuropulmonary blastoma type 1.


Congenital pulmonary airway malformation

A rare respiratory malformation characterized by a hamartomatous mass of non-functioning lung tissue of variable extent and with variable degrees of cystic or adenomatoid change. Clinical presentation, prognosis, and presence of associated abnormalities depend on the subtype of the lesion. Based on histopathological findings, five subtypes (types 0 to 4) can be differentiated.


A rare developmental disorder involving the lung and characterized by pulmonary subpleural, interlobar, perivascular, and peribronchial lymphatic dilatation.

Summary:
Epidemiology
The prevalence is unknown.
Clinical description
Congenital pulmonary lymphangiectasia (PL) presents at birth with severe respiratory distress, tachypnea and cyanosis, with a very high mortality rate at or within a few hours of birth.
Etiology
Most reported cases are sporadic and the etiology is not completely understood. It has been suggested that PL lymphatic channels of the fetal lung do not undergo the normal regression process at 20 weeks of gestation. Secondary PL may be caused by a cardiac lesion.
Diagnostic methods
The diagnostic approach includes obtaining a complete family and obstetric history, conventional radiologic studies, ultrasound and magnetic resonance studies, lymphoscintigraphy, lung functionality tests, lung biopsy, bronchoscopy, and pleural effusion examination.
Differential diagnosis
During the prenatal period, all causes leading to hydrops fetalis should be considered in the diagnosis of PL.
Antenatal diagnosis
Fetal ultrasound evaluation plays a key role in the antenatal diagnosis of PL.
Management and treatment
At birth, mechanical ventilation and pleural drainage are nearly always necessary to obtain a favorable outcome of respiratory distress. Home supplemental oxygen therapy and symptomatic treatment of recurrent cough and wheeze are often necessary during childhood, sometimes associated with prolonged pleural drainage.
Prognosis
Recent advances in intensive neonatal care have changed the previously nearly fatal outcome of PL at birth. Patients affected by PL who survive infancy, present medical problems which are characteristic of chronic lung disease.

                            Last update:
                            October 2006

                            - Expert reviewer(s):
                            Dr Carlo BELLINI  - Pr Francesco BOCCARDO  - Pr Eugenio BONIOLI  - Pr Corradino CAMPISI


Congenital pulmonary sequestration is a rare respiratory malformation characterized by a cystic or solid mass of nonfunctioning primitive segmental lung tissue that does not communicate with the tracheobronchial tree and has anomalous systemic blood supply. Intralobar pulmonary sequestration may be asymptomatic or may present with recurrent pulmonary infections, hemoptysis, chest pain, cough and is usually diagnosed in older children and adults. Extralobar pulmonary sequestration present with respiratory distress, cyanosis, difficulty feeding or infection, may be associated with other anomalies and is mostly diagnosed in neonates or infants.


A rare congenital heart malformation characterized by an obstruction to flow through the pulmonary valve with a clinical presentation that may vary from critical stenosis presenting in the neonatal period to asymptomatic mild stenosis. The obstruction at the valvular level can be associated with obstruction at the subpulmonary, or supravalvar levels (valvar, subpulmonary, supravalvar pulmonary stenosis (PS).

Summary:
Epidemiology
The birth prevalence of isolated pulmonary valvar stenosis is between 1/2,000-10,000 in Europe and, worldwide, accounts for between 5-8% of children born with a congenital heart defect (CHD).
Clinical description
Clinical presentation varies according to age. In neonates, critical pulmonary stenosis is diagnosed on signs of right heart failure associated with cyanosis due to supra-systemic pressures and right-to-left shunt through the oval foramen, with ductal dependency. In severe untreated forms, dyspnea or syncope on exercise can occur. However, most patients are asymptomatic and diagnosed on presentation of a heart murmur during infancy or childhood. Congenital pulmonary valvar stenosis is most often isolated, with usually thin leaflets, dome-shaped with a central narrow opening. In 6% of children it is associated with a genetic syndrome, with usually thick, dysplastic leaflets. The malformation can also be associated with several complex malformations such as double outlet right ventricle, transposition of the great arteries, and Ebstein anomaly of the tricuspid valve.
Etiology
The etiology for isolated forms is unknown. Occasionally the malformation is associated with a genetic syndrome (typically the RASopathies) such as Noonan, LEOPARD or Costello syndromes, harboring mutations of gene PTPN11.
Diagnostic methods
Echocardiography is the best diagnostic tool. It establishes the diagnosis, looks for other levels of right ventricular outflow tract obstruction, and usually provides sufficient information to plan the treatment. CT-scan or MRI can be useful to assess the anatomy of the subpulmonary infundibulum and pulmonary branches.
Differential diagnosis
Differential diagnosis includes primary pulmonary causes of cyanosis in neonates, along with other cyanotic heart lesions, such as transposition of the great vessels and tetralogy of Fallot.
Antenatal diagnosis
Diagnosis on prenatal ultrasound screening is possible but is only detected in approximately 40% of cases; the rate of detection could be improved by the use of color flow Doppler through the outflow tracts.
Genetic counseling
The risk of recurrence of isolated valvar pulmonary stenosis is low, ranging from 1.7 to 3.7%. Relative risk of recurrence of right ventricular outflow tract obstruction as a whole is high at 48.6%.
Management and treatment
Percutaneous balloon valvuloplasty is the treatment of choice of isolated valvar pulmonary stenosis. When the valve is dysplastic with thickened leaflets, or when there is an associated subvalvar or supravalvar obstruction, surgical valvulotomy or valvulectomy is indicated.
Prognosis
The prognosis of mild forms of valvar pulmonary stenosis is good, with stability or even spontaneous decrease of the gradient with age. The prognosis after balloon valvuloplasty is usually excellent. In rare cases of residual or recurrent pulmonary stenosis, a second balloon valvuloplasty can be attempted with good success rates. If it fails, surgery is indicated. Severe pulmonary regurgitation at late follow-up is rare and may require pulmonary valvar replacement, percutaneous or surgical.

