A rare, genetic, multiple congenital anomalies syndrome characterized by variable expression of the holoprosencephaly (HPE) spectrum in association with ectrodactyly, cleft lip/palate and/or other ectodermal anomalies. Developmental delay of variable severity and endocrine abnormalities are often associated.

Summary:
Epidemiology
Approximately 35 patients have been described in the literature to date.
Clinical description
Presentation is heterogeneous; cerebral malformations may present as lobar, semi-lobar and alobar HPE, or milder midline anomalies, such as arhinencephaly, or corpus callosum agenesis. Microcephaly, hypotelorism or hypertelorism, and malformed ears may be observed. Ectrodactyly affects hands and/or feet with variable severity and may involve one to four limbs. Over half of reported individuals have cleft lip and/or palate, which may be uni- or bilateral. Midline brain malformation involving the hypothalamo-pituitary axis may lead a range of endocrine disorders including growth hormone deficiency and subsequent short stature, central diabetes insipidus with a risk of hypernatremic dehydratation, hypogonadotropic hypogonadism, cryptorchidism, micropenis or hypospadias, as well as temperature dysregulation and erratic sleep patterns. Developmental delay is often observed and intellectual disability ranges from mild to severe. In severe cases, individuals are nonverbal, spastic and non-ambulatory. The severity of the neurological impairment in part correlates to the severity of the brain malformation. Seizures are possible. There has been anecdotal reports of skull defects, vertebral anomalies, radial aplasia, eye anomalies, and cardiac malformation.
Etiology
Hartsfield syndrome is most often caused by the presence of heterozygous pathogenic variants in the FGFR1 gene (8p11.23), although bi-allelic pathogenic variants have been described in a minority of patients.
Diagnostic methods
Confirmation of clinical diagnosis is based on FGFR1 sequencing by targeted sanger sequencing, or via NGS (next generation sequencing) multigene panel including FGFR1.
Differential diagnosis
The association of HPE and ectrodactyly is quite unique to Hartsfield syndrome. Phenotypic overlap can be observed in Kallman syndrome, isolated congenital hypogonadotropic hypogonadism, EEC (ectrodactyly ectodermal dysplasia and cleft lip/palate syndrome), HPE, and septo-optic dysplasia spectrum.
Antenatal diagnosis
For parents of an index individual, prenatal diagnosis in subsequent pregnancies should be discussed. Diagnosis involves genetic testing for FGFR1 in the presence of the ultrasound findings of HPE and/or ectrodactyly.
Genetic counseling
Depending on the variants identified, transmission of Hartsfield syndrome can follow an autosomal dominant or recessive mode of inheritance. In most cases, heterozygous FGFR1 variants occur de novo. Several occurrences of parental germline mosaicisms, with recurrences in the sibship, have been reported. Although not known, the recurrence risk in siblings is thus much higher than the usual theoretical 1% estimated risk in the presence of an apparent de novo variant. Recurrence risk is 25% in each pregnancy if bi-allelic variants are identified in the index sib.
Management and treatment
Management and treatment are based on the phenotype. Severity of the HPE must be evaluated by neuroimaging. Spasticity and the possibility of seizures must be assessed. Antiepileptic drugs, physical and occupational therapy may be needed. Nutritional and feeding status should be evaluated. Surgery may be required to treat cleft lip/palate and ectrodactyly. The possibility of endocrine deficiency must be evaluated (growth hormone deficiency, hypogonadotropic hypogonadism, and central diabetes insipidus). Central diabetes insipidus may require treatment with desmopressin.
Prognosis
Prognosis depends on the severity of the phenotype.

                            Last update:
                            December 2020

                            - Expert reviewer(s):
                            Pr Catheline VILAIN | ITHACA*

                                * European Reference Network


A rare inborn error of tyrosine metabolism characterized by failure to thrive, persistent metabolic acidosis, fine and sparse hair, and excretion of the unusual cyclic amino acid metabolite, hawkinsin ((2-l-cystein-S-yl, 4-dihydroxycyclohex-5-en-1-yl)acetic acid), in the urine.


A severe form of alpha-thalassemia that is mostly lethal, and associated with severe long-term outcome and lifelong transfusions in survivors. It is characterized by fetal onset of generalized edema, pleural and pericardial effusions, and severe hypochromic anemia.

Summary:
Epidemiology
The disease occurs predominantly in Southeast Asia. Prevalence at birth in this region is estimated to be between 1/200-2,000. Exact prevalence in other regions is not known.
Clinical description
Affected fetuses suffer from severe anemia in utero, causing severe tissue hypoxia, heart failure and a range of developmental abnormalities associated with hydrops fetalis (marked hepatosplenomegaly, urogenital and limb abnormalities). In survivors, the neonatal period is often stormy, and growth retardation and neurodevelopmental delay are the major adverse long-term outcomes. Maternal complications during pregnancy include preeclampsia, polyhydramnios or oligohydramnios, antepartum hemorrhage, and premature delivery. Although intrauterine transfusions and perinatal intensive care have resulted in increasing fetal survival to the perinatal period. Early therapeutic termination of at-risk pregnancies is usually recommended due to the severity of the syndrome and the risk of potentially serious maternal complications during pregnancy.
Etiology
Bart's hydrops fetalis is caused by deletion or inactivation of all four alpha-globin alleles leading to a severe deficiency in alpha-globin chains of Hb, and to the production of gamma-4 tetramers (Hb Bart's) during fetal life, and beta-4 tetramers (HbH) postnatally. Hb Bart's and HbH have increased oxygen affinity resulting in ineffective tissue oxygen delivery. The disease is mostly the result of combined, biallelic deletions in the HBA1 and HBA2 genes (16p13.3).
Diagnostic methods
The disease can be diagnosed on ultrasound as early as 10 weeks gestation, from ultrasonographic findings of hydrops fetalis followed by fetal DNA analysis and cord blood Hb electrophoresis revealing Hb Bart's.
Differential diagnosis
The main differential diagnosis is hydrops fetalis without alpha-thalassemia, which is a common non-specific sign of numerous fetal or maternal disorders.
Antenatal diagnosis
Prenatal genetic diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Genetic counseling
The pattern of inheritance 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
Death usually occurs in utero or shortly after birth, but fetuses can survive following intrauterine transfusions, and perinatal intensive care. Early intrauterine intervention leads to prolonged gestation, improved Apgar scores, and shortened neonatal mechanical ventilation, but with no clear additional benefits to long-term growth and neurodevelopment. After birth, patients require lifelong and intensive transfusion regimen, targeted at reducing HbH levels, and increasing functional HbA. Treatment is controversial since most treated infants surviving the immediate postnatal period subsequently show abnormal development. These patients may be considered for hematopoietic stem cell transplantation.
Prognosis
Most surviving infants experience a complicated perinatal course and a high prevalence of congenital urogenital and limb defects.

                            Last update:
                            May 2021

                            - Expert reviewer(s):
                            Dr Corinne PONDARRE


Hearing loss-familial salivary gland insensitivity to aldosterone syndrome is characterised by bilateral moderate-to-severe sensorineural hearing loss and salivary gland insensitivity to aldosterone resulting in hyponatremia. It has been described in two brothers. Transmission appeared to be autosomal recessive.


Heart defect-tongue hamartoma-polysyndactyly syndrome

A rare, genetic, multiple congenital anomalies syndrome characterized by congenital heart defects (e.g. coarctation of the aorta with or without atrioventricular canal and subaortic stenosis), associated with tongue hamartomas, postaxial hand polydactyly and toe syndactyly.


A rare multiple congenital anomalies/dysmorphic syndrome characterized by skeletal dysplasia (including coronal clefting of the vertebral bodies and short limbs and variable congenital heart malformations, such as atrial and ventricular septal defects, right ventricular hypoplasia, and valve defects). There have been no further descriptions in the literature since 1990.


Heart-hand syndrome type 2 is an extremely rare heart-hand syndrome (see this term) described in two families to date, that is characterized by upper limb malformations (brachytelephalangy type D, hypoplastic deltoids, mild shortening of the fourth and fifth metacarpals in some individuals, skeletal anomalies in the humerus, radius, ulnae, and thenar bones) and cardiac arrhythmias (junctional rhythms and atrial fibrillation).


Heart-hand syndrome type 3 is a very rare heart-hand syndrome (see this term), described in three members of a Spanish family to date, which is characterized by a cardiac conduction defect (sick sinus, bundle-branch block) and brachydactyly, resembling brachydactyly type C of the hands (see this term), affecting principally the middle phalanges in conjunction with an extra ossicle on the proximal phalanx of both index fingers. Feet abnormalities are more subtle.


A rare autosomal dominant form of heart-hand syndrome that is characterized by adult onset, progressive cardiac conduction disease, tachyarrhythmias that can lead to sudden death, dilated cardiomyopathy and brachydactyly, with the hands less severely affected than the feet. Muscle weakness and/or myopathic electromyographic findings have been observed in some cases.


Heart-hand syndrome refers to a group of congenital disorders characterized by malformations of the upper limbs and heart. To date, heart-hand syndrome comprises the following rare syndromes; Holt-Oram syndrome; heart-hand syndrome type 2; heart-hand syndrome type 3; heart hand syndrome, Slovenian type, brachydactyly-long thumb; and patent ductus arteriosus-bicuspid aortic valve - hand anomalies (see these terms).


A rare non-amyloid monoclonal immunoglobulin deposition disease characterized by production of monoclonal immunoglobulins with truncated heavy chains and no detectable light chains, which are deposited in tissues and cause organ dysfunction, but do not form amyloid beta-pleated sheets or contain an amyloid P component. The condition frequently occurs in association with multiple myeloma. Patients most commonly present with renal involvement (manifesting as hypertension, progressive renal dysfunction, anemia, and nephrotic syndrome with microhematuria), but other organs (such as the liver or skin) may also be affected. Production of IgG1 or IgG3 isotypes results in hypercomplementemia.


Heavy-chain diseases (HCDs) are rare monoclonal lymphoplasma-cell proliferative disorders involving B cells and are characterized by the synthesis of truncated heavy chains without associated light chains.

Summary:
Epidemiology
The prevalence is unknown.
Clinical description
HCDs have been described for the three main immunoglobulin classes: alpha-HCD (see this term) is the most common and has the most uniform presentation whereas gamma- and mu-HCDs (see these terms) have variable clinical presentations and histopathologic features. HCDs can be thought of as variant types of non-Hodgkin lymphoma (NHL; see this term), with alpha-HCD presenting as an extranodal marginal-zone lymphoma of mucosa-associated lymphoid tissue, gamma-HCD as lymphoplasmacytoid NHL, and mu-HCD as small lymphocytic NHL or chronic lymphocytic leukemia (CLL; see this term).
Diagnostic methods
Diagnosis of these conditions requires documentation of a deleted immunoglobulin heavy chain without a bound light chain in the serum or urine.
Prognosis
Prognosis is variable, and no standardized effective treatment programs are available except for alpha-HCD, which in its early stage may respond to antibiotics.

