A rare genetic isolated inherited retinal disorder characterized by primary cone degeneration with significant secondary rod involvement, with a variable fundus appearance. Typical presentation includes decreased visual acuity, central scotoma, photophobia, color vision alteration, followed by night blindness and loss of peripheral visual field.

Summary:
Epidemiology
The prevalence is estimated at 1 in 40,000 in Europe.
Clinical description
Cone rod dystrophy (CRD) is characterized by primary cone involvement or, occasionally, by concomitant loss of both cones and rods, explaining the predominant symptoms of CRDs: decreased visual acuity, color vision defects, photoaversion and decreased sensitivity in the central visual field, later followed by progressive loss in peripheral vision and night blindness. The fundus appearance is varaible ranging from normal in the early stages, with only subtle temporal optic nerve pallor, macular pigment migration and atrophy or a bull's-eye maculopathy, to peripheral retinal pigment epithelium atrophy, intra retinal pigmentation migration, arteriolar attenuation, and optic disc pallor as disease progresses. Cone-rod dystrophy (CRD) should be distinguished from rod-cone dystrophy (RCD), also known as retinitis pigmentosa. Unlike RCD, which typically start with night blindness and progressive visual field constriction while central vision is preserved until late stages, CRD is characterized by a primary decrease in central vision leading to earlier legal blindness. At end stage, however, CRDs do not differ from end stage RCDs. CRDs are most frequently nonsyndromic, however they may also be part of several syndromes, such as Alström syndrome, Bardet-Biedl syndrome and Spinocerebellar Ataxia Type 7.
Etiology
Nonsyndromic CRDs are genetically heterogeneous (28 genes have been identified). The four most commonly mutated genes are ABCA4 (1p22.1) responsible for 30 to 60% of autosomal recessive CRDs, CRX (19q13.33) and GUCY2D (17p13.1) responsible for many reported cases of autosomal dominant CRDs, and RPGR (Xp11.4) responsible for X-linked CRDs.
Diagnostic methods
The diagnosis of CRD is based on clinical history, fundus examination, autofluorescence imaging, optical coherence tomography and full field electroretinogram. Molecular diagnosis can be made for some genes. Fundus examination can be normal at the early stages with only subtle temporal optic disc pallor or may show macular pigment migrations and atrophy or a bull's-eye maculopathy. Late stage findings include peripheral retinal pigment epithelium atrophy, intraretinal pigment migration, arteriolar attenuation, and optic disc pallor.
Differential diagnosis
Differential diagnosis includes other hereditary cone disorders (including achromatopsia and allied cone dysfunction syndromes, cone dystrophy and Stargardt disease) and the rod-cone dystrophy, also known asretinitis pigmentosa, which is distinguished by the sequence of photoreceptor involvement (rod photoreceptors followed by cone photoreceptors).
Genetic counseling
Inheritance patterns depend on the gene involved and can be autosomal dominant, autosomal recessive or X-linked recessive. Genetic counseling is always advised.
Management and treatment
Currently, there is no therapy that stops evolution of the disease or that restores vision. Management aims at slowing down the degenerative process, treating the complications, visual rehabilitation and helping patients to cope with the social and psychological impact of blindness.
Prognosis
Visual prognosis is variable, with early central vision loss and progressive visual dysfunction leading to legal blindness before 40 years of age in most cases.

                            Last update:
                            May 2019

                            - Expert reviewer(s):
                            Pr Isabelle AUDO


A rare, acquired, dermis elastic tissue disorder with decreased elastic tissue characterized by multiple, asymptomatic, well demarcated, flat, hypopigmented atrophic macular skin lesions distributed over upper trunk and proximal upper limbs. Histopathological examination reveals atrophic epidermis with decreased basal pigmentation, perivascular mononuclear infiltration in the upper dermis, and disorganized, hyalinized, coarse collagen bundles, and variable loss of elastic fibers in the dermis.


A rare neuro-ophthalmological disease characterized by dysfunction of the ipsilateral lateral rectus muscle with esotropia in primary position, limited or no abduction of the eyeball, and compensatory horizontal face turn toward the palsied eye. The condition commonly resolves spontaneously.


Congenital achiasma is a rare, genetic, non-syndromic cranial nerve and nuclear aplasia malformation characterized by the congenital absence of the optic chiasm, resulting from the failure of the optic nerve fibers to cross over and decussate to the contralateral hemisphere, leading to decreased vision, strabismus and congenital nystagmus in infancy.


Congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency

A rare form of classic congenital adrenal hyperplasia (CAH) characterized by glucocorticoid deficiency, hyperandrogenism, hypertension and virilization in females.

Summary:
Epidemiology
It accounts for approximately 5-8% of CAH cases and has an annual incidence of 1/100,000-200,000 live births.
Clinical description
Severe virilization is seen in the external genitalia of girls while boys appear normal at birth. If the disorder is not recognized during the neonatal period, both girls and boys undergo rapid postnatal growth with accelerated growth velocity and accelerated skeletal maturation, hypertension, premature adrenarche and precocious puberty leading to reduced adult height. There is also a life-long risk for acute adrenal insufficiency.
Etiology
The disease is caused by a mutation in the CYP11B1 gene that is located on chromosome 8 q21. Steroid 11-beta-hydroxylase deficiency causes decreased cortisol secretion and hypertension due to accumulation of glucocorticoid (GC) and mineralocorticoid precursors.
Diagnostic methods
Diagnosis of girls with classic CAH due to 11-beta-hydroxylase deficiency (11beta-OHD) is usually at birth when virilization of external genitalia is present. Signs of adrenal insufficiency present in both sexes during the second week of life. However, salt wasting is very uncommon, which may delay the time of diagnosis compared with CAH due to 21-hydroxylase deficiency (21-OHD), because of continued mineralocorticoid receptor stimulation due to elevated desoxycorticosterone (DOC) secretion. Serum levels of 11-desoxycortisol, DOC, androstenedione, 17-OH pregnenolone and ACTH are elevated. 17-OH progesterone may be slightly elevated. Simultaneous measurement of these steroids by liquid chromatography with tandem mass spectrometry (LC-MS/MS) is the most convenient method for diagnosis of 11beta-OHD. CAH can be diagnosed prenatally by genotyping through chorionic villus sampling to obtain fetal DNA as early as gestational week 10-12 in families with known CYP11B1 pathogenic genotypes. Methods involving invasive sampling should only be performed if the results will lead to changes in approach or treatment. National systematic screening programs may diagnose cases of 11beta-OHD CAH at birth due to slightly elevated 17-OH progesterone.
Differential diagnosis
Differential diagnosis is CAH due to 21-OHD. 17-OH progesterone may be elevated in the newborn, leading to misdiagnosis of 21-OHD.
Antenatal diagnosis
Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member or in case of genital abnormalties diagnosed antenatally in girls.
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
Prenatal treatment with dexamethasone can be administered to female fetuses at risk of developing classic CAH, but this procedure is still controversial due to potential side effects. When administered before the 9th week of gestation, it prevents the excessive androgen production responsible for genital virilization in females. If diagnosed after birth, vaginoplasty surgery is usually performed on girls, but the timing of the surgery is still debated. Lifelong GC replacement therapy is needed to treat adrenal insufficiency and to decrease elevated androgen hormone levels in order to allow for normal growth and puberty, and normal health without hypertension. Hydrocortisone is usually given to children as GC replacement therapy (10-15mg/m2/day divided into 2 or 3 doses). Dosage is monitored and should be increased during times of stress or intercurrent disease. There is a risk of developing acute adrenal insufficiency (see this term), hypertension and other complications due to chronic hyperandrogenemia in case of poorly controlled disease. Excessive treatment with GC causes cushingoid features and metabolic and cardiovascular disturbances. In all cases, excess mineralocorticoid causes hypertension. Regular follow-up by a multidisciplinary team, including pediatric endocrinologists, surgeons, gynecologists, and psychologists, is important.
Prognosis
Life expectancy may be reduced as patients with CAH have a risk of acute adrenal insufficiency, hypertension and higher metabolic and cardiovascular risk. Poor disease control may increase the risk of acute adrenal insufficiency, hypertension, metabolic and cardiovascular morbidities, testicular adrenal rest tumors (TARTs), menstrual irregularity and subfertility.

                            Last update:
                            February 2022

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

                                * European Reference Network


Congenital adrenal hyperplasia due to 17-alpha-hydroxylase deficiency

A rare form of congenital adrenal hyperplasia due to 17-alpha-hydroxylase (CYP17A1) deficiency and characterized by glucocorticoid deficiency, mineralocorticoid excess leading to hypokalemic hypertension and sex steroid deficiency (hypergonadotrophic hypogonadism). Undervirilization and even female phenotype in 46,XY males, primary amenorrhea in females and lack of pubertal development in both sexes is common. Residual CYP17A1 activity is associated with the severity of this condition with a large spectrum of variability, from presenting in early infancy, to unusually mild courses with isolated sex steroid deficiency but normal ACTH-stimulated cortisol in adult patients.


Congenital adrenal hyperplasia due to 3-beta-hydroxysteroid dehydrogenase deficiency

A rare form of congenital adrenal hyperplasia (CAH) due to 3-beta-hydroxysteroid dehydrogenase (HSD3B2) deficiency and characterized by salt-wasting and non-salt wasting CAH with a wide variety of symptoms, including glucocorticoid and mineralocorticoid deficiencies in both sexes. Salt wasting can lead to dehydration and hypotension in the first few weeks of life. Affected males had undervirilization manifesting as a micropenis to severe perineoscrotal hypospadias. Females show normal or mildly virilized external genitalia (mild clitoromegaly, labial fusion) due to dehydroepiandrosterone (DHEA) accumulation and conversion to androgens by the normal HSD3B1.


Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency

A rare form of congenital adrenal hyperplasia due to P450 oxidoreductase deficiency and characterized by glucocorticoid deficiency, virilization of external genitalia in females, and undervirilization in males. Findings range from severely affected infants with 46,XX and 46,XY disorders/differences of sex development (DSD) and cortisol deficiency to mildly affected women who appear to have polycystic ovary syndrome, or mildly affected men with gonadal insufficiency.


A group of rare inherited endocrine disorders caused by a steroidogenic enzyme deficiency and characterized by adrenal insufficiency and variable degrees of hyper- or hypoandrogenism manifestations, depending on disease type and severity.