                            Last update:
                            February 2021

                            - Expert reviewer(s):
                            Pr Lucile HOUYEL


Congenital pulmonary veins atresia or stenosis

A rare progressive and life-threatening anomaly of the great vessels characterized by narrowing and obstruction of one or more normally positioned pulmonary vein at their junction with the left atrium. Presentation is typically during early infancy with dyspnea, tachypnea, and repeated pulmonary infections. Eventually, when all pulmonary veins of one lung are affected, the disorder results in pulmonary hypertension (PH) and consecutive pulmonary arterial hypertension (PAH). It may manifest as an isolated lesion or associated with other cardiac defects such as congenital pulmonary venous return anomaly and septal defects.


Congenital pulmonary venous return anomaly

A rare developmental defect during embryogenesis where some or all of the pulmonary veins drain into the right atrium or the systemic veins, with or without the presence of pulmonary venous obstruction, leading to various manifestations such as fatigue, exertional dyspnea, pulmonary arterial hypertension, cyanosis and progressive congestive heart failure. The two main subtypes are congenital partial pulmonary venous return anomaly (PAPVC; see this term), where one or a few of the pulmonary veins are anomalous, and congenital total pulmonary venous return anomaly (TAPVC, see this term), where all of the pulmonary veins are anomalous.


A rare renal disease characterized by congenital unilateral or bilateral narrowing of the renal artery leading to severe arterial hypertension and progressive renal failure in the neonate. Manifestations include hypertensive encephalopathy and/or neurological signs and symptoms due to hyponatremia, polyuria, renal electrolyte loss, proteinuria, and hematuria.


Congenital respiratory-biliary fistula (RBF) is a rare developmental defect characterized by an anomalous connection of trachea or bronchus with left hepatic duct presenting with respiratory distress, recurrent respiratory infections and biliary expectoration or vomitus.


Congenital retinal arteriovenous communication

A rare neurovascular malformation characterized by a unilateral, direct communication between the arterial and venous system in the retina via abnormal, enlarged vessels, but without interposed capillaries. The inferotemporal vasculature is most commonly affected. Patients may be asymptomatic or present with variable degrees of visual loss. Local vascular complications include vascular occlusions or retinal or vitreous hemorrhages. The anomaly may occur in isolation or as part of Wyburn-Mason syndrome, in which intracranial (usually ipsilateral) arteriovenous malformations are present.


An infectious embryofetopathy that may present in an infant as a result of maternal infection early in pregnancy and subsequent fetal infection with rubella virus. The disorder can lead to deafness, cataract, and variety of other permanent manifestations including cardiac and neurological defects.

Summary:
Epidemiology
Congenital rubella syndrome (CRS) has been reported to affect an estimated 100,000 infants each year, mainly in developing countries.
Clinical description
Acquired during the first 8-12 weeks of gestation, rubella infection may cause multiple fetal defects (up to 90% of cases) including neurological (microcephaly), ophthalmic (cataracts, microphthalmia, glaucoma, pigmentary retinopathy, chorioretinitis), auditory (sensorineural deafness), cardiac (peripheral pulmonary artery stenosis, patent ductus arteriosus or ventricular septal defects, etc) defects and fetal wastage or stillbirth. Infection occurring later in gestation is associated with a decline in the risk of birth defects. Fetal defects are rarely associated with maternal rubella occurring after the 14th week of pregnancy, although sensorineural hearing deficit can occur with infection as late as week 20. Additional findings may include: meningoencephalitis, interstitial pneumonitis hepatitis with jaundice (within 24 hours after birth), hepatosplenomegaly, purpura, squint, congenital glaucoma and developmental delay. Infants with congenitally acquired infection may develop manifestations of late-onset disease in later childhood or as adults. Endocrine organs, eyes, hearing and central nervous system may be affected and autoimmune disorders and/or behavioral problems may occur.
Etiology
In pregnant women the virus infects the placenta and the developing fetus. Infants with CRS may excrete the virus for a year or more in pharyngeal secretions and urine.
Diagnostic methods
In the prenatal period, ultrasound examination may fail to diagnose CRS but molecular analysis performed on amniotic fluid (collected at least 6 weeks after maternal infection and after 21 weeks of gestation) will confirm or infirm congenital infection. World Health Organization has established diagnostic criteria. In the postnatal period, its classic triad of clinical signs may suspect CRS: cataract, heart disease, and deafness and confirmed by positive Rubella specific IgM in the newborn.
Differential diagnosis
Differential diagnosis of maternal rubella includes all infections responsible of maculo-papular rash (parvovirus B19, measles, streptococcus A, enteroviruses, cytomegalovirus (CMV), Epstein-Barr virus, human immunodeficiency virus) and other rashes from non infectious causes. Differential diagnosis of congenital rubella includes congenital infection with Toxoplasma gondii, enteroviruses, CMV, Herpes simplex virus, Varicella, Syphilis.
Management and treatment
To date, no treatment for rubella or CRS is available. In order to prevent CRS, vaccination of adolescent girls and women of childbearing age is recommended.
Prognosis
Prognosis of rubella congenital infection mainly depends on the term at maternal infection. Infected children surviving the neonatal period may face serious developmental disabilities (for example, visual and hearing impairments) and have an increased risk for developmental delay, including autism, type I diabetes mellitus and thyroiditis. A progressive encephalopathy resembling subacute sclerosing leukoencephalitis has been observed in patients with CRS.