                            Last update:
                            October 2011

                            - Expert reviewer(s):
                            Pr Robert KYLE  - Dr Dietlind WAHNER-ROEDLER


A rare syndromic cardiac disease characterized by communicating hydrocephalus, endocardial fibroelastosis, and congenital cataracts. A history of upper respiratory infection in the mother during the first trimester of pregnancy and polyhydramnios in the third trimester has been associated. No evience of toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus, syphilis, and galactosemia is reported. There have been no further descriptions in the literature since 1995.


Heiner syndrome, also called cow's milk hypersensitivity, is a food induced pulmonary hypersensiting syndrome that affects primarily infants and that is characterized by pulmonary hemosiderosis (see this term), digestive bleeding, anemia and poor growing, improving with elimination of cow's milk from the diet.


Helicoid peripapillary chorioretinal degeneration is a rare autosomal dominantly inherited chorioretinal degeneration disease, presenting at birth or infancy, characterized by progressive bilateral retinal and choroidal atrophy, appearing as lesions on the optic nerve and peripheral ocular fundus and leading to central vision loss. Congenital anterior polar cataracts are sometimes associated with this disease.


A rare hemorrhagic disorder due to an acquired platelet anomaly characterized by hemolysis, elevated liver enzymes and thrombocytopenia that affects pregnant or post-partum women, and is frequently associated with severe preeclampsia. Symptoms are variable, typically including right upper quadrant or epigastric abdominal pain, nausea, vomiting, excessive weight gain, generalized edema, hypertension, general malaise, right shoulder pain, backache, and/or headache. Hepatic hemorrhage and rupture, renal failure, and pulmonary edema can result in maternal and/or fetal death.


Hemangioblastoma is a rare, benign, highly vascularized tumor of the central nervous system, most often located in the cerebellum or spinal cord, presenting in adulthood and manifesting with dizziness, nausea, malaise, headache, bladder or bowel dysfunction, numbness, weakness and pain in the upper or lower extremities, and often associated with von Hippel-Lindau disease (VHL; see this term). Exceptional cases of hemangioblastoma arising outside of the central nervous system have been reported.


A rare inborn error of metabolism characterized by congenital asplenia and childhood or adolescent onset of generalized inflammation, persistent intravascular hemolysis and anemia, severe endothelial injury with abnormal coagulation, bleeding diathesis, and nephropathy. Additional reported manifestations include growth retardation, mild facial dysmorphism, and hepatomegaly.


A rare trigeminal autonomic cephalalgia characterized by indomethacin-sensitive, persistent, strictly unilateral headache lasting for more than three months, associated with ipsilateral conjunctival injection, lacrimation, nasal congestion, rhinorrhea, forehead and facial sweating, miosis, ptosis, eyelid edema, and/or restlessness or agitation, and not better accounted for by another type of headache. Migrainous symptoms such as photophobia are often observed. The headache may be continuous (unremitting subtype) or interrupted by remission periods of more than 24 hours (remitting subtype).


Hemidystonia-hemiatrophy (HD-HA) is a rare dystonia, usually caused by a static cerebral injury occurring at birth or during infancy, that is characterized by a combination of hemidystonia (HD), involving one half of the body, and hemiatrophy (HA) on the same side as the HD.

Summary:
Epidemiology
The prevalence is unknown but between 30 to 100 cases of HD-HA have been described to date.
Clinical description
The mean age of HD onset is 14.9 years (range 1-46 years). HD (sustained and repetitive muscle contractions resulting in abnormal movements or posture involving a single side of the body) is preceded in 90 % of cases by hemiparesis with a marked improvement before the onset of HD. Pyramidal syndrome and seizures may also be observed. In HD-HA, dystonia is associated with ipsilateral somatic atrophy.
Etiology
Common causes of HD-HA are childbirth or perinatal complications, delayed sequelae of stroke or head trauma. The causative injury generally occurs at birth or during early infancy.
Diagnostic methods
Diagnosis of HD-HA is clinical, based on a careful anamnesis of the patient's birth and early childhood period and physical examinations, as well as brain imaging. Cerebral hemiatrophy, nonspecific diffuse atrophy, lesions involving the basal ganglia and thinning of the periventricular white matter with ipsilateral ventricular dilatation may be observed with magnetic resonance imaging (MRI). Brain imaging is characterized by lesions involving the basal ganglia or by cerebral hemiatrophy contralateral to the HD. Cerebral HA can lead to ipsilateral skull thickening and hyperpneumatization of paranasal sinuses, resulting in Dyke-Davidoff syndrome.
Differential diagnosis
HD-HA syndrome should be differentiated from other causes of primary dystonia or dystonia secondary to inherited disorders or neurodegenerative diseases.
Management and treatment
HD responds poorly to medical therapy and drugs such as anticholinergics, baclofen, benzodiazepines, and levodopa, in monotherapy or in combination, result in a modest or transient response. Botulinum toxin injections may be useful for HD if a relevant focal target can be identified. Deep brain stimulation mainly targeting the globus pallidus is not a routine treatment of HD-HA syndrome, but may be discussed in the most severe cases on an individual basis.
Prognosis
The younger the age of the offending cerebral insult, the longer is the delay in the onset of dystonia. The symptoms of delayed HD usually diminish and attain a plateau a few years after initial presentation; while HA of the affected body part usually remains stationary as the patient approaches the second decade of life.

                            Last update:
                            March 2014

                            - Expert reviewer(s):
                            Dr David GRABLI


Hemifacial hyperplasia is a rare morphological anomaly of the maxillofacial region characterized by unilateral overgrowth of all facial structures (bone, soft tissues, teeth), called true hemifacial hypertrophy, or overgrowth of one or more but not all facial structures, called partial hemifacial hypertrophy. It may be isolated or related to some syndromes (e.g. Beckwith-Wiedemann, Proteus, Klippel-Trenaunay-Weber, McCune-Albright syndrome, Neurofibromatosis type 1). It may be associated with airway obstruction, sensorineural hearing loss or swallowing difficulties.


Hemifacial myohyperplasia is a rare developmental defect during embryogenesis characterized by unilateral hyperplasia of the facial musculature with no evidence of hyperplasia of bone or other organ systems. It clinically present with dimpling of the skin, ptosis, enophthalmos, narrow palpebral fissure, auricular displacement, smaller nasal vestibule, and nasal and chin deviation on the affected side. Facial paresis of the affected side and mild ipsilateral hypoplasia of the facial skeleton might be present.


A rare primary myoclonus characterized by progressive, involuntary, irregular, clonic or tonic contractions of the muscles innervated by the facial nerve (cranial nerve VII). The symptoms are typically strictly unilateral, mostly persist during sleep, and often occur in the region of the orbicularis oculi muscle first and gradually spread to other parts of the affected half of the face as the disease progresses. Both familial and acquired forms are reported.


Hemihyperplasia-multiple lipomatosis syndrome is a rare, genetic overgrowth syndrome characterized by non- progressive, asymmetrical, moderate hemihyperplasia (frequently affecting the limbs) associated with slow growing, painless, multiple, recurrent, subcutaneous lipomatous masses distributed throughout entire body (in particular back, torso, extremities, fingers, axillae). Superficial vascular malformations may also be associated. Increased risk of intra-abdominal embryonal malignancies may be associated.


Hemimegalencephaly is a rare cerebral malformation characterized by overgrowth of all or part of a cerebral hemisphere, often with ipsilateral severe cortical dysplasia or dysgenesis, white matter hypertrophy and dilated lateral ventricle, presenting in early infancy with progressive hemiparesis, severe psychomotor retardation and intractable seizures. Hemimegalencephaly may be an isolated finding or associated with other syndromes such as angioosteohypertrophic syndrome, epidermal nevus syndrome and Ito hypomelanosis (see these terms). Management includes seizure control by antiepileptic medications and early hemispherectomy.


Hemiparkinsonism-hemiatrophy syndrome is a rare parkinsonian disorder characterized by unilateral body atrophy and slowly progressive, ipsilateral, hemiparkinsonian signs (bradykinesia, rigidity, and tremor). Patients typically present with unilateral, action-induced dystonia, in upper or lower limbs, that progresses and becomes bilateral or with tremor which occurs predominantly at rest and progresses to hemiparkinsonism. Scoliosis, scapular winging, raised shoulders, brisk reflexes and extensor plantar responses are frequently associated.


Hemoglobin C disease (HbC) is a hemoglobinopathy characterized by production of abnormal variant hemoglobin known as hemoglobin C, with no or mild clinical manifestations (hemolytic anemia).


Hemoglobin C - beta-thalassemia (HbC - BT) is a form of beta-thalassemia (see this term) resulting in moderate hemolytic anemia.

Summary:
Epidemiology
Prevalence of this form is not known but it is predominant in African populations.
Clinical description
Patients are usually asymptomatic and diagnosed during routine tests. When present, clinical manifestations are moderate anemia and splenomegaly. Blood transfusions are rarely needed.
Etiology
HbC - BT patients are compound heterozygotes for hemoglobin C and beta-thalassemia.
Diagnostic methods
Hematological findings always reveal microcytosis and hypochromia. Blood smear shows distinctive HbC crystals with straight parallel edges, target cells, and irregularly contracted cells with features of thalassemia such as microcytosis.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Pr Renzo GALANELLO  - Dr Raffaella ORIGA


Hemoglobin D disease(HbD) is a hemoglobinopathy characterized by production of abnormal variant hemoglobin known as hemoglobin D, with no or mild clinical manifestations (splenomegaly, very mild anemia).


Hemoglobin E disease (HbE) is a hemoglobinopathy characterized by production of abnormal variant hemoglobin known as hemoglobin E, with a generally benign, asymptomatic presentation.


Hemoglobin E - beta-thalassemia (HbE - BT) is a form of beta-thalassemia (see this term) that results in a mild to severe clinical presentation ranging from a condition indistinguishable from beta-thalassemia major to a mild form of beta-thalassemia intermedia (see these terms).