Summary:
Epidemiology
The estimated prevalence is 1/10,000. Annual incidence ranges from 1/5,000 to 1/15,000.
Clinical description
The most frequent form of congenital adrenal hyperplasia (CAH) is classical CAH due to 21-hydroxylase deficiency which can further be divided into simple virilizing, salt wasting or non-classical (N) types. Girls present at birth with variable levels of virilization of external genitalia with variable degrees of clitoral enlargement and labial fusion. They have a normal uterus but abnormal vaginal development. The genital appearance of affected 46,XX infants is occasionally indistinguishable from that of male genitals but empty of gonads. Gonadal development is normal with ovarian function potentially normal. The external genitalia in boys are normal. Salt wasting forms of CAH lead to symptoms of dehydration, hypoglycemia and hypotension in the first few weeks of life and can be life threatening. Premature pubarche can be seen in children as well as accelerated growth velocity, accelerated skeletal maturation and precocious puberty (leading to reduced adult height). NCAH is often not diagnosed until adolescence when the first symptoms appear. Manifestations seen in females are hirsutism, acne, anovulation and menstrual irregularities. Males (and some females) are asymptomatic. Hirsutism continues in adulthood and women can suffer from chronic anovulation, fertility problems, and metabolic and cardiovascular disturbances. Other rare forms can present with arterial hypertension, craniofacial malformations and atypical external genitalia in both sexes.
Etiology
In 90-95% of cases, CAH is caused by a mutation in the CYP21A2 gene located on chromosome 6p21.3 which encodes for an enzyme that controls cortisol and aldosterone production. Other genes are less frequently involved and result in the following variants of CAH: CAH due to 17-alpha-hydroxylase deficiency, 3-beta-hydroxysteroid dehydrogenase deficiency, 11-beta-hydroxylase deficiency, cytochrome P450 oxidoreductase deficiency and congenital lipoid adrenal hyperplasia.
Diagnostic methods
Diagnosis of girls with classical CAH is usually at birth when atypical genitalia are present. Babies can be screened for CAH in order to identify those with the classical forms by measuring 17-hydroxy-progesterone (17-OHP) levels. Genetic screening also confirms a diagnosis of CAH by identifying those with a CAH related gene mutation. In most European countries there are newborn screening programs in place to diagnose CAH at birth.
Differential diagnosis
In adult females a tumor of the ovaries or adrenal glands can mimic the clinical manifestations of CAH with virilization. Polycystic ovarian syndrome is another differential diagnosis.
Antenatal diagnosis
Antenatal diagnosis in families with known pathogenic genotypes is possible by screening for a disease-causing gene by amniocentesis or chorionic villus sampling. Noninvasive prenatal diagnosis has been accomplished by analysis of circulating free fetal DNA in maternal blood in proof-of-concept studies.
Genetic counseling
The disorder is autosomal recessive and genetic counseling can be offered to parents with CAH.
Management and treatment
Lifelong hormone replacement therapy is needed to treat adrenal insufficiency and decrease elevated androgen levels, to allow for normal growth and puberty in children. Hydrocortisone regulates menstrual cycles and promotes fertility in adult females. Hydrocortisone is usually given to children as glucocorticoid replacement therapy (dosage is monitored and should be increased during times of stress or intercurrent disease) and 9 alpha-fludrocortisone acetate for mineralocorticoid replacement. Genital reconstructive surgery in affected females is no longer considered as an emergency procedure and the ideal timing remains to be determined. Psychological support is often needed. Methods of hair removal treat hirsutism. Menstrual cycles can sometimes be regulated with oral contraceptives. Dexamethasone can be given to pregnant women at risk of having offspring with the mutation (when fetus is female) in order to prevent virilization in girls. This treatment is still controversial due to potential adverse effects.
Prognosis
With proper treatment patients may have a normal life expectancy. However, uncontrolled CAH may be associated with life-threatening acute adrenal insufficiency and a higher risk for comorbidities (metabolic, cardiovascular, subfertility).

                            Last update:
                            February 2022

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

                                * European Reference Network


A rare urogenital tract malformation characterized by the complete absence of the scrotal rugae in the perineum between the penis and anus, with bilateral testes being present in a cryptorchid or ectopic position. Hemiscrotal agenesis refers to the unilateral absence of scrotal skin with an intact midline raphe and ipsilateral cryptorchidism. Both malformations may be isolated findings, or occur in association with other anomalies.


A rare hemorrhagic disorder caused by congenital deficiency of alpha2 antiplasmin, leading to dysregulated fibrinolysis and is characterized by a hemorrhagic tendency presenting from childhood with prolonged bleeding and ecchymoses following minor trauma and spontaneous bleeding episodes (often in unusual locations like diaphysis of long bones).


Congenital alveolar capillary dysplasia (ACD) is a rare and fatal developmental lung disease characterized by respiratory distress in neonates due to refractory hypoxemia and severe pulmonary arterial hypertension.


An isolated constitutional thrombocytopenia characterized by an isolated and severe decrease in the number of platelets and megakaryocytes during the first years of life that develops into bone marrow failure with pancytopenia later in childhood.

Summary:
Epidemiology
Congenital amegakaryocytic thrombocytopenia (CAMT) prevalence is unknown and less than 100 cases have been reported in the literature. In addition, the incidence may be underestimated due to difficult and inconsistent diagnosis of the disease.
Clinical description
CAMT manifests since birth, often in the first day or at least within the first month of life, with petechiae, purpura, and gastrointestinal, pulmonary or intracranial hemorrhage due to isolated thrombocytopenia and a near absence of megakaryocytes in the bone marrow. Two types of CAMT have been identified. Type I-CAMT is the severe form of the disease and is characterized by persistently low platelet counts and early progression (usually by the age of 2 years) to bone marrow aplasia associated with pancytopenia. Type II-CAMT is a milder form which presents with transient increase of platelet counts over 50x109/L during the first year of life and late (by the age of 3-6 years) or no development of pancytopenia. Cardiac defects (atrial and ventricular septal defects), abnormalities of the central nervous system (cerebral and cerebellar hypoplasia), and retardation of psychomotor development have occasionally been reported.
Etiology
CAMT is due to mutations in the MPL gene (1p34) coding for Thrombopoietin (TPO) receptor (c-MPL), expressed in pluripotent hematopoietic stem cells and cells of the megakaryocyte lineage. The binding of TPO to c-MPL stimulates platelet and megakaryocyte production. Different types of mutations have been associated with different phenotypes. Nonsense mutations predicted to result in a complete loss of function of the TPO receptor lead to type I-CAMT, whereas missense mutations predicted to lead to a residual function of the receptor are associated with type II-CAMT. Cases with no defects in the MPL gene are referred to as type III-CAMT. Recently, a 21q22 deletion resulting in RUNX1 haploinsufficiency has been reported in a case of CAMT associated with various anomalies (growth retardation, hearing deficits, hernias, poor feeding).
Diagnostic methods
Diagnosis is based on clinical signs, on the evidence by blood tests of thrombocytopenia (platelet count below 50x109/L) with a normal mean platelet volume and of highly elevated serum levels of TPO, and on the observation in a bone marrow aspirate of absent or very few megakaryocytes. Genetic testing can confirm the diagnosis.
Differential diagnosis
The initial presentation of CAMT with isolated thrombocytopenia can be misdiagnosed as idiopathic thrombocytopenic purpura (ITP), while the late pancytopenic phase is indistinguishable from aplastic anemia. Fanconi anemia, thrombocytopenia-absent radius (TAR), syndrome and Wiscott-Aldrich syndrome (WAS) should be also ruled out.
Antenatal diagnosis
Prenatal diagnosis is possible for families in which the disease-causing mutation has been identified.
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 is supportive, mainly consisting of multiple platelet transfusions. At present, hematopoietic stem cell transplantation (HSCT) is the only curative therapy.
Prognosis
Prognosis is poor and with supportive therapy, progression to full marrow failure (tri-linear marrow aplasia) occurs during the first years of life. 30% of patients with CAMT die due to bleeding complications before the HSCT and 20% due to the HSCT.

                            Last update:
                            July 2019

                            - Expert reviewer(s):
                            Pr Joan Lluís VIVES-CORRONS


A rare sporadic arthrogryposis syndrome characterized by multiple congenital contractures presenting in a very specific pattern. It is typically symmetric, involving all four limbs, with internally rotated shoulders, fully extended and fixed elbows, the wrists fixed in flexion, partially flexed fingers, hips fixed in flexion or extension, adducted or abducted, and sometimes dislocated. The knees may be fixed in extension or flexion, and the feet are usually in severe equinovarus position. The jaw and trunk are relatively spared. Normal limb muscle tissue is replaced by fatty, fibrous tissue.


Congenital analbuminemia (CAA) is characterized by the absence or dramatic reduction of circulating human serum albumin (HSA).

Summary:
Epidemiology
Prevalence has been estimated at approximately 1 case per million population, with less than 50 cases being reported in the literature so far. The disorder occurs with no geographic, sex or ethnic predilection.
Clinical description
In the majority of cases, CAA is diagnosed in adulthood. Although albumin is the most abundant plasma protein and has many functions, patients with CAA present with only a few mild clinical signs and biochemical abnormalities: fatigue, low blood pressure, edema, increased concentration of several plasma proteins and a prolonged albumin half-life. HSA is either absent or present at very low levels (<1 g/L) but liver function is normal and there is an absence of conditions leading to significant protein loss. The mildness of the clinical manifestations is attributed to the compensatory increase in hepatic biosynthesis of other plasma proteins, notably a compensatory increase in serum globulin concentrations. However, CAA patients may develop lipodystrophy and hypercholesterolemia, possibly leading to premature atherosclerosis and cardiovascular events. Rarely, CAA may be complicated by hypercoagulability, osteoporosis and respiratory tract infections. The disorder appears to be more severe in the fetus or during early infancy, as intrauterine growth retardation and intrauterine death have been reported.
Etiology
The disorder is caused by homozygous or compound heterozygous mutations in the gene coding for HSA (ALB; 4q13.3). More than ten different causative mutations have been identified to date. The Kayseri mutation (a homozygous AT deletion at nucleotides c.228-229, the 91st and 92nd bases of exon 3) appears to be the most common cause of analbuminemia in humans.
Diagnostic methods
Diagnosis is based on laboratory analysis of blood specimens (albumin immunoassays and serum protein electrophoresis). DNA analysis is required for identification of the mutation involved.
Differential diagnosis
The differential diagnosis should include a wide number of pathological conditions that present with reduction of HSA (glomerulonephritis, nephrosis, ascites, systemic lupus erythematosus, intestinal lymphangiectasia, and protein-losing enteropathies; see these terms).
Genetic counseling
CAA is transmitted as an autosomal recessive trait and consanguinity has been shown in all reported cases with available genealogic data.
Management and treatment
CAA is a relatively benign and tolerable condition. Management aims at prophylaxis and treatment of the possible cardiovascular complications related to hypercholesterolemia and atherosclerosis. Drugs that bind to the albumin plasma protein fraction should be used with caution in patients with CAA.

