Hereditary breast and/or ovarian cancer syndrome

A genetic condition characterized by hereditary susceptibility to breast and/or ovarian cancer. It can be defined using family history criteria, or through identification of germline pathogenic variants (GPVs) in clinically validated HBOC genes. However, the genetic basis of about half of clinical HBOC is currently unknown or unexplained by single-gene variants, and approximately half of individuals who harbour PVs in HBOC genes do not have a suggestive family history.

Summary:
Epidemiology
The prevalence of any germline HBOC-related pathogenic variant has been estimated to be about 1:70 women in the general population.
Clinical description
HBOC is not associated with specific phenotypic features. Individuals with breast cancer may have any histological subtypes, the most common being ductal adenocarcinoma. Early-onset of cancer, bilateral breast cancer, familial occurrence of cancer over several generations, male breast cancer, multiple tumors in a same individual, multifocality and triple negative cancer are features suggestive of hereditary HBOC.
Etiology
Genes associated with HBOC are classified as 1) high-risk genes, increasing breast and/or tubo-ovarian cancer risk by at least fourfold, and 2) moderate-risk genes, increasing risk by two- to fourfold. However, there is considerable overlap between these two groups. Autosomal dominant alterations in BRCA1 and BRCA2 are likely to account for most HBOC cases. Other genes linked to hereditary breast or ovarian cancer are PALB2, ATM, CHEK2, BARD1 (only breast), RAD51C, RAD51D (breast and ovary) and BRIP1 (only ovary). TP53, PTEN, CDH1, and STK11 are linked to increased breast cancer susceptibility and also to other specific syndromes. Disease severity and age at onset may show variability within and between families harboring the same pathogenic variant, suggesting the involvement of other genetic as well as non-genetic factors. These PVs may also increase susceptibility to other cancer types such as prostate cancer and pancreatic cancer.
Diagnostic methods
Diagnosis is based on suggestive clinical features associated with significant family history. Individuals should be offered genetic testing with multigene panels of clinically validated HBOC genes. Analysis of single nucleotide variants and large rearrangements are needed for comprehensive genetic testing. If a pathogenic variant is identified through tumor testing, germline testing can be considered to confirm the diagnosis.
Differential diagnosis
Differential diagnosis includes familial breast cancer not associated with known genetic susceptibility.
Antenatal diagnosis
Once the PV in HBOC-related genes has been identified in the family, prenatal and preimplantation genetic testing for known highly penetrant high cancer risk PV are possible.
Genetic counseling
HBOC-related genes are inherited in an autosomal dominant manner. The vast majority of probands inherited it from a parent, with very few being de novo. Offsprings of affected individuals have a 50% chance of inheriting the PV, but the penetrance of the disease is currently unknown. Molecular genetic testing should be offered to both parents and their at-risk relatives who should be counseled regarding their cancer risk, the risk of transmission, and recommendations for cancer screening and prophylactic surgery. Counseling should also mention possible rare autosomal recessive conditions, such as Fanconi anemia, when biallelic PVs in some genes are inherited (i.e. BRCA2, BRCA1, PALB2) and if the partner's family history is also suggestive of HBOC. Testing of asymptomatic individuals < 18 years of age is not recommended and should be deferred until they reach adulthood and can make independent decisions.
Management and treatment
The management strategies in healthy carriers include yearly surveillance and surgical risk-reduction options. For patients with a BRCA1/2-associated cancer, there are personalized approaches based on DNA-damaging agents or targeted therapies such as poly-ADP-ribose polymerase (PARP) inhibitors. Secondary preventive measures might be considered, such as contralateral risk reducing mastectomy or prophylactic bilateral salpingoophorectomy.
Prognosis
Breast and/or ovarian cancers in carriers of a BRCA1 or BRCA2 pathogenic variant may have increased chemosensitivity which might be linked to a slight survival advantage in the first few years after diagnosis compared to other patients.