Summary:
Epidemiology
Prevalence of this form is not known but HbE - beta-thalassemia is predominant in Southeast Asia.
Clinical description
Mild HbE - BT (about 15% of cases) is characterized by normal Hb levels (9-12 g/dl) and patients usually do not develop clinically significant symptoms. No treatment is required. Moderately severe forms (most cases) are characterized by decreased Hb levels (6-8 g/dl) and the clinical manifestations are similar to those of beta-thalassemia intermedia. Transfusions are not required unless infections precipitate further anemia. Iron overload may occur. Severe forms are characterized by very low Hb levels (4-5 g/dl) and patients present with manifestations similar to beta-thalassemia major and are treated as thalassemia major patients.
Genetic counseling
HbE - BT patients are compound heterozygotes for hemoglobin E and beta-thalassemia.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Pr Renzo GALANELLO  - Dr Raffaella ORIGA


An intermediate form of alpha-thalassemia characterized by increased hemolysis and mild to severe anemia with marked microcytosis and hypochromia. Hemoglobin H disease (HbH) disease belongs to the group of nontransfusion-dependent thalassemia.

Summary:
Epidemiology
HbH disease predominates in people of Southeast Asian, Middle Eastern and Mediterranean descent. Exact prevalence is not known but birth prevalence from newborn screening programs in the USA is estimated at 1/14,000, with individuals of south eastern ethnicity most affected.
Clinical description
Clinical features are highly variable and generally develop in the first years of life. Initial signs may be noticed only during routine hematologic analyses. Patients have variable microcytic hypochromic hemolytic anemia, requiring no or occasional blood transfusions during infectious episodes, exposure to oxidizing agents or pregnancy. Splenomegaly is frequently found. Non-deletional forms of alpha-thalassemia typically have more severe anemia, splenomegaly, hepatomegaly, cholelithiasis, growth retardation, decreased bone density; and have earlier and more frequent transfusion requirements. Skeletal changes mainly affecting the face can rarely occur in non-deletional forms. Iron overload develops secondary to increased intestinal iron absorption even in the absence of transfusion.
Etiology
HbH disease is usually caused by inactivation of three alpha-globin alleles leading to underproduction of alpha-globin chains of Hb, with the formation of beta-4 tetramers (HbH). HbH tetramers have a high affinity for oxygen, and are highly unstable, precipitating as toxic Heinz bodies which predominate in mature red blood cells, leading to premature hemolysis rather than ineffective erythropoiesis. It is increased under oxidative stress, which explains the hyperhemolysis associated with infection or ingestion of oxidant drugs. The disease is typically caused by compound heterozygous or homozygous variants in either of the alpha globulin genes (HBA1 and HBA2; 16p13.3), accompanied by a heterozygous mutation in the other gene. In some cases, the disease is due to homozygous variants in HBA2. The severity of the disease is related to its molecular basis: patients with non-deletional types of HbH disease, such as Constant Spring mutation, are more severely affected than those with the common deletional types.
Diagnostic methods
HbH disease should be considered in infants or children with mild-to-moderate microcytic hypochromic hemolytic anemia and hepatosplenomegaly. Heinz bodies can be detected on blood smears after cresyl blue staining. Hb biochemical analysis reveals the presence of HbH (5-30%). Diagnosis is confirmed by genetic testing.
Differential diagnosis
Differential diagnosis includes other hemolytic anemias and alpha-thalassemia X-linked intellectual deficit (ATRX).
Antenatal diagnosis
Prenatal diagnosis is possible when a severe form of HbH disease has previously been identified in a family member.
Genetic counseling
The pattern of inheritance is autosomal recessive. Genetic counseling depends on the genotype of the parents; where the couple has already an affected offspring, the risk of having an affected offspring in subsequent pregnancies is 25%.
Management and treatment
In the more common milder form, patients may require occasional blood transfusion therapy. In more severe cases, regular transfusions are needed. Splenectomy should be performed only in the presence of manifest hypersplenism, because it is associated with increased thromboembolic and infectious complications. Iron overload should be monitored from adolescence by liver magnetic resonance imaging . Iron chelation is indicated in all patients with hemosiderosis. Management also requires ongoing monitoring of growth, bone health, spleen size, and fatigue level. Supplementation with folic acid is recommended.
Prognosis
Overall survival is variable but usually good. Many patients survive into adulthood but some have a more complicated course.

                            Last update:
                            May 2021

                            - Expert reviewer(s):
                            Dr Corinne PONDARRE


A rare beta-thalassemia associated with another hemoglobin anomaly characterized by the presence of the hemoglobin Lepore variant in association with beta-thalassemia. Clinical presentation is highly variable, depending on the type of beta-thalassemia, and ranges from severe hypochromic microcytic anemia and complete transfusion dependency to moderate, compensated anemia without a need for regular blood transfusions.


A rare hemoglobinopathy characterized by the presence of hemoglobin variants with structural abnormalities in the globin portion of the molecule which lead to auto-oxidation of heme iron, resulting in methemoglobinemia. Patients present with cyanosis for which no treatment is necessary. Mode of inheritance is autosomal dominant.


Hemoglobinopathy Toms River is a rare, genetic hemoglobinopathy disorder, due to a defect in the gamma subunit of the fetal hemoglobin, characterized by neonatal cyanosis, low hemoglobin oxygen saturation levels without arterial hypoxemia, moderate anemia and reticulocytosis, not associated with heart or lung disease. Symptoms progressively subside within the first months of life.


Hemolytic anemia due to adenylate kinase deficiency is a rare hemolytic anemia due to an erythrocyte nucleotide metabolism disorder characterized by moderate to severe chronic nonspherocytic hemolytic anemia that may require regular blood transfusions and/or splenectomy and may be associated with psychomotor impairment.


Hemolytic anemia due to erythrocyte adenosine deaminase overproduction is a rare, genetic, hematologic disease characterized by mild, chronic hemolytic anemia (due to highly elevated adenosine deaminase activity in red blood cells resulting in their premature destruction), elevated reticulocyte count, splenomegaly and mild hyperbilirubinemia. Other cells and tissues are not affected.


Hemolytic anemia due to glucophosphate isomerase deficiency

A rare hemolytic anemia due to a defect of the glycolytic enzyme glucose 6-phosphate isomerase (GPI) characterized by chronic nonspherocytic hemolytic anemia and, rarely, neurological impairment.

Summary:
Epidemiology
Prevalence is unknown. Around 100 cases have been described in the literature so far. GPI deficiency is the second most frequent glycolytic erythroenzymopathy after pyruvate kinase deficiency. Both sexes are equally affected.
Clinical description
GPI deficiency is characterized by splenomegaly and chronic hemolytic anemia of variable degree, from mild to severe, with episodes of crises triggered by viral or bacterial infections. In rare cases, additional manifestations have been observed, including a variable degree of intellectual deficit, hypotonia, muscle weakness, ataxia and dysarthria. In very rare cases, severe GPI deficiency may be associated with hydrops fetalis and neonatal death.
Etiology
GPI deficiency is caused by homozygous or compound heterozygous mutations in the GPI gene (19q13.1). More than 50 different GPI molecular variants have been identified in affected individuals. GPI is a ubiquitous enzyme that catalyses the conversion glucose-6-phosphate into fructose-6-phosphate, the second step in the glycolytic pathway.
Diagnostic methods
Diagnosis is based on the demonstration of a reduced erythrocytic GPI activity and the identification of one homozygote, or two compound heterozygote pathogenic variants in the GPI gene.
Differential diagnosis
The differential diagnosis should include other causes of chronic hereditary hemolytic anemia.
Antenatal diagnosis
Antenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Transfusion support may be required for patients with severe anemia. Splenectomy doesn't cure anemia but reduce the transfusion need, and may increase hemoglobin levels. Indication to splenectomy is based on the severity of clinical presentation.
Prognosis
The prognosis is variable depending on the severity of the anemia and on the presence of neurological manifestations.

                            Last update:
                            July 2024

                            - Expert reviewer(s):
                            Dr Paola BIANCHI | EuroBloodNet*

                                * European Reference Network


Hemolytic anemia due to glutathione reductase deficiency

Haemolytic anaemia due to glutathione reductase (GSR) deficiency is characterised by nearly complete absence of GSR activity in erythrocytes.

Summary:
Epidemiology
It has been described in three children (one male and two females) born to consanguineous parents.
Clinical description
Both parents had intermediate levels of GSR activity. One child presented with favism and two with cataracts.
Differential diagnosis
This disease should be distinguished from glutathione reductase deficiency secondary to dietary riboflavin deficiency and from the acute pharmacologic phenocopy induced by carmustine (BCNU).
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
GSR activity is not restored by riboflavin in vivo or by FAD in vitro.

                            Last update:
                            December 2007


Hemolytic anemia due to pyrimidine 5' nucleotidase deficiency is a rare, hereditary, hemolytic anemia due to an erythrocyte nucleotide metabolism disorder characterized by mild to moderate hemolytic anemia associated with basophilic stippling and the accumulation of high concentrations of pyrimidine nucleotides within the erythrocyte. Patients present with variable features of jaundice, splenomegaly, hepatomegaly, gallstones, and sometimes require transfusions. Rare cases of mild development delay and learning difficulties are reported.


Hemolytic anemia due to red cell pyruvate kinase deficiency

A rare, genetic metabolic disorder due to pyruvate kinase deficiency characterized by a variable degree of chronic nonspherocytic hemolytic anemia resulting in a variable clinical manifestations ranging from fatal anemia at birth to a to a fully compensated hemolysis without apparent anemia.