                            Last update:
                            November 2008


Congenital anomaly of the tricuspid valve chordae

A rare, congenital anomaly of the tricuspid subvalvular apparatus characterized by aberrant tendinous chords, which insert at the clear zone of the leaflet instead of its free edge and connect to the endocardium instead of the papillary muscles. Resulting tethering of one or more tricuspid leaflets leads to their impaired mobility and tricuspid regurgitation. Association with other congenital cardiac anomalies has been reported.


A rare aortic malformation of variable severity and clinical presentation. Clinical presentations range from a neonatal severe presentation often associated with sudden cardiac death, to a slowly progressive stenosis that presents later with cardiac murmur, chest pain, dizziness, and loss of consciousness with exercise-induced exacerbations. Echocardiography reveals atresia or dysplasia of the aortic valve most commonly associated with a bicuspid morphology, restricted left ventricular outflow, and left ventricular hypertrophy.


A rare congenital non-syndromic heart malformation characterized by a communication between the ascending aorta and the pulmonary trunk in the presence of two normally formed semilunar valves. It may be an isolated finding or occur in association with other anomalies. Severe clinical manifestations, such as congestive heart failure or pulmonary hypertension, typically develop in early life.


A rare simple vascular malformation characterized by a congenital abnormal connection between an artery and a vein, appearing as varicose veins with port wine discoloration, leading to a bypass of the capillary bed. Signs and symptoms include palpable continuous thrill in the dilated vessels, continuous machinery murmur with systolic accentuation, collapsing arterial pulse, Nicoladoni Branham sign, as well as local gigantism and hot ulcers due to hypoxia, among others.


Congenital atransferrinemia is a very rare hematologic disease caused by a transferrin (TF) deficiency and characterized by microcytic, hypochromic anemia (manifesting with pallor, fatigue and growth retardation) and iron overload, and that can be fatal if left untreated.

Summary:
Epidemiology
The prevalence is unknown. To date, there have been 16 reported cases from 14 families.
Clinical description
Disease onset usually occurs in infancy or early childhood. Only one reported patient was diagnosed at the age of 20. The presenting manifestations are those of anemia such as fatigue, anorexia, irritability, tachycardia, systolic murmur and pallor. Growth retardation, hepatomegaly and recurrent infections are other frequent manifestations of the disease. In undiagnosed individuals, iron overload can lead to liver cirrhosis, heart failure and arthropathy. Hypothyroidism and splenomegaly have also been reported separately in two isolated cases. Death can occur due to congestive heart failure or pneumonia.
Etiology
Congenital atransferrinemia is due to mutations in the TF gene (3q21) encoding TF, a blood protein necessary for the proper transport of iron to the liver, spleen, and bone marrow. Without the synthesis of TF, there is a reduction of iron delivery to developing erythroid precursors in bone marrow, which results in reduced hemoglobin synthesis and consequently to anemia and iron storage in peripheral tissues (secondary hemochromatosis).
Diagnostic methods
Diagnosis is based on laboratory testing indicating anemia as well as a serum TF level of less than 35mg/dl. An enlarged liver, due to hemosiderosis may be noted on clinical examination in some cases. Molecular genetic testing can identify a mutation in the TF gene, confirming the diagnosis.
Differential diagnosis
Differential diagnoses include other conditions that manifest with hypotransferrinemia such as GRACILE syndrome and nephrotic syndromes (see these terms) and, in adults, those suffering from chronic alcoholism.
Antenatal diagnosis
Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutations in the family.
Genetic counseling
Congenital atransferrinemia is inherited in an autosomal recessive manner and genetic counseling is available.
Management and treatment
There is no cure for congenital atransferrinemia. Treatment usually involves monthly phlebotomies followed by infusions of whole plasma or purified apotransferrin which remove excess iron and replenish TF levels, allowing for the proper formation of hemoglobin. Treatment is life-long and regular follow-up is recommended.
Prognosis
With proper treatment the prognosis is good but due to the small number of patients, long-term complications remain unknown. .

                            Last update:
                            November 2013

                            - Expert reviewer(s):
                            Dr Mayka SÁNCHEZ FERNÁNDEZ


Congenital autosomal recessive small-platelet thrombocytopenia

A rare isolated constitutional thrombocytopenia characterized by neonatal onset of small-platelet thrombocytopenia with significantly increased bleeding tendency. Bleeding symptoms include petechial rash, mucosal bleeding, and heavy menstrual bleeding. Growth and development are normal, and there is no increased susceptibility to infections.


Congenital axonal neuropathy with encephalopathy

A rare, congenital, autosomal recessive axonal hereditary motor and sensory neuropathy disease characterized by axonal neuropathy, manifesting at birth or shortly thereafter with generalized muscular hypotonia, prominently distal muscular weakness, respiratory/swallowing difficulties and diffuse areflexia, associated with central nervous system involvement, which includes progressive microcephaly, seizures, and global developmental delay. Additional variable manifestations include hearing impairment, ocular lesions, skeletal anomalies (e.g. talipes equinovarus, overriding toes, scoliosis, joint contractures), cryptorchidism, and dysmorphic features (such as coarse facies, hypertelorism, high-arched palate). Outcome is typically poor due to respiratory insufficiency and/or aspiration pneumonia.


A rare non-syndromic urogenital tract malformation characterized by improper development of the vas deferens leading to male infertility.

Summary:
Epidemiology
Congenital bilateral absence of vas deferens (CBAVD) affects about 1/1,000 males. It is found in 98% of males with cystic fibrosis and accounts for 6-8% of cases of obstructive azoospermia. In about 50% of cases, the CBAVD is associated with the absence of the seminal vesicles. Unilateral renal agenesis is detected in 5-10% of patients with CBAVD, while is present in 5-40% of congenital unilateral absence of vase deferens (ipsilateral).
Clinical description
CBAVD is usually diagnosed in adult men, either during systematic assessment of cystic fibrosis (CF) or during assessment of isolated infertility (azoospermia). Infertile patients with CBAVD produce small volumes of acidic sperm (< 1 ml with a pH < 7.0). The latter is non-pathognomonic and more common when the seminal vesicles are also absent. CBAVD frequently coexists with kidney anomalies and other comorbidities.
Etiology
In 1990, mutations in the CFTR gene (the causative gene for cystic fibrosis) were identified in 42% of patients in a population of infertile males with CBAVD, suggesting that CBAVD is a genital form of cystic fibrosis. Since then, an exhaustive analysis of the 27 exons of the CFTR gene has led to the classification of CBAVD patients into four groups: I) patients with two mutations in the CFTR gene (19%), II) patients with one mutation in the CFTR gene and having the IVS8-5T allele in the trans position (33%), III) patients with either a mutation in the CFTR gene or having the IVS8-5T allele (27%) and IV) patients with neither the IVS8-5T allele nor a mutation in the CFTR gene (21%).
Diagnostic methods
The diagnosis of CBAVD is clinical. Traditionally, it was based on the absence of the intrascrotal portion of the vas deferens on palpation. The gold standard for diagnosis is scrotal and transrectal ultrasound, which also allows evaluation of the absence of the seminal vesicles. Abdominal ultrasound should be added to rule out a unilateral renal agenesis. Sperm analysis typically shows azoospermia, hypospermia (<1 ml) and acid pH (<7.0). Genetic testing can confirm the mutation in the CFTR gene.
Differential diagnosis
The differential diagnosis includes other causes of azoospermia and obstruction of the seminal tract (e.g. injuries, infections, cysts, etc.).
Genetic counseling
CBAVD patients with CFTR mutations should be informed of the increased risk to develop related diseases and transmit CF to their child. The risk is higher in patient without a solitary kidney. If an affected couple (the male partner is a carrier for a severe CFTR mutation) wishes to have a child with assisted reproductive technology (ART; i.e. surgical sperm retrieval and in vitro fertilization techniques), both partners should be offered genetic testing. If the female partner is not a carrier of one of the CFTR mutations, the risks of having a child affected by CF is <1/1000 (2.5 times higher than in the general population). If a mutation is detected in both partners, the risk of having a child with CF is 25%, and 50% if the mutation is on both alleles in one parent.
Management and treatment
The diagnosis of CBAVD often has implications that go beyond the problem of infertility because of its potential association with renal anomalies and other clinical conditions related to CFTR mutations. Some patients with a CFTR mutation may later present mild CF symptoms such as recurrent respiratory tract infections and could benefit from referral to a pneumologist or CF center for management and follow-up. In the case of solitary kidney, the patient should be followed a nephrologist.
Prognosis
CBAVD has no impact on life expectancy. Nevertheless, associated conditions (namely CF or other CFTR-related conditions) can potentially affect quality of life. If a solitary kidney is present, but renal function otherwise normal, quality of life is usually not impacted.

                            Last update:
                            June 2023

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

                                * European Reference Network


Congenital bile acid synthesis defect type 1 (BAS defect type 1) is the most common anomaly of bile acid synthesis (see this term) characterized by variable manifestations of progressive cholestatic liver disease, and fat malabsorption.