                            Last update:
                            June 2023

                            - Expert reviewer(s):
                            Dr Judith BALMAÑA | ERN GENTURIS* - Dr Maria HAANPÄÄ | ERN GENTURIS* -  Tamara HUSSONG MILAGRE | ERN GENTURIS* - Dr Arvids IRMEJS | ERN GENTURIS* - Dr Mateja KRAJC | ERN GENTURIS* - Pr Svetlana Bajalica LAGERCRANTZ | ERN GENTURIS* - Dr Salvatore TESTA | ERN GENTURIS* - Pr Marc TISCHKOWITZ | ERN GENTURIS*

                                * European Reference Network


A rare genetic, malignant breast tumor characterized by early onset breast cancer in association with a germline mutation. Tumors arising in carriers of BRCA1 and BRCA2 mutations differ morphologically and genetically from each other, as well as from sporadic breast cancers. Most BRCA1-associated tumors are invasive ductal adenocarcinomas of no special type, typically of higher grade than sporadic tumors, and more often negative for hormone receptors. In addition, more cases with features of typical or atypical medullary carcinoma are seen in these patients. Likewise, BRCA2-associated tumors tend to be of higher grade than sporadic ones, although their phenotype is similar. They show a low frequency of HER-2 expression.


Hereditary bullous dystrophy, macular type

A rare X-linked syndromic intellectual disability characterized by intellectual deficit, microcephaly, short stature, and ectodermal anomalies (including alopecia, spontaneous formation of bullae without evident trauma, hyper- or hypopigmented maculae, acrocyanosis, and dystrophic nails) in male patients. Additional reported features are short, tapering fingers, ocular anomalies (such as corneal opacities and cataract), and hypogenitalism. There have been no further descriptions in the literature since 1995.


Butyrylcholinesterase (BChE) deficiency is a metabolic disorder characterised by prolonged apnoea after the use of certain anaesthetic drugs, including the muscle relaxants succinylcholine or mivacurium and other ester local anaesthetics. The duration of the prolonged apnoea varies significantly depending on the extent of the enzyme deficiency.

Summary:
Epidemiology
The prevalence of BChE deficiency is highest in the Caucasian population with between 3.4 and 4% of the population displaying a partial enzyme deficiency leading to slightly prolonged apnoea (between 5 minutes and 1 hour) and 1 in 2500 individuals showing a prolongation of more than 1 hour. Individuals with undetectable levels of BChE activity display a severe prolongation lasting more than 8 hours. The prevalence of this severe form is estimated at 1 in 100 000 individuals.
Etiology
BChE deficiency is a multifactorial disorder. It is caused by mutations in the BChE gene. The BChE gene is located at the E1 locus on chromosome 3 (3q26.1-q26.2) and multiple atypical variants have been identified. However, BChE deficiency and sensitivity to anaesthetic drugs may also occur during pregnancy, in neonates or in association with other pathologies (chronic infections, malnutrition, liver disease, certain cancers etc.).
Diagnostic methods
Diagnosis can be made by analysis of enzyme activity in plasma samples, combined with dibucaine and fluoride inhibition tests. DNA analysis, although not carried out routinely, can be used to identify heterozygous carriers of atypical alleles.
Genetic counseling
The hereditary condition is transmitted as an autosomal recessive trait.
Management and treatment
Affected individuals are asymptomatic unless exposed to neuromuscular blocking agents, however, prolonged respiratory paralysis following anaesthesia makes mechanical ventilation essential until the excess aesthetic agent is metabolised permitting normal neuromuscular function.

                            Last update:
                            October 2006

                            - Expert reviewer(s):
                            Pr Pascale DE LONLAY


A rare gastroenterologic disease characterized by recurrent acute pancreatitis and/or chronic pancreatitis in at least 2 first-degree relatives, or 3 or more second-degree relatives in 2 or more generations, for which no predisposing factors are identified. This rare inherited form of pancreatitis leads to irreversible damage to both exocrine and endocrine components of the pancreas.