Summary:
Epidemiology
Pyruvate kinase (PK) deficiency is the most frequent cause of congenital nonspherocytic hemolytic anemia with a prevalence estimated at 1/20,000 in the general white population.
Clinical description
Clinically, PK-deficient patients suffer from a highly variable degree of chronic hemolysis, ranging from severe neonatal jaundice and fatal anemia at birth, severe transfusion-dependent chronic hemolysis, moderate hemolysis with exacerbation during infection, to a fully compensated hemolysis without apparent anemia. Symptoms are usually present at birth but, due to the variable severity, may not be recognized or acknowledged until later. Chronic icterus, gallstones, iron overload and splenomegaly are common findings.
Etiology
Erythrocyte PK deficiency is caused by mutations in the PKLR gene (1q22). To date, more than 290 mutations in PKLR have been reported. PK is a key regulatory enzyme of glycolysis and two major metabolic abnormalities result from PK deficiency: ATP depletion and increased 2,3-diphosphoglycerate (2,3-DPG) content. The precise mechanisms that cause extravascular hemolysis are as yet unknown, but an important feature involves the selective sequestration of PK-deficient young red blood cells, in particular reticulocytes, by the spleen. The increased 2,3-DPG levels ameliorate the anemia by lowering the oxygen-affinity of hemoglobin.
Diagnostic methods
Diagnosis may be considered on the basis of the clinical features and laboratory findings: a variable degree of anemia, reticulocytosis, increased non-conjugated bilirubin, and decreased levels of haptoglobin. Red blood cell morphology is essentially normal. PK deficiency is diagnosed by measuring PK enzymatic activity. Importantly, due to the fact that the enzymatic activity is red cell age-dependent, a deficiency of PK may be masked by reticulocytosis. Simultaneous measurement of another red cell age-specific enzyme, e.g. hexokinase, may therefore be helpful. Confirmation of the diagnosis requires genetic testing.
Differential diagnosis
Secondary PK deficiency has also been reported, occurring in the context of hematological diseases (acute/chronic leukemia, myelodysplastic syndromes and sideroblastic anemia). In case of persistent normocytic hemolytic anemia in which hemoglobin abnormalities and antiglobulin reactions have been excluded, spherocytes are absent, and osmotic fragility is normal, the diagnosis of hereditary nonspherocytic hemolytic anemia should be considered.
Genetic counseling
Erythrocyte PK deficiency is an autosomal recessive disease and genetic counseling should be offered to affected families. Where both parents are unaffected carriers, there is a 25% risk of disease transmission to offspring.
Management and treatment
The mainstay of treatment is blood transfusion and, in severe cases, splenectomy. The latter should be based on the patient's ability to tolerate the anemia. As a result of splenectomy, transfusion needs are reduced in many patients. Splenectomy is often accompanied by a considerable increase in reticulocyte counts. Bone marrow transplantation can cure PK deficiency but is rarely performed. Small molecule activator therapy is currently in clinical trials.
Prognosis
Prognosis is variable depending on the severity of the anemia, but as in other chronic hemolytic disorders, gallstones and iron overload may develop, requiring appropriate treatment.

                            Last update:
                            June 2020

                            - Expert reviewer(s):
                            Dr R. [Richard] VAN WIJK


Hemolytic disease of the newborn with Kell alloimmunization

A rare hematologic disease characterized by the transfer of maternal alloantibodies against red blood cell antigens of the Kell family to a fetus positive for this antigen across the placental barrier, causing suppression of erythropoiesis with reticulocytopenia and anemia, as well as alloimmune hemolysis. Severe anemia may lead to hydrops fetalis. Significant hyperbilirubinemia is rare in this condition.


Hemolytic uremic syndrome with DGKE deficiency

A rare genetic hemolytic uremic syndrome (HUS) characterized by infantile onset of relapsing episodes of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. The episodes are often preceded by viral infections. Affected individuals typically present persistent hypertension, hematuria, and proteinuria (sometimes in the nephrotic range) and develop chronic kidney disease with age.


Hemophagocytic syndrome (HPS) is a rare immune disease (see this term) and a potentially life-threatening disorder characterized by cytokine storm and overwhelming inflammation causing fever, hepatosplenomegaly, cytopenia, hypertriglyceridemia, hyperferritinemia, and hemophagocytosis in bone marrow, liver, spleen or lymph nodes. It can be either primary due to a genetic defect (primary hemophagocytic lymphohistiocytosis ; see this term), or secondary to malignancies, to infections, most commonly with viruses such as Epstein-Barr virus or cytomegalovirus, human immunodeficiency virus, or to autoimmune disorders such as systemic lupus erythematosus or adult-onset Still disease (secondary hemophagocytic lymphohistiocytosis) (see these termes).


A rare genetic hematological disorder characterized by spontaneous or prolonged hemorrhages due to factor VIII deficiency.

Summary:
Epidemiology
Hemophilia A is the most common form of hemophilia. Prevalence is estimated at around 1 in 6,000 males. It primarily affects males, but females may also be symptomatic with a generally milder clinical picture.
Clinical description
In general, onset of bleeding anomalies occurs when affected infants start to learn to walk. However, newborns with hemophilia are at risk of intra- or extracranial hemorrhage and other bleeding complications. The severity of clinical manifestations depends on the extent of factor VIII deficiency in both males and females. If the biological activity of factor VIII is below 1 IU/dL, hemophilia is severe and manifests as frequent spontaneous hemorrhages and abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction (severe hemophilia A). If the biological activity of factor VIII is between 1 and 5 IU/dL, hemophilia is moderately severe with abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction but spontaneous hemorrhage is rare (moderately severe hemophilia A). If the biological activity of factor VIII is between 5 and 40 IU/dL, hemophilia is mild with abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction but spontaneous hemorrhage does not occur (mild hemophilia A). Patients may also be labeled as having mild hemophilia A if they have a FVIII >40 IU/dL and a DNA change in the F8 gene and one of the following: (i) a family member with the same DNA change and FVIII of <40 IU/dL, and the DNA change is found in <1% of the population; and (ii) the international databases list the DNA change as being associated with hemophilia A and <40 IU/dL FVIII. Bleeding most often occurs in joints (hemarthroses) and muscles (hematomas), but any site may be involved following trauma or injury. Spontaneous hematuria is a frequent and highly characteristic sign of the disorder.
Etiology
Hemophilia A is caused by mutations in the F8 gene (Xq28) encoding coagulation factor VIII.
Diagnostic methods
Diagnosis is suspected based on prolonged coagulation times (activated partial thromboplastin time, aPTT) and can be confirmed by measuring factor VIII activity and antigen levels.
Differential diagnosis
Differential diagnosis includes von Willebrand disease (VWD), including type 2N VWD and other coagulation anomalies leading to prolonged coagulation times, in particular combined factor V and factor VIII deficiency.
Antenatal diagnosis
Prenatal diagnosis on chorionic villi or amniocytes is rapid and informative when the familial, causative mutation is known. Knowing the familial mutation status in the fetus allows for preparation of delivery and early newborn medical management.
Genetic counseling
Inheritance is X-linked recessive and genetic counseling is recommended for affected families. For a female carrier, there is a 50% risk that male offspring will be affected and a 50% risk that each female offspring will be carriers. Overall, there is a 25% risk for each pregnancy that the baby will be a male offspring with hemophilia and a 25% risk that the baby will be a heterozygous female offspring.
Management and treatment
Management is provided by multidisciplinary comprehensive hemophilia care centers. Replacement therapy consisting of administration of the missing factor VIII is the most straight forward treatment approach, using plasma-derived or recombinant factor VIII concentrates. Treatment may be administered after a hemorrhage or prophylactically, to prevent bleeding. The most frequent complication is the production of inhibitory antibodies against the administered coagulation factor. Recently, bioengineered prolonged half-life factor VIII products and non-factor therapeutics such as emicizumab (a bispecific antibody that mimics the function of factor VIIIa) were approved. Emicizumab is approved for bleeding prophylaxis in hemophilia A with and without inhibitors. Other non-factor therapies and gene therapy are under development. Surgical interventions, most notably orthopedic surgery, may be carried out but should be conducted in specialized centers.
Prognosis
Left untreated, the disease course is severe in severe hemophilia A. Insufficient or incorrect treatment of recurrent hemarthroses and hematomas leads to physical impairment with severe disability associated with stiffness, joint deformation and physical disability. However, current treatment approaches (early prophylaxis) prevent these complications and prognosis is favorable. Hemorrhage, HIV and HCV infections, and hepatic disease are the leading causes of death.

                            Last update:
                            March 2022

                            - Expert reviewer(s):
                            Pr Yesim DARGAUD | EuroBloodNet* - Dr Anne LIENHART | EuroBloodNet*

                                * European Reference Network


A rare hematological disorder characterized by spontaneous or prolonged hemorrhages due to factor IX deficiency.

Summary:
Epidemiology
Prevalence is estimated at around 1 in 30,000 males. Hemophilia primarily affects males, but a symptomatic form of hemophilia B in female carriers has also been described with a generally milder clinical picture.
Clinical description
In general, onset of the bleeding anomalies occurs when affected infants start to learn to walk. However, newborns with hemophilia are at risk of intra- or extracranial hemorrhage and other bleeding complications. The severity of the clinical manifestations depends on the extent of the factor IX deficiency, both in males and in females. If the biological activity of factor IX is below 1 IU/dL, hemophilia is severe and manifests as frequent spontaneous hemorrhage and abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction (severe hemophilia B). If the biological activity of factor IX is between 1 and 5 IU/dL, hemophilia is moderately severe with abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction but spontaneous hemorrhage is rare (moderately severe hemophilia B). If the biological activity of factor IX is between 5 and 40 IU/dL, hemophilia is mild with abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction but spontaneous hemorrhage does not occur (mild hemophilia B). Bleeding most often occurs in joints (hemarthroses) and muscles (hematomas), but any site may be involved following trauma or injury. Spontaneous hematuria is a frequent and highly characteristic sign of the disorder.
Etiology
Hemophilia B is caused by mutations in the F9 gene (Xq27) encoding coagulation factor IX.
Diagnostic methods
Diagnosis is suspected on the basis of coagulation tests revealing prolonged blood coagulation times (activated partial thromboplastin time - aPTT) and can be confirmed by specific measurements of factor IX activity and antigen levels.
Differential diagnosis
The differential diagnosis should include hemophilia A, von Willebrand disease, and other coagulation anomalies leading to prolonged blood coagulation times.
Antenatal diagnosis
Prenatal diagnosis performed on chorionic villi or amniocytes is rapid and informative when the familial, causative F9 mutation is known. Knowing the familial F9 mutation status in the fetus allows for preparation of delivery and early newborn medical management.
Genetic counseling
Inheritance is X-linked recessive and genetic counseling is recommended for affected families. For a female carrier, there is a 50% risk that male offspring will be affected and a 50% risk that each female offspring will be carriers. Female carriers may express mild to moderate symptoms. Overall, there is a 25% risk for each pregnancy that the baby will be a male offspring with hemophilia and a 25% risk that the baby will be a heterozygous female offspring.
Management and treatment
Treatment is provided by multidisciplinary comprehensive hemophilia care centers. Replacement therapy consisting of administration of the missing factor IX (plasma-derived or recombinant factor IX concentrates) is the usual treatment approach. Recently, bioengineered prolonged half-life factor IX products were approved for the treatment of hemophilia B and significantly improve the quality of life of patients. Treatment may be administered after a hemorrhage (treatment on demand) or to prevent bleeding (prophylactic treatment). The most serious complications are production of inhibitory antibodies against the administered coagulation factor and anaphylactic shock in response to factor IX therapy. Surgical interventions, most notably orthopedic surgery, may be carried out but should be conducted in specialized centers.
Prognosis
Left untreated, the disease course is severe and in, severe hemophilia B, is generally fatal. Insufficient or incorrect treatment of recurrent hemarthroses and hematomas leads to physical impairment with severe disability associated with stiffness, joint deformation and physical disability. However, current treatment approaches (early prophylaxis) prevent these complications and the prognosis is favorable. Hemorrhage, HIV and HCV infections, and hepatic disease are the leading causes of death in patients with hemophilia.