Summary:
Epidemiology
Prevalence is unknown but may be around 1-9/1,000,000 for overall BAS defects, excluding cerebrotendinous xanthomatosis.
Clinical description
The clinical presentation is heterogeneous, however most patients present with features of neonatal cholestasis. Clinical features include hepatomegaly with or without splenomegaly, jaundice, fat and fat-soluble vitamin malabsorption, and mild steatorrhea. In most cases, pruritus is absent. Liver function tests present elevated serum transaminases (AST, ALT), conjugated hyperbilirubinemia, and normal gamma-GT. The liver histology shows inflammation, giant cells, evidence of cholestasis, and variable degrees of liver fibrosis. The clinical course of early-onset disease is heterogeneous with some patients resolving jaundice and being identified later in life, or with more fulminant disease that results in death or requires liver transplantation at an early age. The disorder may also present as late-onset chronic cholestasis. In such patients, liver disease is not always evident and patients may have fat-soluble vitamin malabsorption with rickets, corrected by vitamin supplementation, and/or other complications including bleeding diathesis (hematochezia or intracranial bleeding), neuroaxonal dystrophy and night blindness. Serum liver enzymes are initially often normal but later show increases with progression of liver disease to fibrosis. Children and adolescents may also present with extensive fibrosis and/or cirrhosis.
Etiology
The disease is caused by a mutation in the gene encoding 3-beta-hydroxy-delta-5-C27 steroid oxidoreductase (HSD3B7, 16p12-p11.2). Transmission is autosomal recessive.
Diagnostic methods
Diagnosis is based on detection of sulfate and glycosulfate conjugates of 3-beta-hydroxy-delta-5 bile acids, which are the signature metabolites of this bile acid defect, on liquid secondary ionization mass spectrometry (LSIMS) analysis of urine. Gas chromatography - mass spectrometry (GC-MS) or electroscopy and tandem mass spectrometry may also be used.
Differential diagnosis
Differential diagnoses include progressive familial intrahepatic cholestasis, diseases that present with neonatal cholestasis, which includes alpha-1-antitrypsin deficiency of ZZ phenotype, Alagille syndrome, biliary atresia, cystic fibrosis, and metabolic diseases (tyrosinemia type I, galactosemia, hereditary fructose intolerance) (see these terms), diseases that present with fat and fat soluble vitamin malabsorption, including other liver diseases, and intestinal disease, or diseases that present with growth failure.
Antenatal diagnosis
Antenatal diagnosis can be made on embryonic tissue obtained when there has been a previously identified sibling. Urine LSIMS in a suspect infant can confirm the diagnosis in the first neonatal days.
Management and treatment
Treatment is based on oral administration of cholic acid which leads to gradual resolution of biochemical and histologic abnormalities and prevents progression of the disease, even in cases with hepatic fibrosis and cirrhosis. Cholic acid therapy stimulates bile flow and suppresses synthesis of atypical bile acids and production of toxic intermediates via the bile acid pathway linked to the pathogenesis of disease.
Prognosis
With early treatment the long-term prognosis is excellent.

                            Last update:
                            January 2011

                            - Expert reviewer(s):
                            Pr James HEUBI


Congenital bile acid synthesis defect type 2 (BAS defect type 2) is an anomaly of bile acid synthesis (see this term) characterized by severe and rapidly progressive cholestatic liver disease, and malabsorption of fat and fat-soluble vitamins.

Summary:
Epidemiology
Prevalence is unknown. This condition is clearly rare but is the second most common anomaly of BAS on screening infants with cholestasis.
Clinical description
Patients present with neonatal cholestasis and rapid progression to cirrhosis and death in infancy without intervention. The clinical presentation resembles that of congenital BAS defect type 1 (see this term) with hepatosplenomegaly, jaundice, fat-soluble vitamin malabsorption, and steatorrhea. However, the average age at diagnosis is lower, in infancy, and disease progression is more rapid and severe. Liver function tests present elevated serum transaminases (AST, ALT) and gamma-GT, markedly elevated conjugated bilirubinemia and coagulopathy.
Etiology
BAS defect type 2 is caused by a mutation in the delta(4)-3-oxosteroid 5-beta-reductase gene (AKR1D1, 7q32-q33). Transmission is autosomal recessive. Liver injury is thought to be caused by diminished primary bile acid synthesis and hepatotoxicity of accumulated atypical bile acids (delta(4)-3-oxo bile acids).
Diagnostic methods
Diagnosis is based on urine analysis using liquid secondary ionization mass spectrometry (LSIMS) and gas chromatography - mass spectrometry (GC-MS). LSIMS urine analysis reveals elevated amounts of delta(4)-3-oxo bile acids including 3-oxo-7alpha-hydroxy-4-cholenoic and 3-oxo-7alpha, 12alpha-dihydroxy-4-cholenoic acids. Increased production of delta4-3-oxo bile acids occurs in infants during the first few weeks of life and in patients with end-stage liver disease of other causes. It is important to perform repeat LSIMS urine analysis as, on rare occasions, a resolution of the liver disease occurs with disappearance of atypical bile acids.
Differential diagnosis
Differential diagnoses include progressive familial intrahepatic cholestasis, diseases that present with neonatal cholestasis, which includes alpha-1-antitrypsin deficiency (ZZ phenotype), tyrosinemia type 1, biliary atresia, choledochal cyst, cystic fibrosis, Alagille syndrome, galactosemia and hereditary fructose intolerance or diseases that present with growth failure (panhypopituitarism) (see these terms).
Antenatal diagnosis
Antenatal diagnosis can be established by analysis of embryonic tissue when there has been a previously identified sibling. Urine LSIMS on siblings of affected patients may be performed in the first neonatal days and therapy begun before serious morbidity develops.
Management and treatment
Treatment is based on oral bile acid therapy, which leads to gradual resolution of biochemical and histologic abnormalities and prevents progression of the disease. Cholic acid therapy creates a pool of bile acids which stimulates bile flow and facilitates fat soluble vitamin absorption and suppresses atypical bile acid synthesis thereby reducing the production of toxic bile acid metabolic intermediates. Ursodeoxycholic acid (UDCA) may be used but is not the therapy of choice because UDCA does not suppress atypical bile acid synthesis and the toxic metabolites that may injure the liver continue to be produced.
Prognosis
With early treatment, the long-term prognosis is excellent. If a patient is identified with advanced liver disease, cholic acid therapy may not be effective and liver transplantation may be required. Without treatment, the condition is generally fatal.

                            Last update:
                            January 2011

                            - Expert reviewer(s):
                            Pr James HEUBI


Congenital bile acid synthesis defect type 3 (BAS defect type 3) is a severe anomaly of bile acid synthesis (see this term) characterized by severe neonatal cholestatic liver disease.

Summary:
Epidemiology
To date, only 2 cases of this disorder have been reported.
Clinical description
The index case was a 10-week-old infant with severe progressive cholestasis, hepatosplenomegaly, coagulopathy, cirrhosis and liver synthetic failure from early infancy. Serum transaminases (AST, ALT) were markedly elevated and gamma-GT was normal. Liver histology showed cholestasis, extensive portal fibrosis, inflammation and giant cell transformation, as well as bile duct proliferation.
Etiology
BAS defect type 3 is caused by mutations in the 7-alpha hydroxylase gene (CYP7B1, 8q21.3). The deficiency in oxysterol 7alpha-hydroxylation leads to the accumulation of hepatotoxic unsaturated monohydroxy bile acids. The mode of transmission is presumed to be autosomal recessive.
Diagnostic methods
Diagnosis, based on analysis of urine using liquid secondary ionization mass spectrometry (LSIMS) shows sulfate and glycosulfate conjugates of unsaturated monohydroxy-cholenoic acids (3beta-hydroxy-5-cholenoic and 3beta-hydroxy-5-cholestenoic acids) and an absence of primary bile acids.
Management and treatment
This anomaly of bile acid synthesis is particularly severe and is not treatable by primary bile acid therapy.

                            Last update:
                            January 2011

                            - Expert reviewer(s):
                            Pr James HEUBI


Congenital bile acid synthesis defect type 4 (BAS defect type 4) is an anomaly of bile acid synthesis (see this term) characterized by mild cholestatic liver disease, fat malabsorption and/or neurological disease.

Summary:
Epidemiology
Five cases have been reported to date: two siblings presenting with neonatal cholestasis and three adults with neurological disease.
Clinical description
The clinical presentation of this defect varies. Infants present with severe fat and fat-soluble vitamin deficiencies, hematochezia and mild cholestasis, whereas adults present with various neurological disorders. It is possible that the adults had undocumented mild liver disease and fat-soluble vitamin deficiency in earlier life that led to neurological disease.
Etiology
BAS defect type 4 is caused by a mutation in the AMACR gene (5p13.2-q11.1).
Diagnostic methods
Diagnosis is based on liquid secondary ionization mass spectrometry (LSIMS), gas chromatography-mass spectrometry (GC-MS) and electrospray ionization-tandem mass spectrometry analysis of urine, serum and bile.
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Treatment is based on primary bile acid therapy with cholic acid. Dietary restriction of phytanic and pristanic acids is likely to be necessary in the long term to prevent neurotoxicity.

                            Last update:
                            September 2011

                            - Expert reviewer(s):
                            Pr James HEUBI


Congenital brachyesophagus-intrathoracic stomach-vertebral anomalies syndrome

A rare syndromic esophageal malformation characterized by severe congenital brachyesophagus with midline diaphragmatic hernia and secondary intrathoracic stomach, and vertebral anomalies (in particular rachischisis of the cervical/thoracic spine). Additional reported manifestations include intrauterine growth restriction, short neck, intestinal malrotation, herniation of other abdominal organs, and cleft lip, among others. The condition is mostly fatal in the neonatal or early infantile period.


Congenital brain dysgenesis due to glutamine synthetase deficiency

A rare neurometabolic disease characterized by neonatal onset of severe epileptic encephalopathy with brain malformations (including cerebral and cerebellar atrophy, white matter abnormalities, delayed gyration or complete agyria, and thin corpus callosum), generalized hypotonia, and lack of normal development. Additional features include facial dysmorphism and necrolytic erythema of the skin. Biochemical hallmarks are decreased levels of glutamine in body fluids and chronic hyperammonemia. Death may occur in the early post-natal period due to multiple organ failure.


Congenital cataract microcornea with corneal opacity

A rare genetic eye disease characterized by congenital cataract, microcornea, and corneal opacity, resulting in severe visual impairment or blindness. Depending on the genetic background, other developmental ocular defects may also be present.


Congenital cataract-anterior segment dysgenesis syndrome

Cataract-glaucoma syndrome is characterised by the association of total bilateral congenital cataract with the secondary occurrence of glaucoma appearing at ages varying between 10 and 40 years.

Summary:
Epidemiology
This very rare syndrome has only been described in three families, one of which contained a few dozen affected individuals spanning eight generations.
Etiology
The syndrome is caused by dysfunction of the PITX3 gene (localised to 10q25). This gene codes for a transcription factor involved in the development of the lens and anterior segment of the eye.
Genetic counseling
The disorder is transmitted as an autosomal dominant trait.
Management and treatment
The cataract can be managed by classical surgery. Yearly monitoring of ocular tonus is advised; hypertonia is treated classically when it appears.
Prognosis
The prognosis is good if the disease is correctly treated, but can lead to blindness if diagnosis is delayed.

                            Last update:
                            July 2006

                            - Expert reviewer(s):
                            Dr Pierre BITOUN


Congenital cataract-hearing loss-severe developmental delay syndrome is a rare, genetic, lethal, neurometabolic disease characterized by congenital cataracts, sensorineural hearing loss, severe psychomotor developmental delay, severe, generalized muscular hypotonia, and central nervous system abnormalities (incl. cerebellar and cerebral hypoplasia, hypomyelination, wide subarachnoid spaces), in the presence of low serum copper and ceruloplasmin. Nystagmus and seizures have also been reported.