Summary:
Epidemiology
The estimated prevalence of hereditary chronic pancreatitis (HCP) is approximately 1/300,000 people in Europe (1/800,000 in Germany, approximately 1/333,000 in France and approximately 1/175,000 in Denmark).
Clinical description
Onset of HCP is typically early in life, during childhood and adolescence. The clinical presentation is highly variable and includes chronic or intermittent mild to severe abdominal pain associated with exocrine pancreatic insufficiency, leading to maldigestion and/or pancreatic endocrine insufficiency (glucose intolerance progressing to diabetes mellitus type 3c) in some cases. The disease is slowly progressive. The risk of developing pancreatic carcinoma after the age of 50 is elevated in patients with HCP. However, the exact risk increase is difficult to assess.
Etiology
Mutations in the PRSS1 (7q34) gene, encoding cationic trypsinogen, play a causative role in chronic pancreatitis. It has been shown that the PRSS1 mutations increase autocatalytic conversion of trypsinogen to active trypsin and thus probably cause premature, intrapancreatic trypsinogen activation disturbing the intrapancreatic balance of proteases and their inhibitors. Other genes, such as the anionic trypsinogen (PRSS2; 7q34), the serine protease inhibitor, Kazal type 1 (SPINK1; 5q32) and the cystic fibrosis transmembrane conductance regulator (CFTR; 7q31.2) have been found to be associated with chronic pancreatitis (idiopathic and hereditary). Recently, mutations in carboxypeptidase A1 (CPA1; 7q32.2), carboxylesterlipase (CEL; 9q34.13) and pancreatic lipase (PNLIP; 10q25.3) have been found to be associated with HCP and idiopathic chronic pancreatitis with early onset.
Diagnostic methods
Diagnosis of HCP is based on clinical features along with family history of chronic pancreatitis, absence of precipitating factors and a negative workup for known causes of chronic pancreatitis. Imaging (abdominal ultrasound, endoscopic ultrasound, exceptionally with endoscopic retrograde cholangiopancreatography (ERCP), magnetic resonance cholangiopancreatography (MRCP) reveals morphological changes like pancreatic calcifications, pancreatic duct changes, pseudocysts, bile duct and duodenal obstruction. The diagnosis might be substantiated by variants in the genes mentioned above.
Differential diagnosis
Differential diagnoses include other forms of chronic pancreatitis mainly alcoholic chronic pancreatitis, idiopathic chronic pancreatitis, autoimmune pancreatitis.
Antenatal diagnosis
Antenatal diagnosis is not encouraged.
Genetic counseling
Genetic testing should only be performed in carefully selected patients by direct DNA sequencing. Mutation in the PRSS1 gene is transmitted in an autosomal dominant manner with incomplete penetrance.
Management and treatment
Mainstays of medical management involve pain control, nutritional support, treatment for diabetes mellitus, and pancreatic enzyme supplementation for exocrine insufficiency. Surgery may be indicated for the management of acute and chronic complications of HCP and includes debridement, drainage, decompression and only very rarely pancreatectomy. Additional risk factors for chronic pancreatitis (smoking, alcohol) should be avoided.
Prognosis
The prognosis of patients with HCP is unpredictable with an increased risk of development of pancreatic carcinoma.

                            Last update:
                            September 2019

                            - Expert reviewer(s):
                            Pr Jonas ROSENDAHL


Hereditary clear cell renal cell carcinoma (ccRCC) is a hereditary renal cancer syndrome defined as development of ccRCC in two or more family members without evidence of constitutional chromosome 3 translocation, von Hippel-Lindau disease or other tumor predisposing syndromes associated with ccRCC, such as tuberous sclerosis or Birt-Hogg-Dubbé syndrome.


Hereditary combined deficiency of vitamin K-dependent clotting factors

Combined vitamin K-dependent clotting factors deficiency (VKCFD) is a congenital bleeding disorder resulting from variably decreased levels of coagulation factors II, VII, IX and X, as well as natural anticoagulants protein C, protein S and protein Z.