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Dr Christelle VAULOUP-FELLOUS


Congenital short bowel syndrome is a rare intestinal disorder of neonates of unknown etiology. Patients are born with a short small bowel (less than 75 cm in length) that compromises proper intestinal absorption and leads chronic diarrhea, vomiting and failure to thrive.


Congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome

A form of constitutional sideroblastic anemia characterized by severe microcytic anemia, B-cell lymphopenia , panhypogammaglobulinemia and variable neurodegeneration. The disease presents in infancy with recurrent febrile illnesses, gastrointestinal disturbances, developmental delay, seizures, ataxia and sensorineural deafness.


Congenital smooth muscle hamartoma (CSMH) is a rare cutaneous hamartomatous lesion most often located on the lumbosacral area or proximal limbs (but rarely on atypical areas such as scalp, eyelid or foot) and characterized by a disorganized proliferation of smooth muscle fibres of arrector pili presenting usually as a localized skin-colored or hyperpigmented plaque (up to 10 cm in diameter) with prominent vellus hairs (most common classic form) or less commonly by multiple skin-colored papules that can coalesce to form irregularly shaped plaques. With time, hyperpigmentation and vellus hairs usually diminish and neither malignant transformation nor associated systemic involvement has been reported.


A rare, genetic, non-syndromic intestinal transport defect characterized by congenital onset of severe watery diarrhea containing high concentrations of sodium, hyponatremia and metabolic acidosis.

Summary:
Epidemiology
Whilst the prevelence is unknown, less than 50 cases of both the syndromic and non-syndromic form have been reported in the literature.
Clinical description
Presentation is typically prenatal with polyhydramnios, prominent abdominal distension due to dilated fluid-filled loops of the intestine. A watery diarrhea is present after birth, independent of oral feeding (breast or formula) or nil by mouth. The diarrhea can be described as 'non-stopping', and can be mistaken for urine. There are increased bowel sounds at examination, and passing of meconium is never reported. The infants become irritable and eventually apathetic, and develop moderate to severe dehydration. Rarely, there is no watery diarrhea noticed either due to severe dehydration or intestinal paralysis. This pseudo-obstruction is caused by dilated fluid-filled loops of intestine, which may result in volvulus, and the affected neonate typically undergoes abdominal surgery. Laboratory findings include high stool sodium levels (importantly, this can be normal when the depletion of body sodium has progressed for some time) and low serum sodium levels, metabolic acidosis and alkaline fecal pH, and low urinary sodium excretion. Histological findings include a structurally intact epithelium and brush border with a normal villus-to-crypt ratio.
Etiology
The classical (non-syndromic) form of the disorder is due to loss of function of the intestinal sodium/hydrogen exchanger 3 (NHE3; encoded by SLC9A3, 5p15.33), resulting in abrogated sodium absorption, enhanced fluid secretion and diarrhea. Causal mutations have been identified in both SCL9A3 and GUCY2C, encoding an intestinal receptor guanylate cyclase C (GC-C) and for which activating mutations inhibit NHE3. In 40% of patients a genetic mutation has not yet been identified.
Diagnostic methods
Diagnosis is suspected on clinical presentation and exclusion of the differential diagnosis. Initial diagnosis might include determination of fecal sodium, chloride and potassium. Separate sampling of watery stool and urine should be performed. Diagnosis is confirmed by genetic testing.
Differential diagnosis
Differential diagnosis includes the syndromic form of congenital sodium diarrhea (due to SPINT2 mutations) which is typically distinguished by the presence of uni- or bilateral choanal atresia at birth. Other differential diagnoses include anatomical bowel obstruction, congenital chloride diarrhea (distinguished by excessive fecal chloride), glucose-galactose malabsorption (which exhibits a diet-induced dehydrating diarrhea with later onset), microvillus inclusion disease and congenital tufting enteropathy (distinguished by histopathology).
Antenatal diagnosis
Diagnosis may be suspected on presentation of polyhydramnios in the third trimester. Early, targeted genetic prenatal testing is possible after identifying disease-causing variants in an index patient; however, general concerns to sampling fetal material and diagnosing genetic conditions late in pregnancy would apply.
Genetic counseling
The pattern of inheritance is autosomal recessive for SLC9A3 mutations and autosomal dominant for GUCY2C mutations. The risk of disease transmission to offspring for autosmal recessive disease is 25% where both parents are unaffected carriers. GUCY2C mutations are most often of de-novo origin; so far, germline mosaicism in unaffected parents of such patients has not been reported, resulting in a very low recurrence risk for sibs of affected patients. If a parent is affected and carrier of the pathogenic GUCY2C mutation, the risk of transmission is 50%. Of note, a number of individuals with GUCY2C and SLC9A3 mutations developed inflammatory bowel disease.
Management and treatment
After birth, total parenteral nutrition for treatment of dehydration for at least several months is required. Sodium supplementation should be provided for treatment of severe dehydration and to maintain normal body growth by preventing total body sodium depletion. In certain cases, patients may be weaned off total parenteral nutrition. For monitoring adequate sodium supplementation, the fractional excretion of sodium (FENa) should be calculated (normal range reportedly between 0.5%-1.5%).
Prognosis
Affected individuals may continue to have mild watery diarrhea but otherwise tend to lead a normal life. Reported complications include growth delay and hypoaldosteronism.

                            Last update:
                            October 2020

                            - Expert reviewer(s):
                            Dr Andreas JANECKE  - Pr Thomas MÜLLER


Congenital stationary night blindness (CSNB) refers to a non-progressive group of retinal disorders characterized by night or dim light vision disturbance or delayed dark adaptation, poor visual acuity (ranging from 20/30 to 20/200), myopia (ranging from low (-0.25 diopters [D] to -4.75 D) to high (≥-10.00 D)), nystagmus, strabismus, normal color vision and fundus abnormalities.