Congenital cataract-hypertrophic cardiomyopathy-mitochondrial myopathy syndrome

Congenital cataract - hypertrophic cardiomyopathy - mitochrondrial myopathy (CCM) is a mitochondrial disease (see this term) characterized by cataracts, hypertrophic cardiomyopathy, muscle weakness and lactic acidosis after exercise.

Summary:
Epidemiology
Prevalence of CCM is unknown; approximately 40 cases have been reported to date in disparate locations throughout the world.
Clinical description
Clinical features include congenital cataract (total or rapidly progressive), hypertrophic cardiomyopathy, muscle weakness and lactic acidosis after exercise. CCM may present in two forms, a neonatal lethal form or a chronic form. Hypertrophic cardiomyopathy is diagnosed at birth in half of the patients in both forms. Approximately half of the patients die within the first year of life due to cardiac failure. Nystagmus, strabismus, hypotonia, hyporeflexia and delayed motor development are occasional features. Marked lactic acidemia occurs with even limited muscular exertion. Patients who survive neonatal period and infancy, manifest the chronic form with stable cardiomyopathy and myopathy and have a normal intellect. Physical mobility is impaired due to muscular weakness in most patients.
Etiology
In the majority of CCM patients mutations (nonsense, frame-shift, start codon or splice site) in the AGK gene have been identified. The AGK gene encodes the mitochondrial acylglycerol kinase which plays a role in the assembly of adenine nucleotide translocator (ANT), an essential component of the oxidative phosphorylation in mitochondria. Two patients with distinct autosomal recessive SLC25A4 mutations have been reported (one of whom had cardiomyopathy but not cataract). The SLC25A4 gene encodes the heart and muscle specific isoform 1 of the mitochondrial ANT. The etiology remains genetically unsolved in the rest of cases of CCM. The milder affected individuals carried either splice site or start codon mutations.
Diagnostic methods
Diagnostic procedures include serum and urine analysis for lactic acid, radiology and echocardiogram for findings of cardiomyopathy. Muscle biopsy from cardiac and skeletal muscle reveals storage of lipid and glycogen, mitochondrial abnormalities, ANT deficiency and mild decrease of respiratory chain complexes I and IV. Genetic testing may reveal autosomal recessive mutations in AGK  and SLC25A4 and it should be considered early in diagnostic workup.
Differential diagnosis
Differential diagnoses include mitochondrial encephalo-cardio-myopathy due to TMEM70 deficiency, isolated ATP synthase deficiency and Barth syndrome (see these terms).
Antenatal diagnosis
Prenatal genetic testing may be possible for families with affected children.
Genetic counseling
The reported mutations are transmitted in an autosomal recessive manner.
Management and treatment
CCM patients require cataract surgery during infancy and medical management of cardiomyopathy with standard therapy. Patients may require palliative care and a wheelchair for locomotion.
Prognosis
Approximately half of the reported patients die in the first year of life due to cardiac failure. The longest surviving patients are in their fifth decade of life.

                            Last update:
                            June 2014

                            - Expert reviewer(s):
                            Dr Tobias HAACK  - Pr Johannes MAYR  - Dr Holger PROKISCH  - Pr Wolfgang SPERL


Congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome

A rare, genetic, mitochondrial myopathy characterized by congenital cataract, progressive muscular hypotonia that particularly affects the lower limbs, reduced deep tendon reflexes, sensorineural hearing loss, global development delay and lactic acidosis. Muscle biopsy reveals reduced complex I, II and IV respiratory chain activity.


Congenital cataract-severe neonatal hepatopathy-global developmental delay syndrome

A rare genetic disease characterized by congenital cataract, neonatal hepatic failure and cholestatic jaundice, and global developmental delay. Neonatal death due to progressive liver failure has been reported.


Congenital cataracts-facial dysmorphism-neuropathy syndrome

A rare autosomal recessive multiple congenital anomalies/dysmorphic syndrome characterized by abnormalities of the eye; mildly dysmorphic facial features; and a hypo/demyelinating, symmetric, distal peripheral neuropathy.

Summary:
Epidemiology
To date, congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome has been found to occur exclusively in patients of Roma ethnicity; over 190 patients have been diagnosed.
Clinical description
Developmental abnormalities include congenital cataracts, microcornea, microphthalmia and micropupils, primary hypomyelinating polyneuropathy, impaired physical growth, delayed early motor and intellectual development, mild facial dysmorphism and hypogonadism. Para-infectious rhabdomyolysis is a serious complication reported in an increasing number of patients. During general anesthesia, patients with CCFDN require careful monitoring as they have an elevated risk of complications.
Etiology
CCFDN is a genetically homogeneous condition in which all patients are homozygous for the same ancestral mutation in the CTDP1 gene. CTDP1 maps to 18qter and encodes a protein phosphatase whose only known substrate is the phosphorylated serine residues of the carboxy-terminal domain of the largest subunit of RNA polymerase II, indicating that CCFDN affects basic cellular processes of gene expression and developmental regulation. All of the affected are homozygous for the CTDP1 Romani founder variant c.863+389C>T.
Diagnostic methods
Diagnosis is clinical and is supported by electrophysiological and brain imaging studies. The definitive diagnosis is molecular, based on homozygosity for the CTDP1 mutation.
Differential diagnosis
The major differential diagnosis is Marinesco-Sjogren syndrome. Some other disorders should be considered as well: Galactokinase (GALK) deficiency, autosomal recessive cerebellar ataxia with late-onset spasticity, INTS1-related neurodevelopmental disorder.
Antenatal diagnosis
Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member. Once the CTDP1 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing for CTDP1-CCFDN are possible.
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 surgical treatment of the cataracts, and rehabilitation and corrective orthopedic surgery for the peripheral neuropathy.
Prognosis
The most disabling manifestations, though not curable, are manageable, and allow for an acceptable quality of life. Current data indicate that patients survive well into adulthood.

                            Last update:
                            October 2023

                            - Expert reviewer(s):
                            Pr Teodora CHAMOVA | EURO-NMD* - Pr Ivailo TOURNEV | EURO-NMD*

                                * European Reference Network


Congenital central hypoventilation syndrome (CCHS) is a rare disease due to a severely impaired central autonomic control of breathing and dysfunction of the autonomous nervous system.

Summary:
Epidemiology
The incidence is estimated to be at 1 of 200 000 livebirths.
Clinical description
Association with a Hirschsprung's disease is observed in 16% of the cases.
Etiology
A heterozygous mutation of PHOX-2B gene is found in 90% of the patients.
Prognosis
Despite a high mortality rate and a lifelong dependence to mechanical ventilation, the long-term outcome of CCHS should be ultimately improved by multidisciplinary and coordinated follow-up of the patients.

                            Last update:
                            February 2006

                            - Expert reviewer(s):
                            Dr Ha Thi-Tuyet TRANG


Congenital cerebellar ataxia due to RNU12 mutation

A rare hereditary ataxia characterized by delayed motor milestones in early infancy, hypotonia, ataxic gait, intention tremor, nystagmus, dysarthric speech, and variable learning difficulties. Neuroimaging shows a mixed picture of cerebellar hypoplasia and degeneration, with an almost absent inferior lobule and thinning of the folia of the vermis. In addition, cisterna magna and fourth ventricle are enlarged with relative sparing of the brain stem volume.


Congenital cervical spinal stenosis is a rare neurological disease characterized by a congenital narrowing of the bony anatomy of the cervical spinal canal (saggital diameter <14mm), predisposing the individual to symptomatic neural compression, such as cramps, paresthesias, pain, muscle hypertonia and weakness, myelopathy and sphincter disturbances.


A rare genetic intestinal disease characterized by persistent, potentially life-threatening, watery diarrhea with excessive levels of chloride in stools, hypochloremia, hyponatremia, hypokalemia, and metabolic alkalosis, resulting in chronic dehydration and failure to thrive. Antenatal ultrasound typically reveals polyhydramnios and significant dilatation of the fetal intestinal loops.


Congenital chronic diarrhea with protein-losing enteropathy is a rare, genetic, intestinal disease characterized by early-onset, chronic, non-infectious, non-bloody, watery diarrhea associated with protein-losing enteropathy which results in hypoalbuminemia, hypogammaglobulinemia and elevated stool alpha-1-antitrypsin. Patients typically present severe, intractable diarrhea, failure to thrive, recurrent infections and edema.


Congenital chylothorax is a rare, potentially life-threatening neonatal condition characterized by the accumulation of chyle within the pleural space leading to respiratory distress, malnutrition and immunological compromise, either immediately after birth or within the first few weeks of life. Congenital chylothorax is the most common cause of pleural effusion in neonates; it can occur primarily due to developmental anomalies of the lymphatic duct or can be associated with chromosomal anomalies (e.g. Noonan syndrome, Turner syndrome and Down syndrome), hydrops fetalis, mediastinal neuroblastoma and other congenital malformations.


Congenital complete agenesis of pericardium is a rare, mostly asymptomatic, congenital heart malformation characterized by the complete absence of the entire pericardium, or by the absence of either the right (uncommon) or left pericardium. It is occasionally associated with chest pain (common), dyspnea, dizziness, bradycardia and syncope, while exertional manifestations are rare. The disease is usually incidentally diagnosed during surgery or at autopsy.


A rare connective tissue disorder characterized by multiple flexion contractures, arachnodactyly, kyphoscoliosis, abnormal pinnae and muscular hypoplasia.