Summary:
Epidemiology
Prevalence is unknown but less than 30 affected families have been reported in the literature so far.
Clinical description
The spectrum of bleeding symptoms ranges from mild to severe with onset in the neonatal period in severe cases. The bleeding symptoms are often life-threatening, occur both spontaneously and in a surgical setting and usually involve the skin and mucosae. A range of nonhemostatic symptoms are often present, including developmental and skeletal anomalies (stippling of the long bones, shortness of the distal phalanges of the fingers, osteoporosis) and pseudoxanthoma elasticum-like syndrome (see this term).
Etiology
VKCFD is an autosomal recessive disorder caused by mutations in the genes encoding either gamma-glutamyl carboxylase (GGCX; 2p12) or the vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1; 16p11.2). These two proteins are necessary for gamma-carboxylation, a postsynthetic modification that allows coagulation proteins to display their proper function. The developmental and skeletal anomalies seen in VKCFD are the result of defective gamma-carboxylation of a number of nonhemostatic proteins.
Diagnostic methods
Diagnosis of VKCFD should only be considered after exclusion of acquired forms of the disease, associated with intestinal malabsorption of vitamin K in patients with inflammatory bowel diseases or celiac disease (see these terms), liver cirrhosis or accidental ingestion of warfarins and superwarfarins. After exclusion of other causes, diagnosis of VKCFD is suspected in the context of an excessive bleeding pattern compared to the extent of the decrease in individual clotting factors, and is confirmed by molecular analysis.
Differential diagnosis
Other congenital clotting defects such as isolated factor II, VII, IX (hemophilia B) and X deficiencies, combined factor VII and X deficiency (see these terms) and acquired bleeding anomalies due to the presence of autoantibodies (acquired hemophilia [see this term] and factor VII deficiency due to the presence of autoantibodies against factor VII) must also be considered as differential diagnoses.
Antenatal diagnosis
Prenatal genetic testing is not generally recommended.
Genetic counseling
Genetic counseling may be offered to affected families.
Management and treatment
Administration of vitamin K during the third trimester of pregnancy may be useful in women suspected of carrying a child with VKCFD. Vitamin K administration (oral or intravenously) is the mainstay of therapy in symptomatic VKCFD. Plasma supplementation and prothrombin complex concentrates are needed during surgery or severe bleeding episodes. In addition, combination therapy with both recombinant activated FVII (eptacog alfa) and vitamin K supplementation may constitute an alternative treatment option for surgical procedures and severe manifestations.
Prognosis
The overall prognosis is good and, with the availability of several effective therapeutic options, VKCFD has only a small impact on the quality of life of affected patients.

                            Last update:
                            March 2010

                            - Expert reviewer(s):
                            Dr Mario LAPECORELLA  - Dr G MARIANI  - Dr Mariasanta NAPOLITANO


Hereditary continuous muscle fiber activity is a rare, non-dystrophic myopathy characterized by generalized myokymia and increased muscle tone associated with delayed motor milestones, leg stiffness, spastic gait, hyperreflexia and Babinski sign. Symptoms may be worsened by febrile illness or anesthesia.


A rare acute hepatic porphyria characterized by neurovisceral attacks and, more rarely, skin lesions.

Summary:
Epidemiology
Prevalence in Europe is estimated at about 1/1,000,000.
Clinical description
The disease manifests after puberty, predominantly affecting women. Patients suffer neurovisceral episodes that can persist for several weeks, manifesting severe abdominal pain (85-95% of cases), neurological disorders, and psychological disturbances. Abdominal pain is very often associated with low back pain irradiating to the legs, and with nausea, vomiting and constipation. Several psychological disturbances can be observed: irritability, emotional sensitivity, depressive disorder, anxiety and, more rarely, auditory or visual hallucinations, disorientation, and mental confusion. Neurological manifestations can affect both the central and peripheral nervous systems (myalgia, paresis, ascending flaccid paralysis of the limbs or convulsions), and can lead to severe complications such as motor paralysis. Tachycardia and hyponatremia are common during these episodes. In the rare case of cardiac arrhythmia or respiratory paralysis, it can be fatal. Such episodes are most commonly triggered by exogenous factors (porphyrinogenic drugs, alcohol, infections, a low-calorie diet, stress), and/or endogenous factors (hormonal, linked to menstrual cycle). In 30% of cases, patients develop skin lesions as a result of photosensitivity. Lesions predominantly appear on sun-exposed areas (hands, face) and come with more or less painful bullae, usually leaving hyperpigmented scars.
Etiology
The disease is caused by a deficiency in coproporphyrinogen oxidase (CPOX, the sixth enzyme in the heme biosynthesis pathway) which leads to an accumulation of porphyrins and their precursors (delta aminolevulinic acid, ALA, and porphobilinogen, PBG) in the liver. The enzyme deficiency is due to mutations of the CPOX gene (NM_000088; 3q12) coding for CPOX.
Diagnostic methods
Reddish or brown coloration of urine following exposure to warm light is suggestive of the disease. Diagnosis is based on significantly elevated concentrations of PBG (pathognomonic of acute porphyria attack) and ALA in urine, and defective CPOX enzyme activity in circulating lymphocytes. Identification of a causal mutation of the CPOX gene confirms the diagnosis.
Differential diagnosis
Differential diagnoses include acute intermittent porphyria, porphyria cutanea tarda and, above all, variegate porphyria.
Antenatal diagnosis
Antenatal diagnosis is possible if a pathogenic variant has been identified in the family. It is offered to families at risk of homozygous form.
Genetic counseling
Genetic counseling is recommended to patients and families to identify individuals at risk of developing or transmitting the disease. Transmission is autosomal dominant. Affected individuals have a 50% risk of transmitting the disease on to their offspring.
Management and treatment
Acute episodes must be considered as medical emergencies and treated by injection of human hemin and/or perfusion of carbohydrates. Management includes elimination of one or more triggers, relief of pain (opioids), vomiting, and anxiety, and prevention of acute attacks (avoidance of triggers, particularly drugs).
Prognosis
With early diagnosis and management, acute episodes are rarely severe. In hereditary coproporphyria, acute episodes are less frequent compared to acute intermittent porphryia, and the disease is rarely progressive if the triggering factors are eliminated.