                            Last update:
                            March 2022

                            - Expert reviewer(s):
                            Pr Yesim DARGAUD | EuroBloodNet* - Dr Anne LIENHART | EuroBloodNet*

                                * European Reference Network


A rare hematological disorder characterized by spontaneous hemorrhage or prolonged bleeding due to factor VIII or IX deficiency.

Summary:
Epidemiology
Prevalence in the general population is estimated at 1/12,000. Prevalence at birth is estimated at 1/5,000 in males.
Clinical description
Hemophilia primarily affects males, but female carriers of disease-causing mutations may also manifest generally milder forms of the disease. In general, onset of bleeding anomalies occurs when affected infants start to learn to walk. However, newborns with hemophilia are at risk of intra- or extracranial hemorrhage and other bleeding complications. The severity of clinical manifestations depends on the extent of the coagulation factor deficiency. If the biological activity of the coagulation factor is below 1 IU/dL, hemophilia is severe and manifests as frequent spontaneous hemorrhage and abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction (severe hemophilia A and B). If the biological activity of the coagulation factor is between 1 and 5 IU/dL, hemophilia is moderately severe with abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction but spontaneous hemorrhage is rare (moderately severe hemophilia A and B). If the biological activity of the coagulation factor is between 5 and 40 IU/dL, hemophilia is mild with abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction but spontaneous hemorrhage does not occur (mild hemophilia A and B). In patients with severe hemophilia, bleeding most often occurs in joints (hemarthroses) and muscles (hematomas), but any site may be involved following trauma or injury. Spontaneous hematuria is a frequent and highly characteristic sign of the disorder.
Etiology
The disorder is caused by mutations in the F8 gene (Xq28) encoding coagulation factor VIII, or in the F9 gene (Xq27) encoding coagulation factor IX, which are implicated in hemophilia types A and B, respectively.
Diagnostic methods
Diagnosis is made on the basis of coagulation tests revealing prolonged coagulation times (activated partial thromboplastin time, aPTT). Type and severity of hemophilia are determined through specific measurements of factor VIII and IX activity and antigen levels.
Differential diagnosis
Differential diagnosis includes von Willebrand disease, combined factor VIII and factor V deficiency and other coagulation anomalies leading to prolonged coagulation times.
Antenatal diagnosis
Prenatal diagnosis performed on chorionic villi or amniocytes is rapid and informative when the familial, causative mutation is known. Knowing the familial mutation status in the fetus allows for preparation of delivery and early newborn medical management.
Genetic counseling
Inheritance is X-linked recessive and genetic counseling is recommended for affected families. For female carriers, there is a 50% risk that male offspring will be affected and a 50% risk that female offspring will be carriers. Overall, there is a 25% risk for each pregnancy that the baby will be a male offspring with hemophilia and a 25% risk that the baby will be a heterozygous female offspring.
Management and treatment
Management is provided by multidisciplinary comprehensive hemophilia care centers. Replacement therapy consisting of administration of the missing factor VIII (hemophilia A) or factor IX (hemophilia B) is the most straightforward treatment approach. Plasma-derived and recombinant factor VIII and factor IX concentrates are available. Non-factor therapies also exist for hemophilia A and new therapeutical approaches including gene therapy are under development. Treatment may be administered after a hemorrhage or prophylactically, to prevent bleeding. The most frequent complication is the production of inhibitory antibodies against the administered coagulation factor. Surgical interventions, most notably orthopedic surgery, may be carried out but should be conducted in specialized centers.
Prognosis
Left untreated, the disease course is severe and, in severe hemophilia, is generally fatal. Insufficient or incorrect treatment of recurrent hemarthroses and hematomas leads to physical impairment with severe disability associated with stiffness, joint deformation and physical disability. However, current treatment approaches (early prophylaxis) prevent these complications and the prognosis is favorable. Hemorrhage, HIV and HCV infections, and hepatic disease are the leading causes of death.

                            Last update:
                            March 2022

                            - Expert reviewer(s):
                            Pr Yesim DARGAUD | EuroBloodNet* - Dr Anne LIENHART | EuroBloodNet*

                                * European Reference Network


Hemorrhagic disease due to alpha-1-antitrypsin Pittsburgh mutation

A rare, genetic, constitutional coagulation factor defect disorder characterized by a bleeding tendancy of variable severity due to methionine 358 to arginine replacement (Pittsburgh mutation) in the alpha-1-antitrypsin protein. Patients present with spontaneous hematomas, hematomas following minor trauma or surgery and, in female patients, ovarian hematomas after ovulation.


A rare rodent-borne, potentially severe, hemorrhagic disease caused by Old World Hantaviruses characterized by high fever, malaise, headache, myalgia, arthralgia, backache, abdominal pain, oliguria/renal failure and systemic hemorrhagic manifestations.


Hendra virus infection is a rare viral infection disorder caused by the Hendra virus characterized by onset of flu-like symptoms (fever, myalgia, headaches, lethargy) approximately one week after having been in close contact with bodily fluids of infected horses. Neurological manifestations (e.g. vertigo, confusion, ataxia) and progressive respiratory failure, leading to death, have also been reported.


A rare syndromic lymphedema characterized by the association of primary lymphedema, intestinal lymphangiectasia, intellectual deficit and unusual facial characteristics.

Summary:
Epidemiology
The exact prevalence is unknown but around 100 cases have been reported in the literature. The entity occurs in all ethnic groups.
Clinical description
The lymphedema has invariably been present at birth, and is mainly present in the lower limbs and genitalia, although it can also be present elsewhere, including ascites. Lymphangiectasia is common in the intestines but can also be present in lungs, pericardium, thyroid and kidneys. The degree of intellectual deficit is highly variable, even within a single family. Facial characteristics are a flat face, a broad and depressed nasal bridge, hypertelorism, epicanthi, a small mouth, and low-set ears with a narrow meatus. Other features include mild growth retardation, delayed puberty, tooth anomalies, gingival hypertrophy, seizures, and blood vessel anomalies.
Etiology
The syndrome can be caused by bi-allelic variants in CCBE1 (18q21.32), FAT4 (4q28.1) or ADAMTS3 (4q13.3).
Diagnostic methods
The diagnosis is based on the clinical phenotype. Intestinal lymphangiectasia may be suspected because of hypogammaglobulinemia, hypoalbuminemia, and lymphopenia, but a definitive diagnosis can only be made by biopsies (often several are needed). Molecular studies may confirm the clinical diagnosis.
Differential diagnosis
The differential diagnosis includes other entities associated with congenital lymphedema such as Noonan syndrome, Milroy syndrome and cholestasis-lymphedema syndrome, and Van Maldergem syndrome.
Antenatal diagnosis
Prenatal genetic testing is possible in families with known mutations.
Genetic counseling
The syndrome is transmitted as an autosomal recessive trait and genetic counseling is recommended.
Management and treatment
There is no curative therapy, only supportive management including decongestive therapy for edema control, typically needing lymphologists. Rarely surgery is performed. Medium-chain triglyceride-rich diet is usually helpful because of the intestinal lymphangiectasias but recurrent albumin infusions are not uncommon. Vitamin and electrolyte supplements should be considered. Pulmonary lymphangiectasia may need temporary artificial ventilation (positive end-expiratory pressure). Penicillin prophylaxis may be needed to prevent erysipelas.
Prognosis
The signs and symptoms vary widely among affected individuals and even those within the same family. The course of the lymphedema may vary considerably within a person, for instance by hormonal influences, but often for unknown reasons. Life expectancy depends on the severity of manifestations, and may lead to early death.

                            Last update:
                            July 2020

                            - Expert reviewer(s):
                            Pr Raoul HENNEKAM | ITHACA*

                                * European Reference Network


A rare multiple congenital anomalies syndrome characterized by cutaneous mastocytosis, microcephaly, microtia and/or hearing loss, hypotonia and skeletal anomalies (e.g. clinodactyly, camptodactyly, scoliosis). Additional common features are short stature, intellectual disability and difficulties. Facial dysmorphism may include upslanted palpebral fissures, highly arched palate and micrognathia. Rarely, seizures and asymmetrically small feet have been reported.


A rare drug-induced, immune-mediated prothrombotic disorder associated with thrombocytopenia and venous and/or arterial thrombosis.

Summary:
Epidemiology
Approximately 1% of patients exposed to unfractionated heparin for at least 5 days develop heparin-induced thrombocytopenia (HIT), and approximately 30-50% of them will have thrombosis. HIT is less frequent (incidence approximately 0.1%) in patients treated with low-molecular weight heparins.
Clinical description
HIT may develop at any age (>3 months) but pediatric cases are rare. Moderate thrombocytopenia begins typically 5- 10 days after heparin administration. If the patient had already been exposed to heparin within the last 100 days, rapid-onset is possible, with the platelet count drop occurring within minutes or hours after heparin administration. Delayed-onset HIT is also possible with thrombocytopenia beginning after heparin has already been discontinued. Thrombocytopenia is usually asymptomatic; bleeding is rare. HIT is associated with a high risk of thrombotic complications (e.g. pulmonary embolism, myocardial infarction, stroke), with a predilection for arterial thrombosis involving limb arteries and deep vein thrombosis. Additional microvascular thrombosis can lead to venous limb gangrene/amputation. Other complications include skin necrosis at heparin injection sites and anaphylactoid reactions (e.g. fever, hypotension, chest pain, dyspnea, cardiorespiratory arrest) that could be secondary to post-intravenous heparin bolus.
Etiology
HIT results from a humoral immune reaction directed against a complex involving endogenous platelet factor 4 (PF4) and exogenous heparin. Rarely, auto-antibodies recognize PF4 alone. PF4/heparin/IgG immune complexes activate circulating platelets via low affinity immunoglobulin gamma Fc region receptor II-a, leading to consumptive thrombocytopenia and hypercoagulability. The source of heparin (bovine > porcine), its formulation (unfractionated >low molecular weight > fondaparinux), the dose (prophylactic > therapeutic > heparin flushes), route of administration (subcutaneous > intravenous) and duration of administration (over 4 days > 4 days or less) are determining factors.
Diagnostic methods
Diagnosis of HIT is suspected from the clinical picture based on the ''4 T's'' (Thrombocytopenia, Timing, Thrombosis, no oTher cause of platelet fall) or the HIT Expert Probability (HEP) scoring system. It is supported by detection of anti-PF4/heparin antibodies, most often by ELISA (although 50% of ELISA-positive patients do not have HIT), and confirmed by detection of pathologic platelet-activating antibodies with functional assays such as serotonin-release assay or heparin-induced platelet activation test.
Differential diagnosis
Differential diagnosis includes nonimmune heparin-associated thrombocytopenia (due to the direct interaction of heparin with circulating platelets, occurring during the first days of heparin administration), as well as postoperative hemodilution, sepsis, non-HIT drug-induced thrombocytopenia, vaccine-induced immune thrombotic thrombocytopenia, disseminated intravascular coagulation, and multiorgan system failure.
Management and treatment
For certain patient populations receiving heparin, a regular monitoring of platelet counts is recommended. In case of strongly-suspected or confirmed HIT, treatment consists of stopping heparin and initiating alternative anticoagulant treatment, either with non-heparin anti-factor Xa therapies (danaparoid, fondaparinux, rivaroxaban), or with direct thrombin inhibitors (e.g., argatroban, bivalirudin). Warfarin is contraindicated during the acute thrombocytopenic phase as it can cause microvascular thrombosis, with potential for ischemic limb necrosis (venous limb gangrene syndrome). Thrombocytopenia generally resolves to greater than 150 x 109/L at a median of 4 days, although 1 week to 1 month can be required in some cases.
Prognosis
The prognosis for platelet count recovery is excellent; however, long-term post-thrombotic sequelae (e.g. limb amputation in 5-10% of HIT patients, disabling stroke, bilateral adrenal hemorrhagic necrosis with adrenal failure) can occur. HIT-related mortality (e.g. fatal pulmonary embolism) is observed in 5-10% of cases.