Summary:
Epidemiology
The incidence of congenital contractural arachnodactyly (CCA) is unknown and its prevalence is difficult to estimate due to the overlap in phenotype with MFS. About 70 probands have been described with no geographical predilection.
Clinical description
CCA often presents at birth with congenital contractures, 'crumpled' ear helices, arachnodactyly, and a lean body habitus. Congenital scoliosis is rare. Over the years, the congenital contractures and ear malformations tend to improve, but usually remain noticeable, as well as a lean body habitus. The external ear in adults often shows a prominent anterior crus of the antihelix resulting in a 'tram tracks' appearance with the helical crus. Individuals with CCA are at risk for developing mitral valve prolapse and aortic root dilatation, but the exact risk for complications is unknown but esteemed low. Ocular complications include keratoconus. Ectopia lentis has not been confirmed in individuals with a molecularly proven diagnosis. At the mildest end, parents who are diagnosed retrospectively upon evaluation of their more severely affected child may show a lean body build, mild arachnodactyly, prominent anterior crus of the antihelix, and/or mild contractures without impairment. At the most severe end congenital heart defects and gastrointestinal malrotation and atresia have been documented, though a clear correlation with the genotype remains to be established.
Etiology
CCA is caused by a mutation in the FBN2 gene on chromosome 5q23.
Diagnostic methods
During pregnancy, ultrasound imaging may be used to demonstrate joint contractures and hypokinesia in suspected cases. A clinical scoring system for CCA has been published and can be used for the diagnosis of probands: arachnodactyly, camptodactyly, large joint contractures are each allotted 3 points, dolichostenomelia and pectus deformity are allotted 2 points, (kypho)scoliosis, muscle hypoplasia, highly arched palate, and micrognathia are allotted 1 point. A score of 7 points or more indicates a likely diagnosis of CCA. Confirmation with molecular analysis is advised.
Differential diagnosis
Although the clinical features can be similar to Marfan syndrome (MFS), multiple joint contractures (especially of the elbow, knee, and finger joints), and crumpled ears in the absence of significant aortic root dilatation are characteristic of CCA. Crumpled ears can be present in neonatal MFS, that however additionally shows severe valvular disease and/or aortic dilatation.
Antenatal diagnosis
Antenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Genetic counseling
Transmission is autosomal dominant. Genetic counseling should be offered to at risk individuals informing them that there is a 50% risk of having an affected child at each pregnancy.
Management and treatment
Management of children with CCA is symptomatic. Early physiotherapy for contractures and scoliosis can prevent morbidity later in life. Cardiac and ophthalmologic evaluations are recommended.
Prognosis
Spontaneous improvement in camptodactyly and contractures is observed but residual camptodactyly usually remains. Ear malformations tend to improve. Joint pain may occur later in life and scoliosis can, rarely, be disabling. The risk for aortic dissection has not been established.

                            Last update:
                            October 2023

                            - Expert reviewer(s):
                            Pr Bert CALLEWAERT | VASCERN*

                                * European Reference Network


A rare developmental defect of the eye characterized by usually bilateral absence of the normal protrusion of the cornea from the sclera, the corneal curvature being the same as that of the adjacent sclera. Most patients develop hyperopia, hazy corneal limbus, and arcus lipoides at an early age. The condition may present as an autosomal dominant or an autosomal recessive form, with the latter showing more severe signs and symptoms (such as a round and opaque thickening located centrally in the cornea) and more frequent association with other ocular anomalies.


Congenital coronary artery aneurysm is a rare congenital coronary artery malformation defined as a more than 1.5 fold the normal size dilatation of a coronary artery segment with no identified underlying inflammatory or connective tissue disease. It may be asymptomatic or may present with angina pectoris, myocardial infarction, sudden cardiac death, fistula formation, pericardial tamponade, compression of surrounding structures, or congestive heart failure.


A rare structural developmental eye defect characterized by a persistent cyst replacing the eye due to partial or complete failure of the invagination of the optic vesicle during the fetal period. If the failure of invagination is only partial, dysplastic ocular structures may be present. The wall of the cyst is composed of connective tissue lined by neuroglial material. The defect is usually unilateral and may be an isolated finding or occur in association with intra- or extraocular malformations.


Congenital deficiency in alpha-fetoprotein is a benign genetic condition characterized by a dramatically decreased level of alpha-fetoprotein in fetus or neonate.


A rare developmental defect during embryogenesis which can be a non-syndromic (70%) or syndromic (30%) diaphragmatic malformation characterized by a posterolateral defect of the diaphragm that allows passage of abdominal viscera into the thorax, leading to respiratory insufficiency and persistent pulmonary hypertension.

Summary:
Epidemiology
Congenital diaphragmatic hernia (CDH) is a rare condition occuring in 1-5/10,000 births.
Clinical description
Newborns display respiratory distress with hypoxia, excavated abdomen with sternal protrusion and in severe cases low APGAR scores at 1 and 5 minutes. Auscultation may reveal a contralateral cardiac displacement and respiratory bruits are absent or decreased on the affected side. Insufficient gas exchange and persistent pulmonary hypertension are associated with hypoplastic lungs. Pulmonary hypertension may become manifest after a brief period of adaptation to post-natal circulation. The defect and hence herniation of the intestine and/or the liver into the thorax occurs more often on the left side. Malrotation or malfixation of the intestine are frequent. One third of cases present with cardiovascular malformations and lesser proportions with skeletal, neural, genitourinary, gastrointestinal or other defects. CDH may be isolated (non-syndromic) or a component of Fryns, Denys-Drash and Donnai-Barrow syndromes as well as certain chromosomal anomalies.
Etiology
The causes of CDH are largely unknown; abnormal embryogenesis due to retinoid signaling dysfunction is likely involved as are mutations of ZFPM2 and GATA6 in some cases. Persistent pulmonary hypertension is due to arteriolar constriction and closure of the pulmonary arterial bed.
Diagnostic methods
Thoracic and abdominal X-rays locate herniated viscera. Blood gases and pH status, and other derived indexes, reflect the efficiency of gas exchange. Echocardiography of the heart is necessary to exclude associated malformations, to measure the right-to-left shunt and to estimate the severity of pulmonary hypertension.
Differential diagnosis
CDH should be differentiated from cystic malformation of the lung.
Antenatal diagnosis
Prenatal ultrasonography reveals herniation, polyhydramnios may appear. Genetic testing for associated chromosomal aberrations and syndromes may indicate syndromic CDH if other manifestations are present. Small lungs size related to the size of the head indicates lung hypoplasia and can be prognostic.
Genetic counseling
Most cases are sporadic and appear to be multifactorial, two thirds are male. Recurrence in siblings is 2%. Genetic counseling should be offered.
Management and treatment
Termination of pregnancy may be offered when chromosomal aberrations and syndromes are present. Fetoscopic endoluminal tracheal occlusion (FETO) with a balloon, particularly for fetuses considered otherwise unviable, has yielded survival rates approaching 50%. Gestation should be prolonged until near term if possible; maternal corticosteroids have also been proposed. In newborns, pre- and post-ductal percutaneous oxygen saturation measurements may assess the pulmonary function. Spontaneous ventilation or high frequency, low pressure ventilation (<20-25 cm H2O), no relaxation, alkalinization and adoption of modest gasometric goals (pre-ductal saturation of 80-95%, PaO2 60 mm Hg, hypercapnia <60 mm Hg) are now the standard. Extra-corporeal membrane oxygenation (ECMO) has also been used. Inotropic drugs (eg: dobutamine, dopamine) may be used to treat cardiac anomalies. Surgical repair of the hernia, undertaken only after cardio-respiratory functions are stable, replaces viscera into the abdomen and closes the diaphragmatic defect; a prosthetic patch may be necessary to repair the defect. Some surgeons perform this operation by video-assisted thoracoscopy.
Prognosis
Considering prenatal and preoperative fatalities, mortality is 50-60%. Post-operative survival rate is 70-80%, up to 90% in certain institutions, particularly in non-syndromic CDH. Right-sided hernias seem to have a worse prognosis and may require more ECMO support. After surgical repair, pleural effusions and chronic respiratory tract disease are frequent, along with gastroesophageal reflux. Neurodevelopmental deficits are a risk following bouts of cerebral hypoxia. Neurosensorial deafness has been reported in a small proportion of patients.

                            Last update:
                            August 2020

                            - Expert reviewer(s):
                            Pr Richard KEIJZER


A fast growing group of inborn errors of metabolism characterized by defective activity of enzymes that participate in glycosylation (modification of proteins and other macromolecules by adding and processing of oligosaccharide side chains). This group is comprised of phenotypically diverse disorders affecting multiple systems including the central nervous system, muscle function, immunity, endocrine system, and coagulation. The numerous entities in this group are subdivided, based on the synthetic pathway affected, into disorder of protein N-glycosylation, disorder of protein O-glycosylation, disorder of multiple glycosylation, and disorder of glycosphingolipid and glycosylphosphatidylinositol anchor glycosylation.


Congenital dyserythropoietic anemia type I

Congenital dyserythropoietic anemiatype I (CDA I) is a hematologic disorder of erythropoiesis characterized by moderate to severe macrocytic anemia occasionally associated with limb or nail deformities and scoliosis.

Summary:
Epidemiology
The prevalence is unknown. Over a 42 year period (from 1967-2009), 122 CDA I cases were reported in Europe.
Clinical description
CDA I usually presents in the first decade of life. Manifestations include a moderate macrocytic anemia associated with intermittent jaundice, frequent splenomegaly and occasional hepatomegaly. Approximately 1/3 of CDA I patients may also have congenital malformations of the limbs (supernummary toes, hand or feet syndactyly, absence of nails) or heart (ventricular septal defect), double kidneys, short stature or hip dysplasia. Later, cholelithiasis or gallstones may occur. The main complication is iron overload which can lead to organ damage.
Etiology
CDA I etiology is not fully understood, but most cases have been associated with mutations in the CDAN1 gene (15q15.2), coding for a histone chaperone interacting protein. Mutations in a predicted endonulease protein encoded by the C15ORF41 gene (15q14) have recently been described in three CDAN1 mutation-negative patients, making it a second causative gene of CDA I. Since some cases of CDA I have no known mutations in either of these two genes, a third locus may exist.
Diagnostic methods
Laboratory findings, characterization of erythrocytes and bone marrow (BM) observation are diagnostic. Hemoglobin and haptoglobin are low, bilirubin and ferritin are high, blood smear shows anisopoikilocytosis and basophilic stippled erythrocytes. BM aspirate or trephine biopsy reveals erythroid hyperplasia (erythropoietic to granulopoietic cells ratio of 3 to 8), megablastoid aberrations of chromatin structure, large polyploidy cells with irregular nuclear shape, some bi-, tri- or tetra-nucleated polychromatic erythroblasts and internuclear chromatin bridges in 1-8% of all erythroblasts. Electon microscopy shows spongy heterochromatin with a ''Swiss cheese'' appearance.
Differential diagnosis
The diagnosis of CDA should be considered following exclusion of other causes of macrocytosis (B12 deficiency, folic acid deficiency or other megaloblastic anemias such as pernicious anemia or thiamine-responsive megaloblastic anemia syndrome; see this term), acquired dyserythropoiesis (myelodysplastic disorders) and hemolytic anemias. Gilbert syndrome (see this term) and infections should be also excluded.
Antenatal diagnosis
Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutations in the family.
Genetic counseling
Genetic counseling is possible in CDA I. It is inherited in an autosomal recessive manner.
Management and treatment
Treatment focuses on hemoglobin normalization with the administration of interferon (IFN) alpha for patients with CDAN1 mutations. The 3 cases reported with mutations in the C15ORF41 gene were unresponsive to IFN-alpha treatment. Serum ferritin must be thoroughly controlled to monitor iron overload and induce iron depletion when needed. Splenectomy is not recommended and individual decisions have to be made in cases with transfusion dependency and enlarged spleen. Transfusion may be necessary in some cases. In-utero transfusions are required for severe cases of fetal anemia. Cholecystectomy is often indicated. Successful allogenic bone marrow transplantation has been described in a few individuals and should be considered only in those transfusion-dependent persons who are resistant to IFN therapy.
Prognosis
Prognosis is usually good even if life expectancy is slightly reduced. Morbidity may be important due to iron overload complications that can be fatal if untreated.