                            Last update:
                            March 2024

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

                                * European Reference Network


Hereditary cryohydrocytosis with normal stomatin is a rare, hereditary, hemolytic anemia due to a red cell membrane anomaly characterized by fatigue, mild anemia and pseudohyperkalemia due to a potassium leak from the red blood cells. A hallmark of this condition is that red blood cells lyse on storage at 4 degrees centigrade.


Hereditary cryohydrocytosis with reduced stomatin

A rare hemolytic anemia characterized by combination of neurologic features, such as psychomotor delay, seizures, variable movement disorders, and hemolytic anemia with stomatocytosis, resulting in cation-leaky erythrocytes, pseudohyperkalemia, hemolytic crises and hepatosplenomegaly. Cataracts are also a presenting feature.


The hereditary dentin disorders, dentinogenesis imperfecta (DGI) and dentin dysplasia (DD), comprise a group of conditions characterized by abnormal dentin structure affecting either the primary or both the primary and secondary dentitions.

Summary:
Epidemiology
DGI is reported to have an incidence of 1 in 6,000 to 1 in 8,000 births, whereas that of DD type 1 is 1 in 100,000.
Clinical description
Clinically, the teeth are discolored and show structural defects such as bulbous crowns and small pulp chambers on radiographs. The underlying defect of mineralization often results in shearing of the overlying enamel leaving exposed weakened dentin which is prone to wear. Currently, three subtypes of DGI and two subtypes of DD are recognized but this categorization may change when further causative mutations are identified.
Etiology
DGI type 1 is inherited with osteogenesis imperfecta and recent genetic studies have shown that mutations in the genes encoding collagen type 1, COL1A1 and COL1A2, underlie this condition. All other forms of DGI and DD, except DD type 1, appear to result from mutations in the gene encoding dentine sialophosphoprotein (DSPP).
Diagnostic methods
Diagnosis is based on family history, pedigree construction and detailed clinical examination, but genetic diagnosis may become useful in the future once a sufficient number of disease-causing mutations have been identified.
Differential diagnosis
Differential diagnoses include hypocalcified forms of amelogenesis imperfecta, congenital erythropoietic porphyria, conditions leading to early tooth loss (Kostmann syndrome, cyclic neutropenia, Chediak-Higashi syndrome, histiocytosis X and Papillon-Lefevre syndrome), permanent teeth discoloration due to tetracyclines, and Vitamin D-dependent and vitamin D-resistant rickets (see these terms).
Genetic counseling
Both DGI and DD are transmitted as autosomal dominant conditions.
Management and treatment
Treatment involves removal of sources of infection or pain, improvement of aesthetics and protection of the posterior teeth from wear. Beginning in infancy, treatment usually continues into adulthood with a number of options including the use of crowns, over-dentures and dental implants depending on the age of the patient and the condition of the dentition.
Prognosis
Where diagnosis occurs early in life and treatment follows the outlined recommendations, good esthetics and function can be obtained.