                            Last update:
                            October 2021

                            - Expert reviewer(s):
                            Pr Yves GRUEL


Hepatic cystic hamartoma, also named Mesenchyma hamartoma of liver, is a rare benign liver tumor of childhood, usually before the age of 2, of mesenchymal origin and variable clinical presentation (abdominal dissension, abdominal mass, pain, vomiting and signs of inferior vena cava compression).


Hepatic fibrosis-renal cysts-intellectual disability syndrome is a rare, syndromic intellectual disability characterized by early developmental delay with failure to thrive, intellectual disability, congenital hepatic fibrosis, renal cystic dysplasia, and dysmorphic facial features (bilateral ptosis, anteverted nostrils, high arched palate, and micrognathia). Variable additional features have been reported, including cerebellar anomalies, postaxial polydactyly, syndactyly, genital anomalies, tachypnea. There have been no further descriptions in the literature since 1987.


Hepatic veno-occlusive disease-immunodeficiency syndrome

A rare syndrome with combined immunodeficiency characterized by the association of severe hypogammaglobulinemia, combined T and B cell immunodeficiency, absent lymph node germinal centers, absent tissue plasma cells and hepatic veno-occlusive disease.


A rare vascular liver disease characterized by toxic injury to the hepatic sinusoidal capillaries that leads to obstruction of the small hepatic veins and sinusoids. Clinical manifestations include painful hepatomegaly, jaundice, and fluid retention that manifests by weight gain, edemas, and ascites.

Summary:
Epidemiology
Prevalence is difficult to estimate as the frequency varies according to the underlying cause. The incidence due to pyrrolizidine alkaloid plant exposure is unknown, although in Ethiopia it has been estimated at 29.6/mill/year. In addition, epidemics may occur due to harvest contamination with these plants. Hepatic veno-occlusive disease (HVOD) develops in between 0. 3- 2.3% of patients who receive liver transplant; in up to 15% of those treated with gemtuzumab ozogamicin (GO); and in 2-15% of those who receive hematopoietic stem cell transplantation (HSCT), rising to 40% in patients with a history of GO treatment.
Clinical description
It affects children and adults. The clinical picture is characterized by painful hepatomegaly, jaundice, and fluid retention that manifests by weight gain, edemas, and ascites. Hepatic insufficiency manifesting as jaundice, and hepatic encephalopathy may occur. Functional renal insufficiency is common. In severe cases, multiple organ failure or severe bacterial infections may occur. In developed countries, the disease is mainly associated with the conditioning regimen for HSCT, with currently less than 10% of transplant patients (depending on the conditioning regimen protocol used) developing HVOD. HVOD may also occur after chemotherapy or radiation therapy.
Etiology
Hepatic sinusoidal endothelial cell lesions appear to be the primary cause of the disease, leading to non-thrombotic occlusion of hepatic veins with concentric subendothelial thickening associated with edema and eventually fibrosis.
Diagnostic methods
Diagnosis is based on recognition of the clinical manifestations (hepatomegaly, jaundice, and weight gain) and their association with a potential cause of HVOD (HSCT or chemotherapy, exposure to pyrrolizidine alkaloids), together with exclusion of other causes of liver disease. Liver biopsy is often indicated, and recent data support its indication. Imaging studies, particularly hepatic Doppler-ultrasonography, may help to confirm the diagnosis.
Differential diagnosis
Differential diagnoses include other causes of acute or chronic liver disease, and, in the case of HSCT, graft-versus-host disease and severe infections.
Management and treatment
No specific treatment is available. Defibrotide is recommended for severe sinusoidal obstruction syndrome, mainly on the basis of limited studies (historic comparisons) and because side effects are uncommon. Management is with supportive care (nutritional support, intensive care unit if needed for respiratory or renal support), renal function monitoring, and avoidance of other liver drug toxicity. Preventive treatment with ursodeoxycholic acid is indicated from beginning of conditioning to 90 days post-transplantation. In case of HSCT, the risk of disease is managed prophylactically by the characterization of risk factors prior to transplantation. Liver transplantation should be discussed in patients with excellent hematologic prognosis.
Prognosis
Severity and course of the disease varies between patients. In severe cases, the prognosis is poor with a high mortality rate (up to 90%) due to multiple organ failure.

                            Last update:
                            December 2021

                            - Expert reviewer(s):
                            Dr Aurélie PLESSIER | RARE-LIVER*

                                * European Reference Network


Hepatitis B reinfection following liver transplantation

A rare hepatic disease characterized by graft infection with the hepatitis B virus (HBV) after liver transplantation, due to persistence and reactivation of HBV in extrahepatic sites (also despite previous clearance of the HBs antigen from serum, as shown by laboratory examination), followed by re-invasion of the graft. It may develop between two weeks and several years post transplantation. Clinico-pathological features are variable and range from mild self-limited hepatitis, chronic active hepatitis, and fulminant hepatitis, to fibrosing cholestatic hepatitis. The condition is associated with significantly reduced graft survival rates and overall patient survival.


Hepatitis delta is a rare hepatic disease characterized by variable degrees of acute hepatitis resulting from infection with the hepatitis delta virus. Occasionally it may present a benign course, but most frequently it manifests with severe liver disease that may include fulminant liver failure, hepatic decompensation and rapid progression to cirrhosis. All patients present concomitant hepatitis B virus infection and an increased risk of developing hepatocellular carcinoma has been reported.


A malignant hepatic tumor, typically affecting the pediatric population, arising mostly in an otherwise healthy liver. The most common signs are abdominal distension and abdominal mass. Sometimes patients present with anorexia, weight loss, fatigue. Most HBLs are sporadic, but some cases are associated with genetic factors, especially overgrowth syndromes, such as Beckwith-Wiedemann syndrome (BWS) or hemihypertrophy, and familial adenomatous polyposis (FAP).

Summary:
Epidemiology
Hepatoblastoma (HB) accounts for about 0,5-2% of all pediatric tumors and for 2/3 of primary hepatic tumors in children. Its incidence is estimated to be 1/1,000,000 in Europe and 1-1,5/1,000,000 in USA. A slight male predilection (1.5:1 to 2:1) has been observed. The incidence of HBL in children has been increasing by about 5% annually.
Clinical description
The age of disease onset lies in infancy or early childhood (median age of occurrence is 18 months and 90% of HBs present before 5 years). The most common signs are: (1) abdominal distension and abdominal mass, (2) anorexia, weight loss, fatigue, (3) abdominal pain, nausea and vomiting, (4) jaundice is less frequently observed, (5) anemia and thrombocytosis detected by laboratory tests. Rare cases present with precocious puberty/virilization due to beta-human chorionic gonadotropin (hCG) secretion by the tumor. FAP and BWS are associated with an increased risk of HB. Trisomy 13 and 18, Goldenhar syndrome, Noonan syndrome, Fragile X syndrome, Sotos syndrome, Prader-Willi syndrome, Prune belly syndrome, Aicardi syndrome and neurofibromatosis type 1 may also predispose to HB. Genetic syndromes are associated with 20% of HB cases. High-risk patients are those with distant metastases, very low initial alpha-fetoprotein (AFP) level (under 100 ng/ml), older age (over 8 years), tumor rupture at diagnosis and/or tumor involvement of all 4 hepatic sections.
Etiology
The etiology of HB is still unknown. However, it is hypothesized to derive from primary hepatoblasts, and likely from less differentiated hepatic stem cells or human fetal liver multi-potent progenitor cells (hFLMPCs). Mutations of the genes APC (5q21-q22), AXIN1 (16p13.3) and AXIN2 (17q24.1), that prevent degradation of beta-catenin, have been found in syndromic forms of HB but have rarely been described in sporadic HB. However, a high rate of oncogenic mutations of the beta-catenin gene (CTNNB1; 3p21) (60%-70%) has been reported in HB and it is thought to be associated with constitutive activation of the Wnt/beta-catenin signaling pathway. Overall, Wnt pathway abnormalities account for up to 90% of genetic defects in hepatoblastoma tumor.
Differential diagnosis
Differential diagnosis includes: (1) hemangioma and infantile hemangioendothelioma (IHE), (2) hepatic mesenchymal hamartoma, (3) focal nodular hyperplasia (FNH), (4) pediatric hepatocellular carcinoma (HCC), (5) undifferentiated embryonal sarcoma of the liver (UESL), (6) embryonal rhabdomyosarcoma (eRMS), (7) rhabdoid tumor of the liver, (8) hepatic adenoma.
Management and treatment
A diagnostic tumor biopsy should be mandatory for all patients with primary liver tumor. HB is definitely a surgical tumor. Surgery remains the cornerstone of management and complete resection is crucial for cure. In most cases complete resection of the tumor can be achieved with a partial hepatectomy (hemihepatectomy). The PRETEXT (PRETreatment EXtent of Disease) system (based on liver anatomy and imaging) is used for assessment of chemotherapy response and planning the extent of liver resection. Resection at diagnosis is currently recommended for very low risk tumors (PRETEXT I/II, M-, surgically resectable at diagnosis (VPEFR-), and additionally in PRETEXT II: age under 8 years, AFP over100 ng/ml) and only when a segmentectomy or hemihepatectomy with at least 1 cm margin on middle hepatic vein and/or bifurcation of portal vein is possible. For unresectable tumors, preoperative chemotherapy (mostly systemic or, in highly selected cases, transcatheter arterial chemoembolization [TACE], sometimes combined with systemic chemotherapy) is used. Total hepatectomy with liver transplantation is a treatment option for HB in conditions where the tumors remain unresectable after chemotherapy or for multifocal HB invading all 4 sections of the liver. 10-20% of all HB cases require liver transplantation. In most cases postoperative chemotherapy is used routinely.
Prognosis
Current prognosis for patients with resectable tumors and no high risk features is fairly favorable (90%), whereas the outcome for those with metastases is around 50-70%, while the prognosis of patients with non-resectable or recurrent disease is relatively poor (around 20-30%). Relapse in HB occurs in less than 12% of the children who have achieved complete remission.