                            Last update:
                            September 2013

                            - Expert reviewer(s):
                            Dr Mayka SÁNCHEZ FERNÁNDEZ


Congenital dyserythropoietic anemia type II (CDA II) is the most common form of CDA (see this term) characterized by anemia, jaundice and splenomegaly and often leading to liver iron overload and gallstones.

Summary:
Epidemiology
The prevalence is unknown. Over a 42 year period (1967-2009), 367 CDA II cases were reported in Europe.
Clinical description
The disease usually presents with jaundice and normocytic anemia (mild to severe) in neonates but in some cases symptoms may be so mild that diagnosis can be delayed until adulthood. Splenomegaly and hepatomegaly are also frequent manifestations. Less commonly, posterior mediastinal or paravertebral masses (that consist of extramedullary hemopoietic tissue) are present. In rare cases, hydrops fetalis (see this term) has been associated with CDA II. Long-term complications include secondary hemochromatosis that, if left untreated, can lead to organ damage.
Etiology
Most cases of CDA II are caused by mutations in the SEC23B gene (20p11.23), coding for a coating protein involved in the reticulum-Golgi trafficking.
Diagnostic methods
Diagnosis of CDA II is based on the presence of congenital anemia, 10-50% binuclearity of bone marrow erythroblasts and increased ferritin levels. Further diagnostic findings include a positive serum acidification (Ham) test, a SDS-PAGE red blood cell (RBC) membrane electrophoresis that reveals a narrow and fast migrating band 3 and a bone marrow electron microscope that reveals the presence of a double membrane in RBC precursors. Molecular genetic analysis can also be used to identify a SEC23B mutation.
Differential diagnosis
The diagnosis of CDA should be considered following exclusion of other causes of hemolytic anemias (especially hereditary spherocytosis), acquired dyserythropoiesis (myelodysplastic syndromes, acute erythroid leukemia) and microcytic anemias (thalassemias or iron deficiency anemias) (see these terms). Gilbert syndrome (see this term) and infections should be also excluded.
Antenatal diagnosis
Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutations in the family.
Genetic counseling
CDA II is inherited in an autosomal recessive manner and genetic counseling is possible.
Management and treatment
Treatment chosen depends on disease severity and age of patients. Neonates may require an erythrocyte transfusion and in severe cases may be transfusion-dependent for years to come. This need usually diminishes in adolescence and adulthood except under certain circumstances (pregnancy, aplastic crisis, major operations and infections). Hydrops fetalis-associated anemia can be treated with intrauterine transfusions. Vitamin B12 and folic acid supplements are frequently used, although without any evidence of efficacy. The use of erythropoietin formulations also appears to be ineffective. Allogenic bone marrow transplantation has been successful in a few severe cases. Cholecystectomy is often suggested for treatment of cholethiasis. Transfusions can worsen the problem of iron loading and ferritin levels should be monitored annually. Body iron overload can also be monitored by magnetic resonance imaging. Phlebotomies can decrease ferritin concentrations but as they are not well tolerated by some, they should be accompanied by oral chelating agents.
Prognosis
The prognosis of CDA II is usually good. However, morbidity may be important due to iron overload complications that can be fatal if untreated.

                            Last update:
                            September 2013

                            - Expert reviewer(s):
                            Dr Mayka SÁNCHEZ FERNÁNDEZ


Congenital dyserythropoietic anemia type III

A rare form of congenital dyserythropoietic anemia (CDA) characterized by dyserythropoiesis, with big multinucleated erythroblasts in the bone marrow, and manifesting with mild to moderate anemia.

Summary:
Epidemiology
The prevalence is unknown. Three families have been reported with autosomal dominant CDA III in Sweden, America and Argentina. Four families have been described for the autosomal recessive CDA IIIb form with Spanish or latinoamerican origin. Other sporadic CDA III-like cases have been described. In total, more than 60 cases have been reported worldwide.
Clinical description
The clinical presentation is variable. CDA III can manifest with mild anaemia and jaundice in neonates but it may not be discovered until childhood or adulthood. Intensity of symptoms increases during infections, following trauma, and during pregnancy. The autosomal dominant (AD) CDA IIIa form was associated with monoclonal gammopathies, multiple myeloma and retinal angioid streaks, which can lead to visual impairment. The autosomal recessive CDA IIIb form was associated with macrocytic anaemia with marked dyserythropoiesis, erythroid hyperplasia, giant multinucleated erythroblasts, hepatospenomegaly and skull defects secondary to increased extramedullary hematopoiesis. Other sporadic cases of CDA III have been associated with severe erythroid hyperplasia, skeletal disorders, intellectual deficit, and hepatosplenomegaly.
Etiology
Mutations in KIF23 gene (15q23) has been identified as the causal mutation for AD CDA IIIa. Recently, mutations in the RACGAP1 gene (12q13) were reported as the cause for the autosomal recessive form of CDAIII (named CDAIIIb). KIF23 encodes mitotic kinesin-like protein (MKLP1), which dimerizes and combines with a homodimer of the RACGAP1 protein (Rac GTPase-activating protein 1), to form the centralspindlin complex, crucial for cytokinesis.
Diagnostic methods
Diagnosis is based on laboratory findings. The disorder is characterized by mild anaemia, macrocytosis in the peripheral blood, and giant multinucleated erythroblasts (containing up to 12 nuclei) in the bone marrow. Increased levels of serum thymidine kinase, lactate dehydrogenase and bilirubin and very low or undetectable haptoglobin are also characteristic of this disease. Mutations in the KIF23 gene or the RACGAP1 gene can also determine a diagnosis of CDA III, type a or b, respectively.
Differential diagnosis
The diagnosis of CDA IIIa/CDAIIIb should be considered following exclusion of other causes of macrocytosis (B12 deficiency, folic acid deficiency or other megaloblastic anemias such as pernicious anemia or thiamine-responsive megaloblastic anemia syndrome), acquired dyserythropoiesis (myelodysplastic syndrome, acute erythroid leukemia), hemolytic anemias (hereditary spherocytosis) or microcytic anemias (thalassemias and iron deficiency anemias). Gilbert syndrome and infections should be also excluded.
Antenatal diagnosis
Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutations in the family.
Genetic counseling
Genetic counseling is possible in CDA IIIa and CDA IIIb. CDA IIIa is inherited in an autosomal dominant mode (50% risk of having an affected child at each pregnancy), while CDA IIIb is inherited in an autosomal recessive mode (25% risk of having an affected child at each pregnancy).
Management and treatment
In most cases anaemia is mild and treatment is not necessary. Only during times of extreme anaemia (often due to pregnancy or surgery), may a transfusion be needed. Ophthalmological follow-up is recommended in those with eye manifestations in CDA IIIa cases. In some cases, splenectomy could be necessary to manage with splenomegaly. Iron overload was reported in one CDAIIIb patient that was regularly treated with blood transfusions. Chelation treatment is recommended for managing iron overload.
Prognosis
In most cases the prognosis is good and there is no decrease in life expectancy. Quality of life may be affected in those with visual impairment or with iron overload complications.

                            Last update:
                            July 2023

                            - Expert reviewer(s):
                            Dr Mayka SÁNCHEZ FERNÁNDEZ


Congenital dyserythropoietic anemia type IV (CDA IV) is a newly discovered form of CDA (see this term) characterized by ineffective erythropoiesis and hemolysis that leads to severe anemia at birth.

Summary:
Epidemiology
The prevalence is unknown. Only 4 cases have been reported to date.
Clinical description
Patients have been described as having severe anemia at birth that requires repeated transfusions. Hepatomegaly, splenomegaly, jaundice, hypertrophic cardiomyopathy, and occasional dysmorphic features (large anterior fontanel, hypertelorism, micropenis, and hypospadias) have also been reported. These cases showed increased levels of fetal hemoglobin, a very large number of nucleated red blood cells in peripheral blood and bone marrow erythroblast morphologic abnormalities.
Etiology
CDA IV is due to mutations in the KLF1 gene (19p13.2), encoding an erythroid transcription factor that plays a fundamental role in the expression of globin genes and also additional genes that may be involved in erythropoiesis.
Genetic counseling
Genetic counseling is possible for CDA IV. It is inherited in an autosomal dominant manner.

                            Last update:
                            September 2013

                            - Expert reviewer(s):
                            Dr Mayka SÁNCHEZ FERNÁNDEZ


Congenital dyserythropoietic anemia (CDA) is a heterogenous group of hematological disorders of late erythropoiesis and red cell abnormalities that lead to anemia. Five types of CDA are defined: CDA I, CDA II, CDA III, CDA IV and thrombocytopenia with CDA (see these terms).

Summary:
Epidemiology
A global CDA prevalence figure is not precisely known. Over a 42 year period (1967-2009), 122 CDA I and 367 CDA II cases were reported in Europe. About 60 cases of CDA III have been reported worldwide as well as 4 cases of CDA IV to date. Three families have been reported to have thrombocytopenia with CDA.
Clinical description
Onset of CDA generally occurs in childhood or early adulthood, even if clinical signs can occasionally be observed in the neonatal period. Patients share chronic anemia of variable severity and jaundice, frequently associated with splenomegaly and/or hepatomegaly. Symptoms of anemia include fatigue, failure to thrive in infants, headache, dizziness, leg cramps, tachycardia and insomnia. Erythropoiesis is always dysfunctional, as revealed by cellular anomalies and erythroid hyperplasia. CDA I patients have a moderate macrocytic anemia with frequent splenomegaly and occasional hepatomegaly. Jaundice is intermittent and approximately 1/3 of patients have congenital malformations, mostly involving the limbs, but also the heart, kidneys or hip. The main complication is iron overload which can lead to organ damage. In CDA II, the most frequent type, anemia and/or jaundice is usually detected in children or young adults with splenomegaly. Liver iron overload and gallstones are frequent. CDA III is a very rare subtype characterized by mild hemolytic anemia and a predisposition to retinal angioid streaks, gammopathies and myeloma. CDA IV is characterized by the presence of a very large number of nucleated erythrocytes in the peripheral blood. Thrombocytopenia with CDA is characterized by dysmorphic erythrocytes and paucity of the platelets.
Etiology
Etiology of CDA is not fully defined. CDA I is due to mutations in the CDAN1 gene (15q15.2), coding for a histone chaperone interacting protein, or in the C15ORF41 gene (15q14), coding for a predicted endonuclease putatively involved in DNA replication and/or chromatin assembly. Since some cases of CDA I have no known mutations in any of these two genes, a third locus may exist. Most cases of CDA II are caused by mutations in the SEC23B gene (20p11.23), coding for a coating protein involved in reticulum-Golgi trafficking. CDA III is due to mutations in the KIF23 gene (15q23), encoding a conserved mitotic kinesin (MKLP1) crucial for cytokinesis. The last 2 CDA types are caused by mutations in the erythroid transcription factor genes KLF1 (19p13.2) and GATA1 (Xp11.23).
Genetic counseling
CDA I and CDA II are inherited autosomal recessively while CDA III and CDA IV are inherited autosomal dominantly. Thrombocytopenia with CDA has an X-linked inheritance pattern. Genetic counseling is possible for all types of CDA with a known mutation.