                            Last update:
                            November 2008

                            - Expert reviewer(s):
                            Dr Martin BARRON  - Pr Mike DIXON  - Dr Iain MACKIE  - Dr Sinead MCDONNELL


Hereditary diffuse gastric cancer is a rare epithelial tumor of the stomach, characterized by the development of diffuse (signet ring cell) gastric cancer at a young age, associated with germline heterozygous mutations of CDH1, MAP3K6 and CTNNA1 genes. In early stages it presents with non-specific and vague symptoms, in advanced stages it may cause nausea and vomiting, dysphagia, loss of appetite, abdominal mass or weight loss. Women have an increased risk of lobular breast cancer as well.


Hereditary elliptocytosis (HE) is a rare clinically and genetically heterogeneous disorder of the red cell membrane characterized by manifestations ranging from mild to severe transfusion-dependent hemolytic anemia but with the majority of patients being asymptomatic.

Summary:
Epidemiology
HE is ubiquitously distributed with an estimated prevalence of 1/1,000-1/4,000 but may be underestimated due to asymptomatic patients. The prevalence may reach up to 1/50 in malaria endemic areas like West and Central Africa. Less than 10% of HE patients manifest with the severe variant of hereditary pyropoikilocytosis (HPP).
Clinical description
HE can present at any age and the clinical picture is heterogeneous. Most have common HE, which is mainly asymptomatic or which can present with mild hemolytic anemia as well as jaundice, splenomegaly and gallstones. Hydrops fetalis (see this term) may be seen in rare cases. A neonatal poikilocytic HE variant may be severe during the first year of life but afterwards (from 4 months-2 years) hemolysis declines and the phenotype becomes that of common HE. Transient poikilocytosis may also occur during infections or pregnancy, leading to hemolytic anemia in previously asymptomatic patients. The HPP variant is characterized by severe, transfusion-dependent hemolytic anemia with onset in infancy and that can also manifest with neonatal jaundice. Complications that can occur due to severe anemia include growth retardation, frontal bossing, marked splenomegaly and early gallbladder disease. Aplastic crisis, brought on by a Parvovirus B19 infection, may occur in some cases.
Etiology
HE is caused by abnormalities of proteins involved in the red cell membrane horizontal skeletal network including the spectrin dimer-dimer interaction or the spectrin-actin-protein 4.1 junctional complex. The genes involved in HE are: alpha-spectrin erythrocytic 1 (SPTA1) located to 1q21, beta-spectrin erythrocytic (SPTB) located to 14q24.1-q24.2, erythrocyte membrane protein band 4.1 (EPB41) located to 1p33-p32 or glycophorin C (Gerbich blood group) (GYPC) located to 2q14-q21. Heterozygous mutations usually result in common HE. Patients with HPP are either compound heterozygotes or homozygotes for a missense mutation of alpha/beta spectrin. HPP is also due to the presence of one alpha-spectrin mutation in trans to a low-expression alpha-spectrin allele (alpha-LELY).
Diagnostic methods
The laboratory hallmark of HE is the presence of elliptocytes (sometimes also ovalocytes, spherocytes, stomatocytes and fragmented cells) on peripheral blood smears. Osmotic fragility is not informative in common HE, but is usually increased in HPP. SDS-PAGE analysis of red cell membrane proteins may reveal quantitative/qualitative abnormalities of cytoskeletal proteins. The mean corpuscular volume in HPP is of 50-60 fL and marked poikilocytosis and red cell fragmentation is present. Genetic mutation analysis can identify causal mutations, confirming diagnosis.
Differential diagnosis
Differential diagnoses include other acquired causes of elliptocytic or fragmented red cells (i.e. iron, vitamin B12 and folate deficiency, and microangiopathic hemolytic anemia), congenital dyserythropoietic anemia and alpha and beta thalassemia (see these terms).
Antenatal diagnosis
Since HE is very rarely life threatening, antenatal diagnosis is not necessary, except for HPP cases, where screening for low expression polymorphism (i.e. alpha- LELY) is also needed.
Genetic counseling
All HE variants, apart from HPP (inherited autosomal recessively), follow an autosomal dominant pattern of inheritance and genetic counseling is possible.
Management and treatment
In most cases treatment is not necessary. In the most severe variants, folic acid, red cell transfusion and splenectomy (after the age of 5) may be required. Patients should be monitored during events known to precipitate hemolysis.
Prognosis
In the majority of cases HE is not life threatening and has no effect on life expectancy.