Congenital stenosis of the inferior vena cava

A rare vascular anomaly characterized by congenital narrowing of the inferior vena cava mostly at the diaphragmatic level or hepatic segment, with or without web formation. Patients may present with deep vein thrombosis below the obstructed segment as well as swelling, pain, and varices of the lower extremities, abdominal pain/varices, or hematochezia. Presence of collateral veins between upper and lower segments of the stenosis, as well as venous aneurysms are typical associated findings.


Congenital stromal corneal dystrophy (CSCD) is an extremely rare form of stromal corneal dystrophy (see this term) characterized by opaque flaky or feathery clouding of the corneal stroma, and moderate to severe visual loss.

Summary:
Epidemiology
The exact prevalence of this corneal dystrophy is not known but it is very rare: CSCD has been reported in 4 families to date in Germany, France, Belgium and Norway.
Clinical description
Patients develop bilateral corneal lesions before birth. The flakes and spots become more numerous with age, progressively increasing the effect on vision. Corneal erosions, photophobia and corneal vascularization are absent. Some patients have strabismus or primary open-angle glaucoma.
Etiology
The etiology of this condition is not known but mutations in the DCN gene (12q23) which codes for decorin have been identified in affected patients. DCN codes for a protein that may affect the rate of fibril formation.
Diagnostic methods
The morphologic abnormalities observed in CSCD include a peculiar arrangement of tightly packed lamellae having highly aligned collagen fibrils of an unusually small diameter.
Genetic counseling
Transmission appears to be autosomal dominant.
Management and treatment
A penetrating keratoplasty is the treatment of choice.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Dr Gordon KLINTWORTH


A rare larynx anomaly characterized by a partial or complete narrowing of the upper airway extending from just below the vocal folds to the lower border of the cricoid cartilage. Clinical presentation is variable and includes recurrent, croup-like, upper respiratory infections, stridor, dyspnea, barking cough, and in most severe cases acute airway compromise at delivery. It may be an isolated finding, or associated with other congenital anomalies and syndromes.


A rare, genetic, congenital carbohydrate intolerance disorder characterized by lack of endogenous sucrase activity, marked reduction in isomaltase activity, and moderate decrease in maltase activity, and clinically manifesting with diarrhea, abdominal pain and bloating, failure to thrive.

Summary:
Epidemiology
The prevalence for the classical type in the European population is estimated at 1/5,000 but it is higher among the indigenous populations of Alaska, Greenland and Canada. Many cases are probably undiagnosed, especially in patients with milder phenotypes.
Clinical description
Onset is usually after weaning from breast milk or lactose-only formula to foods containing sucrose and/or starch. Clinical manifestations include osmotic diarrhea, abdominal bloating and discomfort, flatulence and vomiting. This may result in failure to thrive, dehydration and malnutrition. Mildly affected individuals may present with irritable bowel syndrome and loose/frequent stools. Symptom severity depends on residual sucrase and isomaltase activity, as well as the amount of sugar and starch consumed, and thus onset may be later in life. CSID may coexist with other disaccharidase deficiencies (e.g. lactase, maltase-glucoamylase and/or peptidase deficiencies).
Etiology
CSID is caused by mutations in genes encoding the brush-border membrane complex, sucrase-isomaltase (SI), which is required for the breakdown of sucrose and starch into monosaccharides. These can then readily be absorbed in the gut facilitated by specific monosaccharide transporters. Amylase (salivary and pancreatic) facilitates the limited digestion of nutritional starch leading to oligomers but debranching has to be catalyzed by isomaltase. The SI deficiency results in an accumulation of disaccharides and glucose-oligomers in the lumen of the gut, causing the abdominal symptoms.
Diagnostic methods
Diagnosis may be suspected after presentation with osmotic diarrhea, bloating, abdominal pain and failure to thrive. Duodenal or jejunal mucosal biopsy and assay of disaccharidases is the 'gold standard' diagnostic technique. Samples must be immediately frozen and transported frozen to the analytical lab as preanalytical errors result in false positive findings. Presumed diagnosis can be made by a flat sucrose tolerance test and development of gastrointestinal symptoms, or via the 13C-sucrose breath hydrogen test, which is neither specific nor sensitive. Genetic testing is both an alternative and a supplement to enzymatic studies.
Differential diagnosis
Differential diagnosis includes the numerous causes of chronic diarrhea (allergic gastroenteropathy, celiac disease, Crohn's disease, irritable bowel syndrome, infection, severe gastro-enteritis, cystic fibrosis, diverticulitis, lactose intolerance, glucose-galactose intolerance, and fructose intolerance) as well as secondary causes of sucrase-isomaltase deficiency (medication, environmental).
Antenatal diagnosis
Prenatal diagnosis is possible when there is an index case. Due to relatively good treatment options and outcome, prenatal diagnosis is rarely indicated.
Genetic counseling
CSID is transmitted as an autosomal-recessive or autosomal-dominant trait. Offspring of affected individuals are obligate carriers. Heterozygous carriers may also experience symptoms like irritable bowel syndrome.
Management and treatment
Treatment used to be based on a strict sucrose- and starch-restricted diet. However, this is challenging and mostly still associated with CSID- symptoms. Regular consultation with a dietician is strongly recommended. Adjuvant enzyme replacement therapy (ERT) with sacrosidase is recommended to aid in sucrose digestion. The amount of enzyme given has to be titrated based on the residual sucrose activity and the amount of sucrose in the diet. However, sacrosidase ERT does not correct starch maldigestion, patients under sacrosidase treatment are often not symptom-free and still have to stick to starch restriction. Other tailor-made enzyme preparations distributed by specialized pharmacists contain a combination of sacrosidase, amylase and amyloglucosidases, and facilites the complete digestion of starch to monomers. Vitamin supplementation is typically required in infants and children.
Prognosis
Dietary restriction typically reduces symptoms, but is not sufficient in most patients. Treatment with sacrosidase is effective but not able to mediate starch digestion, and starch-restriction is still necessary. Improved enzyme replacement therapy limits the need for starch restriction in many patients and, frequently, a normal unrestricted diet is possible.