                            Last update:
                            September 2013

                            - Expert reviewer(s):
                            Dr Mayka SÁNCHEZ FERNÁNDEZ


Congenital ectropion uveae is a rare, genetic, non-syndromic developmental defect of the eye characterized by the presence of iris pigment epithelium on the anterior surface of the iris, anterior insertion of the iris, angle dysgenesis and progressive open-angle glaucoma (the latter may present in infancy or may develop later in life). Patients may manifest with headaches, ocular pain, photophobia, and redness, watering and/or swelling of the eye. It can often be associated with neurofibromatosis and less commonly with other ocular abnormalities.


Congenital enterocyte heparan sulfate deficiency

A rare, severe, genetic, intestinal disease characterized by congenital absence of heparan sulfate from small intestine epithelium manifesting with secretory diarrhea and massive enteric protein loss. Patients present intolerance to enteral feeds during the first few weeks to months of life. Apart from absence of heparan sulfate from the basolateral surface of small intestine enterocytes, small bowel biopsy is otherwise normal.


Congenital enteropathy due to enteropeptidase deficiency is a rare, genetic, gastroenterological disease characterized by early-onset failure to thrive, edema, hypoproteinemia, diarrhea and fat malabsorption (or steatorrhea) in the presence of very low or absent trypsin activity in duodenal fluid. Celiac disease, or other pancreatic or mucosal disorders, may be associated.


An infectious embryofetopathy including coxsackie viruses and ECHO viruses that have been reported to cause spontaneous abortion, stillbirth, acute systemic illness in the newborn, and possibly fetal malformations.

Summary:
Epidemiology
Congenital enterovirus infection (EV) prevalence is still unknown. EV infections are underdiagnosed in the mother (mainly because of frequent subclinical infections) and hence may be far more frequent than supposed.
Clinical description
Clinical manifestations of congenital EV infection ranges from asymptomatic to benign, febrile to severe illness consisting of variable combinations of sepsis, hepatitis, coagulopathy, myocarditis, pneumonitis and meningoencephalitis. Clinical features are observed in utero or occurring in the first 1-2 days of life, some with viremia detected within hours after delivery. Additional features of congenital EV infection include spontaneous abortion, hydrops fetalis and stillbirths in which multiorgan disease may include myocarditis or pancarditis. Fetal anomalies of the cardiovascular, gastrointestinal and genitourinary system, along with neurodevelopmental delay, bilateral pleural effusion, abdominal ascitis, severe respiratory failure, cortical necrosis (that may lead to severe long-term neurologic sequelae) have also been scarcely reported. Infants may also develop a ''sepsis-like syndrome'' characterized by hypotension, leucopenia or leukocytosis, neutropenia, thrombocytopenia, and disseminated intravascular coagulopathy.
Etiology
Coxsackie A, B, ECHO viruses, and numbered EVs are believed to cross the placenta and cause fetal disease. Severity and outcome of perinatally acquired enteroviral infection is influenced by several factors, including term at delivery (premature neonates are more susceptible to severe infections), symptoms in the mother, infection in the 10 first days of life, virus strain, route of transmission (in utero or during delivery), and presence of passively acquired serotype-specific maternal antibody.
Diagnostic methods
In case of ultrasound findings antenatal diagnosis of congenital EV infection is achieved by molecular detection of the virus' RNA in amniotic fluid. Postnatal diagnosis of EV infection (congenital or not) relies on molecular detection of the virus' RNA in plasma (including cord blood at birth), stool, nasopharyngeal swab, and cerebrospinal fluid.
Differential diagnosis
Differential diagnosis includes congenital infection with Toxoplasma gondii, Rubella, Cytomegalovirus, Herpes simplex virus, Parvovirus B19, Syphilis.
Management and treatment
There is no specific curative treatment for EV maternal or congenital infection.
Prognosis
Prognosis of mild congenital EV infections is quite good if reanimation procedures are available. Prognosis of severe congenital EV infections is poor and the disease has been reported to be fatal.

                            Last update:
                            March 2020

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


A rare infectious disease that causes no clinical manifestations in the majority of infants. Indeed, the occurrence of congenital infection with EBV has never been demonstrated conclusively and must be very rare. One case have been reported to present after birth, multiple congenital anomalies (micrognathia, cryptorchidism, central cataracts), dystrophy, generalized hypotonia, hepatosplenomegaly, diffuse petechiae and hematomas and multiple areas of metaphysitis of the long bones at birth. A low birth weight was also reported. No specific follow-up of the fetus is recommended following maternal EBV primary-infection.


A rare soft tissue tumor characterized by a benign space occupying lesion in neonates, most typically located on the gingival mucosa overlying the anterior alveolar ridge of the maxilla near the canine, although the mandibular region may also be involved. Females are much more frequently affected than males. The tumor mostly presents as a single lesion, potentially interfering with feeding and respiration. Metastasis, malignant transformation, or recurrence after excision have not been reported.


Congenital erosive and vesicular dermatosis

A rare, idiopathic skin disease characterized by widespread, congenital, superficial erosions and vesicles (often involving more than 75% of the body) which heal leaving scars with a supple, symmetrical, reticulated pattern, frequently resulting in cicatricial alopecia and hyperthermia and/or hypohydrosis. Nail anomalies, neurodevelopmental and ophtalmologic abnormalities, tongue atrophy and preterm birth, with or without history of choriomnionitis, are commonly associated.


A rare erythropoietic porphyria characterized by a non-photoalgesic, polymorphic, mutilating and very severe photodermatosis.

Summary:
Epidemiology
Since its description in the late 19th century, around 220 cases of congenital erythropoietic porphyria (CEP) have been reported in the literature.
Clinical description
The disease most often manifests from birth as extremely severe, mutilating cutaneous photosensitivity, sometimes revealed by phototherapy used for the treatment of neonatal jaundice. The main symptoms include rapidly-erosive bullous skin lesions on photoexposed surfaces (hands, face, feet), which can progress to mutilating lesions and disabling retractive scars. Hypertrichosis is common. Urine is often pink to dark red and stains the diaper of affected infants. In severe forms, patients present more or less intense hemolysis. Significant splenomegaly may appear, linked to hemolytic anemia. Bone involvement is constant, with rarefaction of the architecture and risk of multiple fractures.
Etiology
CEP is caused by a deficiency in uroporphyrinogen synthase (UROS, the fourth enzyme in the heme biosynthesis pathway), which leads to a massive accumulation of isomeric type I porphyrins (uro and coproporphyrins) in the bone marrow. The enzyme deficiency is due to mutations of the UROS gene (NM_000375.3), coding for UROS. A certain degree of genotype-phenotype correlation has been demonstrated by the identification of so-called "severe" or "moderate" mutations. In 50 % of cases, the "severe" C73R mutation is present.
Diagnostic methods
The diagnosis is easily made based on the evidence of massive accumulation of isomeric type I porphyrins in urine and blood. Detection of UROS deficiency in red blood cells and identification of causative mutations in the UROS gene confirm the diagnosis. Differential diagnosis The differential diagnosis includes hepatoerythropoietic porphyria, porphyria cutanea tarda, acute hepatic porphyrias with cutaneous expression, and epidermolysis bullosa.
Differential diagnosis
The differential diagnosis includes hepatoerythropoietic porphyria, porphyria cutanea tarda, acute hepatic porphyrias with cutaneous expression, and epidermolysis bullosa.
Antenatal diagnosis
In families at risk, antenatal diagnosis is possible by amniotic fluid analysis, UROS enzyme activity assay, and/or molecular genetic analysis of amniotic fluid cells.
Genetic counseling
The pattern of inheritance is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a heterozygous pathogenic variant) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Intense preventive photoprotection is necessary to avoid the skin lesions and their aggravation. It incorporates the preventive measures proposed for erythropoietic protoporphyria. The risk of lesion infection is constant, but generally controlled by antibiotic therapy. Hemolytic anemia, splenic sequestration, and thrombocytopenia characterize the severity of the disease, often requiring repeated blood transfusions and associated iron overload, which is often difficult to manage. Splenectomy is often necessary. Induction of iron deficiency in moderate forms of CEP by careful phlebotomy has proved effective in some cases, and could be a lifelong supportive treatment option with varying degrees of acceptance by patients and their families. Allogeneic bone marrow transplantation remains the curative treatment of choice for CEP, with spectacular results including disappearance of hemolytic anemia and healing of skin lesions.
Prognosis
In severe forms, the prognosis is dominated by hemolytic anemia and, above all, thrombocytopenia, which can greatly reduce patients' life expectancy. Multiple fractures often lead to motor disability. For the treatment of CEP, an ex vivo gene therapy project using bone marrow cells is currently under development.

                            Last update:
                            March 2024

                            - Expert reviewer(s):
                            Dr Neila TALBI | MetabERN*

                                * European Reference Network


A rare, non-syndromic, congenital esophageal malformation characterized by a false diverticulum, most often located in the upper, posterior esophagus (pharyngo-esophageal) but may occur anywhere along the esophagus (mid-thoracic or epiphrenic). Many patients are asymptomatic, but bad breath, chronic cough, respiratory distress, food regurgitation, dysphagia, chest pain or discomfort, and aspiration pneumonia are typical presenting manifestations.


Congenital eyelid retraction is a very rare kinetic eyelid anomaly that can affect the upper or lower eyelid, presents at birth, that in some cases can result in corneal exposure, and that may be associated with accessory levator muscle slips.