                            Last update:
                            July 2020

                            - Expert reviewer(s):
                            Pr Piotr CZAUDERNA  - Dr Maciej MURAWSKI


Hepatocellular adenoma (HA) is a rare benign tumor of the liver.

Summary:
Epidemiology
Annual incidence is estimated at one case per million.
Clinical description
Mean age at diagnosis is 34 years (ranging from 15 to 64 years). HA rarely occurs in children. Most patients with HA are asymptomatic and lesions are found incidentally during laparotomy or radiologic studies performed for other reasons. Pain or discomfort in the right upper quadrant or epigastric region is common, but not always related to the adenoma. HA may be revealed by spontaneous rupture or hemorrhage (leading to acute abdominal pain and possibly progressing to hemorrhagic shock, hypotension and even death). These complications are estimated to occur in 30% of patients with an adenoma over 5 cm in diameter. HA patients have normal liver function and no elevation of serum tumor markers. Serum aminotransferases and gamma-glutamyl transpeptidase may be mildly elevated. HA is typically solitary, although multiple lesions have been reported under the denomination `hepatocellular adenomatosis'. Size varies from about 1 cm (the detection limit for usual imaging methods) to over 20 cm. There appears to be a zero risk of complications for patients with a HA below 5 cm in diameter. In rare cases, and more frequently in males, the largest tumors may harbor malignant features. Histologically, adenoma cells are larger than normal hepatocytes but do not show cytonuclear atypia. Few or no portal tracts, central veins or bile ducts are present but there are isolated arteries. Kupffer cells are less numerous or absent.
Etiology
In most cases, adenomas develop for unclear reasons in an otherwise healthy liver. Some predisposing conditions have been identified: prolonged oral contraceptive use, glycogenosis type III and IV, congenital portocaval shunt and, in males, use of anabolic steroids. Molecular analysis has disclosed specific mutations in adenomatous cells, each associated with specific histological features: HNF1 mutations are associated with fatty hepatocytes, and mutations in beta-catenin are associated with dysplasia and malignant transformation. An additional type of hepatic adenoma has recently been characterized as telangiectatic adenoma. This type of adenoma features sinusoidal dilatation and inflammatory infiltrates.
Diagnostic methods
Diagnosis is made by a characteristic pattern of enhancement after injection of intravascular contrast medium, using contrast enhanced ultrasound, multiphasic computed tomography, or gadolinium-enhanced MRI. Biopsy and/or resection may be necessary to confirm the diagnosis.
Differential diagnosis
Differential diagnosis includes some forms of angiomas, focal nodular hyperplasia, hepatocellular carcinoma (see these terms), and certain types of liver metastases.
Management and treatment
Oral contraceptives are contraindicated and should be stopped. Surgical resection is advocated in most patients with a HA greater than 5 cm in diameter. When diagnosis is certain, and the tumor is less than 5 cm in diameter and asymptomatic, it can be left in place but surveillance is required.
Prognosis
Malignant transformation is rare and the long-term prognosis is good.

                            Last update:
                            April 2008

                            - Expert reviewer(s):
                            Pr Dominique VALLA


Hepatocellular carcinoma is a primary hepatic cancer derived from well-differentiated hepatocytes. It is more frequent in adults than in childhood. Symptoms are hepatic mass, abdominal pain and, in advanced stages, jaundice, cachexia and liver failure.


Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1

A rare, inherited mitochondrial disorder due to a defect in mitochondrial protein synthesis characterized by intrauterine growth retardation, metabolic decompensation with recurrent vomiting, persistent severe lactic acidosis, encephalopathy, seizures, failure to thrive, severe global developmental delay, poor eye contact, severe muscular hypotonia or axial hypotonia with limb hypertonia, hepatomegaly and/or liver dysfunction and/or liver failure, leading to fatal outcome in severe cases. Neuroimaging abnormalities may include corpus callosum thinning, leukodystrophy, delayed myelination and basal ganglia involvement.


A rare form of hepatic porphyria characterized by bullous photodermatosis.

Summary:
Epidemiology
Fewer than a hundred cases of hepato-erythropoietic porphyria (HEP) have been described worldwide.
Clinical description
The disease begins in childhood. The main clinical signs include skin fragility, and sometimes erosive or even mutilating bullous skin lesions on sun-exposed surfaces (hands, face). Anemia and splenomegaly may be present. At bone level, delayed metacarpophalangeal growth is usually present. Hepatoerythropoietic porphyria corresponds to homozygous or heterozygous compound cases of porphyria cutanea tarda.
Etiology
The disease is due to a deficiency of uroporphyrinogen decarboxylase (UROD; the fifth enzyme in the heme biosynthesis pathway) resulting from a mutation in the UROD gene (NM_000374.5), which leads to an accumulation of porphyrins mostly in the liver. At least 30 different mutations have been described in the UROD gene, including one predominant substitution: G281D.
Diagnostic methods
Diagnosis is based on evidence of porphyrin accumulation in urine and stool with a characteristic chromatographic profile, and very high porphyrin concentrations in plasma and erythrocytes. The presence of a major (< 10%) UROD deficiency in red blood cells confirms the diagnosis. Skin biopsy is not very informative and is not recommended.
Differential diagnosis
Günther's disease is the main differential diagnosis.
Antenatal diagnosis
Antenatal diagnosis is theoretically possible, but is not proposed.
Genetic counseling
Transmission pattern is autosomal recessive. Genetic counseling should be offered to affected families to identify individuals likely to develop or transmit the disease. Genetic counselling 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
Care and support mainly involves protecting the skin against light, and blood transfusions in case of anemia. Treatment with hydroxyurea and splenectomy are rarely necessary. Chloroquine and phlebotomy are of limited effectiveness in the treatment of hepato-erythropoietic porphyria.
Prognosis
The long-term prognosis is good.

                            Last update:
                            March 2024

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

                                * European Reference Network


A form of portosinusoidal vascular disease characterized histologically by varying degrees of phlebosclerosis, primarily involving the small and medium branches of the portal vein with heterogeneous distribution, in the absence of cirrhosis.


A rare T-cell non-Hodgkin lymphoma characterized by a proliferation of cytotoxic T-cells, usually gamma delta T-cells, with involvement of the liver and spleen, but without involvement of lymph nodes. The bone marrow is consistently affected. Patients typically present during adolescence or young adulthood with hepatosplenomegaly, pancytopenia, and systemic symptoms. Peripheral blood involvement may develop later in the disease course. There is a clear male preponderance. The disease often occurs in the context of long-term immunosuppression. The course is aggressive with poor therapy response.


A rare hereditary poikiloderma characterized by infantile onset of vesicopustule formation on hands and feet and widespread eczematoid dermatitis (both spontaneously resolving during childhood), as well as gradually developing diffuse poikiloderma with striate and reticulate atrophy (excluding the face, scalp, and ears), and development of keratotic papules on hands, feet, elbows, and knees, beginning in early childhood. There have been no further descriptions in the literature since 1981.


Hereditary amyloidosis with primary renal involvement

A group of rare renal diseases, characterized by amyloid fibril deposition of apolipoprotein A-I or A-II (AApoAI or AApoAII amyloidosis), lysozyme (ALys amyloidosis) or fibrinogen A-alpha chain (AFib amyloidosis) in one or several organs. Renal involvement leading to chronic renal disease and renal failure is a common sign. Additional manifestations depend on the organ involved and the type of amyloid fibrils deposited.


A form of hereditary angioedema characterized by acute edema in subcutaneous tissues, viscera and/or the upper airway.

Summary:
Epidemiology
Prevalence is unknown but HAE type 1 is the most common form of HAE accounting for 85% of the cases and is seen equally in males and females.
Clinical description
Like HAE 2 and 3 (see these terms), it occurs generally in childhood with symptoms becoming more severe in adolescence. Precipitating factors of HAE 1 thought to trigger attacks include: trauma, anxiety, puberty, infection, alcohol consumption, exercise and stress.
Etiology
It is caused by a missence mutation in the SERPING1 gene encoding the C1 inhibitor (C1-INH). These mutations cause C1-INH levels to decrease leading to an increase in bradykinin formation.
Management and treatment
Treatment usually consists of intravenous C1 inhibitor concentrate or subcutaneous administration of the orphan drug icatibant (bradykinin receptor antagonist). Prophylaxis with danazol is often given before surgical procedures.

                            Last update:
                            August 2011

                            - Expert reviewer(s):
                            Pr Laurence BOUILLET


Hereditary angioedema type 2 (HAE 2) is a form of hereditary angioedema (see this term) characterized by acute edema in subcutaneous tissues, viscera and/or the upper airway.

Summary:
Epidemiology
Prevalence is unknown. HAE 2 is the less common form of HAE, accounting for 15% of HAE cases and is seen equally in men and women.
Clinical description
Like HAE 1 and 3 (see these terms) it occurs generally in childhood with symptoms becoming more severe in adolescence. Precipitating factors of HAE 2 thought to trigger attacks include: trauma, anxiety, puberty, infection, alcohol consumption, exercise and stress.
Etiology
It is caused by deletions, frameshift or splice mutations in the SERPING1 gene encoding the C1 inhibitor (C1-INH). These mutations cause a decrease in C1-INH activity (while C1 inhibitor serum levels remain normal) leading to an increase in bradykinin formation.
Management and treatment
Treatment usually consists of intravenous C1 inhibitor concentrate or subcutaneous administration of the orphan drug icatibant (bradykinin receptor antagonist). Prophylaxis with danazol is often given before surgical procedures.