                            Last update:
                            September 2020

                            - Expert reviewer(s):
                            Pr Anibh Martin DAS


Congenital supravalvular mitral ring is a rare, congenital, mitral valve malformation characterized by an abnormal ridge of the connective tissue on the atrial side of the mitral valve, which can present clinically with signs and symptoms of left ventricle inflow obstruction (dyspnea, tachypnea, pulmonary hypertension, right ventricle hypertrophy, pulmonary edema). Association with other mitral valve anomalies, aortic stenosis, ventricular septal defect, patent ductus arteriosus, double-outlet right ventricle, pulmonary hypertension, and Shone complex has been reported.


A rare teratologic disease caused by vertical transmission of the spirochete Treponema pallidum from an infected mother to the fetus, characterized by early congenital syphilis during the first two years of life (maculopapular rash progressing to desquamation, hepatosplenomegaly, osteochondritis, snuffles, and iritis), followed by late congenital syphilis with the classic Hutchinson's triad of Hutchinson's teeth, interstitial keratitis, and eighth nerve deafness. Additional signs may include saddle nose, saber shins, seizures, and mental retardation. Congenital syphilis can also result in stillbirth, neonatal death, and nonimmune hydrops.


Congenital systemic arteriovenous fistula is a rare, potentially life-threatening, vascular malformation characterized by a direct communication between an artery and a vein, without the interposition of the capillary bed, ocurring in the systemic circulation (mainly the cranium, liver, lungs, extremities, and vessels in or near the thoracic wall). Manifestations are variable depending on size and extent of the fistula, the involved blood vessels and the precise location of the collaterals and may include systolic or continuous murmur over the affected organ, tachycardia, increased stroke volume, cardiomegaly and increased pulmonary vascular markings.


Congenital temporomandibular joint ankylosis is a rare maxillofacial disorder characterized by significant reduction in mouth opening (i.e. from a few millimeters to a few centimeters) in the absence of acquired factors (e.g. trauma, infection) contributing to the ankylosis. It is associated with variable degrees of facial dysmorphism (i.e. lateral deviation of the mandible and chin, lower facial asymmetry, retrognathia, micrognathia, dental malocclusion) and patients typically present with feeding and breathing difficulties. Developmental delay, hypotonia, seizures, and additional dysmorphic features (e.g. pectus excavatum, low-set ears, hypoplastic alae nasi) have also been reported.


Congenital thrombotic thrombocytopenic purpura

A hereditary form of thrombotic thrombocytopenic purpura (TTP) characterized by profound peripheral thrombocytopenia, microangiopathic hemolytic anemia (MAHA) and single or multiple organ failure of variable severity.

Summary:
Epidemiology
Congenital TTP is much less common than the immune-mediated form of the disease (immune-mediated TTP), accounting for up to only 5% of all TTP cases. Up until 2017, 123 cases had been reported by the International Hereditary Thrombotic Thrombocytopenic Purpura Registry. The annual incidence is estimated at less than 1/1,000,000.
Clinical description
The majority of patients present during the neonatal period or during childhood but the clinical manifestations are highly variable with mild manifestations of isolated thrombocytopenia throughout childhood in some, and severe neonatal hyperbilirubinemia with episodes of thrombocytopenia and MAHA developing soon after birth in others. In addition, onset may also occur during adulthood, particularly in women when the initial episode of overt TTP is triggered by the first pregnancy. Infections and vaccinations are also precipitating factors. The clinical course in congenital TTP is characterized typically by more long term relapses than in the immune-mediated form (iTTP), with around 50% of congenital TTP patients developing chronic, frequently relapsing disease. As in immune-mediated TTP, patients may also develop neurological anomalies, renal manifestations, cardiac dysfunction and gastrointestinal symptoms due to widespread microvascular thrombosis.
Etiology
Congenital TTP is caused by a mutation in the ADAMTS13 gene (9q34), encoding ADAMTS13, a metalloprotease involved in the cleavage of ultra-large von Willebrand factor multimers with a penetrance of over 90%. Mutations are mainly compound heterozygous and less commonly homozygous, which explains the varied age of onset and severity/frequency of episodes seen in patients with congenital TTP.
Diagnostic methods
A diagnosis of TTP should be considered in all patients with thrombocytopenia and microangiopathic hemolytic anemia. A positive familial history, laboratory studies (revealing schistocytes on peripheral blood smears, high serum lactate dehydrogenase levels, low platelet counts and reticulocytosis) and a severe ADAMTS13 deficiency (< 10% of normal values), in the absence of anti-ADAMTS13 antibodies, suggests a diagnosis of congenital TTP. Diagnosis is confirmed by molecular analysis revealing a double heterozygous or homozygous mutation in the ADAMTS13 gene.
Differential diagnosis
In pregnant patients, congenital TTP needs to be distinguished from iTTP, atypical hemolytic-uremic syndrome and HELLP syndrome.
Genetic counseling
Congenital TTP is transmitted in an autosomal recessive manner. Genetic counseling should be provided to affected families. Women diagnosed with congenital TTP should also receive pregnancy counseling in order to inform them of the major risk of TTP exacerbations and to allow for the timely planning of a management strategy (from conception to post-partum period), which mainly includes a prophylactic plasmatherapy. Screening of siblings for ADAMTS13 activity is also recommended.
Management and treatment
Acute episodes in congenital TTP can be treated by plasma infusion (10-15 ml/kg/day until remission) but exchange transfusion is usually required in newborns. Patients with a chronic relapsing disease course may be considered for prophylactic plasma therapy. Regular plasma infusions to maintain ADAMTS13 activity level around 15% are required during pregnancy, in addition to close clinical and biological monitoring by a reference center. During the third trimester, therapeutic plasma exchanges may be required to prevent fluid overload.
Prognosis
In the absence of treatment, TTP is a rapidly fatal disease (mortality rate > 90%). The introduction of therapeutic plasma exchange and plasma infusion has led to a decrease in the mortality rate to around 15%. Plasmatherapy also prevents long term organ complications due to chronic relapses.

                            Last update:
                            November 2020

                            - Expert reviewer(s):
                            Pr Paul COPPO


Congenital total pulmonary venous return anomaly

A form of congenital pulmonary venous return where all of the pulmonary veins drain into the right atrium or one of its tributaries, instead of the left atrium, leading to various manifestations such as fatigue, exertional dyspnea, pulmonary arterial hypertension, cyanosis and progressive congestive heart failure.


A rare fetopathy characterized by ocular, visceral or intracranial lesions secondary to maternal primary infection by Toxoplasma gondii (Tg).

Summary:
Epidemiology
Given its infectious origin, incidence of congenital toxoplasmosis (CTX) is variable over time and geographically. Screening policies and methods also influence prevalence calculation. Prevalence at birth is estimated to be 0.5 to 1.6/10 000 in Europe.
Clinical description
Clinical presentation is highly variable. Earlier infection is generally more severe but less frequent. Infections in the first trimester may result in miscarriage or fetal death in utero, whereas later ones may be limited to ocular anomalies. Intracranial calcifications, micro- or macrocephaly, ventricular dilatation and hydrocephalus, hepatomegaly, splenomegaly, cardiomegaly, ascites and intrauterine growth retardation can be observed in infected fetuses. When present, clinical manifestations at birth are maculopapular rash, jaundice, generalized lymphadenopathy, organomegaly, central nervous system anomalies and hyperbilirubinemia, anemia, and thrombocytopenia. The first neurologic manifestations are hypotonia, seizures, nystagmus, and, later, delay of developmental milestone acquisition can be seen. The triad of chorioretinitis, intracranial calcifications and hydrocephalus is present in at least 10% of clinical cases. Ocular involvement involves most frequently chorioretinitis, followed by microphthalmia and strabismus. New lesions of chorioretinitis or relapses may develop after months or years: Visual impairment is highly dependent on the parasite genotype, and probably on prenatal and postnatal treatments.
Etiology
CTX is caused by the mother's primary infection by Tg, an intracellular protozoan parasite of the Apicomplexa phylum, and the trans-placental infection of the fetus. Nearly 25% of exposed fetuses are infected. Mother is infected by Tg through ingestion of oocysts present in cat feces and soil, or of cysts present in uncooked meat.
Diagnostic methods
Diagnosis of pergravidic maternal infection is based on the detection of 1) a true seroconversion with appearance of IgG in a woman previously known to be uninfected, or if the first serology is already positive of 2) of a significant increase in IgG in the context of high IgM titters. The diagnosis of congenital toxoplasmosis relies on the detection of Tg DNA in amniotic fluid or in other products, or of a neosynthesis of IgG, IgM or IgA in the child after birth. Persistence of anti-Toxoplasma IgG at one year of age is considered as the gold standard for congenital toxoplasmosis diagnosis. RT-PCR targeting repetitive DNA segments should be used for the molecular diagnosis of congenital toxoplasmosis. Diagnosis of maternal and congenital infections should be confirmed by expert laboratories.
Differential diagnosis
Differential diagnosis includes other congenital infections (rubella, CMV, HSV1 and HSV2, regrouped with Tg infection in the TORCH syndrome) and pseudo-TORCH and Aicardi-Goutières syndromes.
Antenatal diagnosis
Fetal ultrasonography and/or magnetic resonance imaging (MRI) detect and characterize brain, cardiac or placental anomalies. Diagnosis is confirmed only with serological findings in the mother and with PCR findings of Tg infection the amniotic fluid. Fetal ultrasound examination should be repeated in the context of a proven maternal infection. Amniocentesis for PCR should be performed too, after 18 weeks of gestation, and at least 4 weeks after the mother's seroconversion to avoid false negative results. Ultrasound examinations should be more frequent if PCR on amniotic fluid is found to be positive.
Management and treatment
In several countries, a systematic serological status follow-up of each pregnant woman is organized in order to reduce the number of severely infected children. Seronegative pregnant women are tested regularly to detect seroconversion, with, if needed, a spiramycin-based treatment, expected to reduce vertical transmission. A pyrimethamine-sulphonamide combination is recommended in case of confirmed fetal infection. It is also used after 14 weeks of gestation to prevent vertical transmission. Neonates who are recognized as infected should also be treated even if they are asymptomatic at birth since complications may occur later. The benefits of prenatal and postnatal treatment remain to be quantified.
Prognosis
Prognosis is highly dependent on the parasite virulence, the gestational age at maternal infection and on the timing of prenatal and postnatal treatment.

                            Last update:
                            August 2020

                            - Expert reviewer(s):
                            Pr Martine WALLON


A rare malformation characterized by fixed narrowing of the tracheal lumen primarily due to complete tracheal cartilage rings and an absent membranous trachea, which causes breathing difficulty.


Congenital tracheomalacia is a rare condition where the trachea is soft and flexible causing the tracheal wall to collapse when exhaling, coughing or crying, that usually presents in infancy, and that is characterized by stridor and noisy breathing or upper respiratory infections. Tracheomalacia improves by the age of 18-24 months.