                            Last update:
                            August 2011

                            - Expert reviewer(s):
                            Pr Laurence BOUILLET


Hereditary angioedema with C1Inh deficiency

A rare hereditary angioedema characterized by potentially life-threatening episodes of subcutaneous and/or submucosal edema without urticaria, associated with C1 esterase inhibitor (C1-INH) deficiency. Hereditary angioedema (HAE) type 1 is caused by quantitative, HAE type 2 by qualitative defects of C1-INH. The two subtypes are clinically indistinguishable. Patients may present at any age (but most commonly in childhood) with recurrent attacks of nonpitting edema of the skin, severe abdominal symptoms such as pain and swelling, and/or respiratory distress due to upper respiratory airways involvement. Genital, bladder, muscle, or joint swelling may occur in some cases.


A rare hereditary angioedema characterized by potentially life-threatening episodes of subcutaneous and/or submucosal edema without urticaria and with normal levels and function of C1 esterase inhibitor. Patients present with prolonged attacks which last for approximately two to five days and may include nonpitting edema of the skin, severe abdominal symptoms such as pain and swelling, and/or respiratory distress due to upper respiratory airways involvement. Affected locations and frequency of attacks differ slightly between subtypes. Estrogen-containing oral contraceptives and pregnancy are precipitating factors, especially in patients with a factor XII mutation.


Hereditary angioedema (HAE) is a genetic disease characterized by the occurrence of transitory and recurrent subcutaneous and/or submucosal edemas resulting in swelling and/or abdominal pain.

Summary:
Epidemiology
Prevalence has been estimated at 1/100,000.
Clinical description
Onset may occur at any age but is most common during childhood or adolescence. Patients present with white, circumscribed nonpruritic edemas that remain for a period of 48 to 72 hours and recur with variable frequency. Edemas may involve the digestive tract resulting in a clinical picture similar to that seen in intestinal occlusion syndrome, sometimes associated with ascites and hypovolemic shock. Laryngeal edema can be life-threatening with a risk of death of 25% in the absence of appropriate treatment. Dental procedures are a triggering factor for laryngeal edema. Edemas of the face are a risk factor for laryngeal involvement.
Etiology
Three types of HAE have been described. HAE types 1 and 2 are caused by anomalies in the SERPING1 gene (11q12-q13-1) encoding the C1 inhibitor (C1-INH): type 1 is caused by deletion or by expression of a truncated transcript leading to a quantitative defect in C1-INH; type 2 is caused by point mutations leading to a qualitative defect in C1-INH. Transmission is autosomal dominant and most cases involve heterozygotes. The edemas are triggered by increased permeability of the blood vessels in response to elevated levels of bradykinin as a result of the C1-INH deficiency. HAE type 3 predominantly involves females, with the use of estrogen-containing oral contraceptives and pregnancy being precipitating factors. HAE type 3 is not caused by C1-INH deficiency but is associated with an increase in kininogenase activity leading to elevated levels of bradykinin. Some cases are associated with coagulation factor 12 (Hageman factor; F12; 5q33-qter) gain-of-function mutations but other genetic anomalies remain to be identified.
Diagnostic methods
Diagnosis of HAE types 1 and 2 relies on measurement of C4 concentrations and on quantitative and functional analysis of C1-INH. Diagnosis of HAE type 3 revolves around recognition of the clinical picture; C4 and C1-INH levels are normal. Analysis for mutations in the F12 gene may be proposed but are present in only 15% of patients.
Differential diagnosis
The differential diagnosis should include acquired angioedema (see this term), intestinal occlusion syndrome and histamine-induced angioedema (of allergenic or nonallergenic origin) generally associated with urticaria. Screening of family members, including asymptomatic individuals, is recommended.
Management and treatment
Corticosteroid treatments are not effective. In Europe, acute attacks should be treated with subcutaneous icatibant (a bradykinin receptor antagonist) or intravenous administration of C1-INH concentrate. Prophylactic treatment with tranexamic acid or danazol may be proposed for patients with frequent episodes.
Prognosis
The vital prognosis is good for patients who have been diagnosed and have access to the proper treatment in case of an ear-nose-throat (ENT) edema. Significant morbidity may be associated with digestive involvement resulting in pain and patients becoming bedridden for at least three days following an episode.

                            Last update:
                            August 2011

                            - Expert reviewer(s):
                            Pr Laurence BOUILLET


Hereditary arginine vasopressin deficiency

Hereditary central diabetes insipidus is a rare genetic subtype of central diabetes insipidus (CDI, see this term) characterized by polyuria and polydipsia due to a deficiency in vasopressin (AVP) synthesis.

Summary:
Epidemiology
The prevalence is unknown.
Clinical description
Symptoms usually develop between 1 and 6 years of age but onset in the neonatal period or in elderly patients has been described. They include polyuria, polydipsia and nocturia (often manifesting as enuresis in children). Additional symptoms seen in children can include: lethargy, irritability, growth retardation, weight loss, fever, vomiting or diarrhea. In the autosomal recessive form, symptoms are secondary to reduced biological activity of mutant AVP; heterozygous carriers have subclinical manifestations or are asymptomatic.
Etiology
The origin of the disease is genetic and is usually due to a mutation in the AVP gene located on chromosome 20p13 that encodes a precursor protein consisting of arginine vasopressin and two associated proteins, neurophysin 2 and copeptin. All except a few cases show an autosomal dominant pattern of inheritance. Rarely, an autosomal recessive or X-linked pattern of inheritance is reported.

                            Last update:
                            July 2012

                            - Expert reviewer(s):
                            Dr Stefano GHIRARDELLO


Hereditary arterial and articular multiple calcification syndrome is a very rare genetic vascular disease of autosomal recessive inheritance, described in less than 20 patients to date, characterized by adult-onset (as early as the second decade of life) isolated calcification of the arteries of the lower extremities (including the iliac, femoral, and tibial arteries) as well as the capsule joints of the fingers, wrists, ankles and feet, and that usually manifests with mild paresthesias of the lower extremities, intense joint pain and swelling, and early onset arthritis of affected joints.


A rare genetic systemic disease characterized by adult onset, progressive sensorimotor and autonomic neuropathy and infiltrative cardiomyopathy. Neurological involvement usually starts with sensory loss in the extremities and progresses with motor neuropathy. Cardiomyopathy presents with rhythm abnormalities and heart failure. The disease also frequently manifests with a range of additional clinical signs and symptoms due to associated ocular, renal, central nervous system and gastrointestinal involvement.

Summary:
Epidemiology
Hereditary ATTR amyloidosis (hATTR) is estimated to affect >10,000 individuals globally.
Clinical description
Disease onset typically occurs in adult life, with age and presenting symptoms largely depending on genotype. Initial signs usually include pain, temperature sensation loss, numbness or tingling in lower limbs extremities. Motor neuropathy progressively ensues causing walking instability, inability to walk unassisted and ultimately need for a wheelchair. Autonomic symptoms, including bowel abnormalities, early satiety, orthostatic hypotension and erectile dysfunction may appear in the initial stages of the disease, particularly in patients with an early onset phenotype. Heart involvement, with signs of infiltrative cardiomyopathy leading to heart failure, develops in the majority of patients. Most patients are therefore classified as mixed phenotype (both neurological and cardiac). With respect to drug prescription, impairment due to polyneuropathy is scored with the familial amyloidotic polyneuropathy (FAP) staging system which has three stages : stage 1 is defined by unassisted walking; stage 2 is defined by need for assisted walking and stage 3 is defined by wheelchair-bound or bedridden patient.
Etiology
Over 140 mutations in the TTR gene are presently associated with hATTR. Mutations cause TTR tetramer instability, proteolytic remodeling and dissociation into monomers, leading to misfolding, aggregation and deposition as amyloid in tissues and organs.
Diagnostic methods
Genetic testing revealing a heterozygous pathogenic TTR and tissue biopsy (preferably non-invasive like minor labial salivary gland, subcutaneous fat tissue or rectal mucosa) are required for a complete diagnosis. Green birefringence on polarized light microscopy after Congo red staining reveal amyloid deposits. In the absence of a serum and/or urinary monoclonal gammopathy, bone tracer scintigraphy with a Perugini score ≥2 represents indirect evidence of TTR amyloid deposition. Amyloid deposits must be typed by immunohistochemistry or mass spectrometry for definite diagnosis when a patient also presents with a serum and/or urinary monoclonal gammopathy.
Differential diagnosis
The differential diagnosis includes diabetic neuropathy, chronic inflammatory demyelinating polyneuropathy, and AL, AGel and AApoAI amyloidosis. Increased left ventricular wall thickness should be differentiated from hypertensive heart disease, concentric hypertrophy from aortic stenosis, hypertrophic cardiomyopathy or other infiltrative cardiomyopathies, such as Fabry disease.
Antenatal diagnosis
Prenatal and preimplantation diagnosis is possible when the pathogenic variant has previously been identified in a family member. However for TTR variants associated with a late-onset phenotype antenatal diagnosis is very rarely requested, particularly in light of emerging disease-modifying therapies.
Genetic counseling
hATTR is dominantly transmitted. Genetic counseling is highly recommended to at-risk patients' relatives, informing them there is a 50% risk of inheritance in siblings and offspring. Pre-symptomatic testing is increasingly offered in hATTR due to emerging disease-modifying therapies.
Management and treatment
There are two different classes of disease-modifying therapies for hereditary transthyretin amyloidosis: TTR stabilizers and gene-silencing agents. Tafamidis is the first-in-class transthyretin stabilizer that prevents misfolding and aggregation by stabilizing the native protein structure. It is approved for hATTR with FAP stage 1 polyneuropathy at the dose of 20 mg/daily and for hATTR with cardiomyopathy at the dose of 61 mg/daily. Gene-silencing agents approved by EMA for hATTR with polyneuropathy (FAP stages 1 and 2) include RNAi agents patisiran and vutrisiran and the antisense oligonucleotide (ASO) inotersen.
Prognosis
Prognosis depends on disease stage at treatment start. Advanced heart involvement is associated with worse prognosis.

                            Last update:
                            May 2023

                            - Expert reviewer(s):
                            Dr Laura OBICI | RITA*

                                * European Reference Network


Hereditary benign intraepithelial dyskeratosis

A rare, genetic, superficial corneal dystrophy disease characterized by white, elevated, epithelial plaques located on the bulbar conjunctiva (sometimes with encroachment of the cornea) and oral mucosa (in any part of the oral cavity), associated with dilated, hyperemic, conjunctival blood vessels, observed mainly in Haliwa-Saponi Native American descendents. Patients may be asymptomatic or present with ocular itching, superficial corneal scarring, excessive lacrimation, photophobia and visual loss due to corneal opacity. Histologically, both ocular and oral lesions display acanthosis with hyperkeratosis and prominent dyskeratosis.