A rare congenital tricuspid malformation characterized by narrowing of the tricuspid valve orifice due to congenital valve anomalies, such as incompletely developed leaflets, shortened and malformed chordae tendineae, small annulus, and/or abnormal number and size of papillary muscles, resulting in right ventricular inflow obstruction. Clinical presentation depends on the degree of stenosis, as well as the presence or absence of additional cardiac anomalies, and includes easy fatigability, swelling of the lower limbs, and hepatomegaly, among others.


A rare congenital tricuspid malformation characterized by irregular thickening of the leaflet tissue by myxoid connective tissue in a normally delaminated tricuspid valve, without septal leaflet displacement, and without an atrialized right ventricle. The chordae tendineae may be short or absent. The affected valve is stenotic and/or incompetent. Clinically, most patients are asymptomatic and are diagnosed in the context of the evaluation of a murmur.


Congenital trigeminal anesthesia is a rare neuro-ophtalmological disorder characterized by a congenital sensory deficit involving all or some of the sensory components of the trigeminal nerve. Due to corneal anesthesia, it usually presents with recurrent, painless eye infections, painless corneal opacities and/or poorly healing, ulcerated wounds on the facial skin and mucosa (typically the buccal mucosa and/or nasal septum).


A rare ophthalmic disorder with cranial nerve involvement characterized by dysfunction of the superior oblique muscle with typical eye motility patterns including elevation in adduction, V-pattern related to reduced abduction force in downgaze with unopposed adduction by the inferior rectus muscle, and excyclotorsion. Patients may present with contralateral head tilt to compensate for vertical binocular misalignment and diplopia.


Congenital Tufting Enteropathy is a rare congenital enteropathy presenting with early-onset severe and intractable diarrhea that leads to irreversible intestinal failure.

Summary:
Epidemiology
No epidemiological data is available, however, the prevalence can be estimated at around 1/200,000 births in Europe. The prevalence is higher in areas with high degrees of consanguinity, but cases have been reported worldwide.
Clinical description
Most affected patients develop digestive intolerance with vomiting and watery diarrhea within the first few months of life. Diarrhea is severe, chronic and persistent despite bowel rest, resulting in electrolyte imbalance and dehydration. Moreover, an intestinal insufficiency leads to malabsorption, malnutrition, and growth impairment. Although most children present with isolated diarrhea, a small number of congenital tufting enteropathy (CTE) patients present with a syndromic form where diarrhea is associated with non-specific punctuated keratitis, and various malformations such as choanal atresia, esophageal atresia, imperforate anus, dysmorphic features, skeletal dysplasia, and (in one case) Dubowitz syndrome.
Etiology
CTE is related to abnormal enterocyte development and differentiation. Mutations in the EPCAM gene (2p21) are seen in 73% of CTE patients and are associated with the isolated intestinal disease. Mutations in the SPINT2 gene (19q13.2) are seen in 21% of CTE cases which are clinically characterized by the syndromic form of the disease. Rarely, CTE patients may present with isolated diarrhea but have no mutations in either EPCAM or SPINT2.
Diagnostic methods
Diagnosis is based on the combination of clinical and histological criteria. A congenital chronic diarrhea in the absence of an infectious or an inflammatory process, in association with various degrees of small and large bowel villous atrophy and specific histological abnormalities involving the focal crowding of surface enterocytes resembling ''tufts'', and branching crypts, allow for the diagnosis of CTE. When not all criteria are obvious one can be helped by the association of the non-syndromic form of the disease with negative EpCAM immunostaining on patient's duodenal biopsies; or conversely in case of the syndromic form of the disease with a normal EpCAM immunostaining. To date, SPINT2 immunostaining on duodenal biopsies seems useless for the diagnosis. Molecular genetic testing, identifying a mutation in the EPCAM gene or SPINT2 can confirm diagnosis, however, some CTE patients do not have any identified genetic mutations.
Differential diagnosis
The differential diagnosis primarily includes other protracted congenital diarrhea disorders such as microvillus inclusion disease, congenital chloride diarrhea, congenital sodium diarrhea, and syndromic diarrhea, as well as glucose-galactose malabsorption.
Antenatal diagnosis
Prenatal diagnosis is available but can only be offered to families where a first case has already been described. The rarity of CTE and the absence of prenatal signs do not make it an appropriate candidate for either antenatal or postnatal mass screening.
Genetic counseling
CTE is transmitted in an autosomal recessive manner with high prevalence of consanguinity and affected siblings in families.
Management and treatment
To date there is no known curative treatment for CTE. Oral or enteral feedings worsen the diarrhea, however they should be maintained at the minimum tolerated level. CTE patients require daily, long-term parenteral support in order to maintain an adequate nutritional status. Life threatening complications related to intestinal failure and long-term parenteral nutrition may become an indication for intestinal transplantation, thus timing of referral to an expert center is crucial before the onset of severe complications.
Prognosis
Currently, children with CTE reach adulthood if long-term parenteral nutrition is conducted appropriately in an experienced center, otherwise the long-term prognosis may be reserved due to the complications of this delicate palliative treatment.

                            Last update:
                            April 2017

                            - Expert reviewer(s):
                            Pr Olivier GOULET  - Dr Julie SALOMON


Congenital unguarded mitral orifice is a rare, congenital, mitral valve malformation characterized by complete absence of mitral valve leaflets and tensor apparatus at the mitral annulus, which can present clinically with cyanosis, heart murmur, electrocardiogram abnormalities, mild cardiomegaly, or congestive heart failure. Association with heterotaxy, discordant atrioventricular connections, double-outlet right ventricle, pulmonary atresia or stenosis, thin left ventricular wall, and hypoplastic left heart syndrome has been reported.


Congenital unilateral hypoplasia of depressor anguli oris

A rare, isolated, congenital, head and neck morphological anomaly characterized by the unilateral hypoplasia/agenesis of the depressor anguli oris muscle, resulting in an asymmetric crying facies in neonatal period/infancy (drooping of one corner of the mouth during crying) while eye closure, nasolabial fold and forehead wrinkling are symmetric. Although isolated in the majority of cases, newborns presenting with this morphological anomaly should be referred for further screening for 22q11.2 deletion syndrome and/or other coexisting cardiovascular, musculoskeletal, cervicofacial, respiratory, genitourinary and endocrine anomalies.


Congenital urachal anomaly (CUA) describes a group of urachal remnants, found more frequently in males than females, that result from incomplete closure of the urachus (an embryological remnant of the allantois) during prenatal development, and that are usually asymptomatic (and found as an incidental finding on a radiological study) but can also present with umbilical discharge (in patent urachus or urachal sinus), infraumblical mass and pain, or with complications such as obstruction and infection. CUAs include patent urachus, urachal sinus, urachal cyst and urachal diverticulum (see these terms).


A rare acquired developmental anomaly syndrome characterized by skin, neurological, ocular, limbs and growth defects secondary to maternal Varicella-Zoster Virus (VZV) infection.


A rare otorhinolaryngologic malformation characterized by the isolated finding of a short and immobile soft palate with anatomical disproportion of the velopharyngeal structures, preventing velopharyngeal closure. Patients present with delayed speech development and hypernasal speech.


Congenital vertebral-cardiac-renal anomalies syndrome

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by vertebral segmentation defects associated with cardiac (patent ductus arteriosus, atrial septal defect, hypoplastic left heart) and renal (hypoplastic kidneys, chronic kidney disease) anomalies. Additional reported features include limb defects, short stature, global developmental delay, intellectual disability, and sensorineural hearing loss, among others.


Isolated congenital vertical talus (CVT) is a rare pedal deformity recognizable at birth by a dislocation of the talonavicular joint, resulting in a characteristic radiographic near-vertical orientation of the talus.

Summary:
Clinical description
It occurs more commonly in males than females. Some patients have vertical talus in one foot and clubfoot in the other.
Etiology
The etiology and epidemiology of this condition are largely unknown. The reported familial cases are consistent with an autosomal dominant mode of inheritance with incomplete penetrance and mutations in HOXD10 gene have been detected in two families.
Management and treatment
Serial manipulation and cast immobilization followed by limited surgery provides excellent results.

                            Last update:
                            October 2010


Congenitally corrected transposition of the great arteries

Congenitally corrected transposition (CCT) of the great vessels is a rare cardiac malformation characterized by the combination of discordant atrioventricular and ventriculo-arterial connections, usually accompanied by other cardiovascular malformations.

Summary:
Epidemiology
Prevalence is unknown. Annual incidence has been reported to be around 1/33,000 live births, accounting for approximately 0.05% of congenital heart malformations.
Clinical description
Associated malformations typically include ventricular septal defects, obstructions of the outlet from the morphologically left ventricle, and morphological anomalies of the tricuspid valve, although any anatomically feasible lesion can co-exist. The clinical picture and age of onset depend on the associated malformations, with bradycardia, a single loud second heart sound, and heart murmurs being the most common manifestations. Cyanosis is observed in patients with pulmonary stenosis and a ventricular septal defect, while cardiac failure develops earlier in life if there is a hemodynamically significant ventricular septal defect, evidenced in children by easy fatigability, poor weight gain, and feeding intolerance. In the rare cases where there are no associated malformations, congenitally corrected transposition can lead to progressive atrioventricular valvar regurgitation and failure of the systemic ventricle.
Etiology
The etiology of congenitally corrected transposition is currently unknown.
Diagnostic methods
Diagnosis can be made by fetal echocardiography, but is more commonly made postnatally based on clinical signs and echocardiography. The anatomical delineation can be further assessed by magnetic resonance imaging (MRI) and catheterization. Diagnosis can also be made late in life when the patient presents with complete heart block or cardiac failure.
Differential diagnosis
The differential diagnosis is centered on assessing whether the patient presents isolated malformations, or a spectrum of malformations, and includes double inlet left ventricle (see this term) with left-sided incomplete right ventricle, isomerism of atrial appendages with left-handed ventricular topology.
Antenatal diagnosis
Prenatal diagnosis of congenitally corrected transposition can readily be made during fetal life by an experienced sonographer.
Genetic counseling
CCT is sporadic. There is, however, a higher incidence in families with previous cases of the condition, with a recurrence risk in siblings of between 2.6% to 5.2%.
Management and treatment
Medical management involves treatment of the failing systemic morphologically right ventricle, with timing depending on the severity of the associated malformations. It involves treatment with diuretics, angiotensin-converting enzyme (ACE) inhibitors, and digoxin. If there are conduction abnormalities, the patient may require implantation of a pacemaker, for example in the setting of advanced 2nd or 3rd degree atrioventricular block, or in the presence of symptoms of ventricular dysfunction. Surgical management consists of repair of the associated malformations, or redirection of the systemic and pulmonary venous return associated with an arterial switch, the so-called double switch approach. Regular follow-up by a pediatric cardiologist or by an adult cardiologist who has had special training and experience caring for patients with congenital heart disease is recommended.
Prognosis
Prognosis depends on the associated malformations, and on the type and timing of surgical interventions. Life expectancy depends on the associated malformations and the severity of the individual lesions.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Pr Robert ANDERSON


Congenitally short costocoracoid ligament

A rare thoracic malformation characterized by fixation of the scapula to the first rib by a congenitally short costocoracoid ligament, leading to limited rotation or retraction of the scapula, as well as rounding of the shoulders and loss of the anterior clavicular contour. There have been no further descriptions in the literature since 1989.