                            Last update:
                            April 2014

                            - Expert reviewer(s):
                            Dr Alberto ZANELLA


Hereditary episodic ataxia (EA) represents a group of neurological disorders characterized by recurrent episodes of ataxia and vertigo which may be progressive. Weakness, dystonia and ataxia are sometimes present in the interictal period. Seven types of EA have been described to date (EA type 1 to EA type 7, see these terms), but most of the reported cases belong to EA1 and EA2.


Hereditary fibrosing poikiloderma-tendon contractures-myopathy-pulmonary fibrosis syndrome is a rare, genetic, hereditary poikiloderma syndrome characterized by early-onset poikiloderma (mainly on the face), hypotrichosis, hypohidrosis, muscle and tendon contractures with varus foot deformity, progressive proximal and distal muscle weakness in all extremities, and progressive pulmonary fibrosis. Mild lymphedema of the extremities, growth retardation, liver impairment, exocrine pancreatic insufficiency and hematologic abnormalities are additional variable features.


Hereditary folate malabsorption (HFM) is an inherited disorder of folate transport characterized by a systemic and central nervous system (CNS) folate deficiency manifesting as megaloblastic anemia, failure to thrive, diarrhea and/or oral mucositis, immunologic dysfunction and neurological disorders.

Summary:
Epidemiology
The prevalence is unknown. Approximately 30 cases have been reported to date.
Clinical description
Disease onset usually occurs a few months after birth. Manifestations include failure to thrive, diarrhea and/or mouth ulcers, various neurological manifestations (motor impairment, seizures, developmental delay, cognitive and behavioral disorders), megaloblastic anemia and hypoimmunoglobulinemia. Megaloblastic anemia is the primary manifestation of HFM and can be very severe if untreated. Hypoimmunoglobulinemia results in unusual infections with Pneumocystis jiroveccii, C. difficile and cytomegalovirus (CMV) which can be recurrent and life-threatening in undiagnosed infants. Neurological manifestations may be the presenting symptoms in some but are absent in others. Seizures, if present, begin in infancy or later in childhood. Intracranial calcifications have been observed in some.
Etiology
HFM is caused by mutations in the SLC46A1 gene found on chromosome 17q11.2 which encodes the proton-coupled folate transporter (PCFT). PCFT is essential for intestinal folate absorption and transport of folates across the blood-cerebrospinal fluid (CSF) barrier. A defect in this protein leads to a systemic folate and CNS folate deficiency. Infants cannot absorb adequate folate from breast milk/formula and become deficient once their stores accumulated during gestation are exhausted.
Diagnostic methods
Diagnosis is based on clinical and laboratory findings. It is confirmed by findings of an impaired absorption of an oral folate load (even after correction of serum folate concentration) and a low CSF folate concentration (0-1.5nM). Bone marrow biopsy confirms the presence of megaloblastic anemia. Sequence analysis of the SLC46A1 coding region can identify any mutations present in the gene, also confirming diagnosis of HFM.
Differential diagnosis
The immunodeficiency seen in HFM may resemble severe combined immune deficiency (SCID; see this term). Other differential diagnoses include methionine synthase deficiency with megaloblastic anemia and developmental delay, formiminoglutamic aciduria, tyrosinemia type 1, methylenetetrahydrofolate reductase deficiency and erythroleukemia (see these terms).
Antenatal diagnosis
Antenatal diagnosis is possible via prenatal testing. Screening of newborns with a family history of HFM allows for early diagnosis and treatment with folate immediately after birth, before symptoms occur.
Genetic counseling
HFM is inherited autosomal recessively. Genetic counseling is possible.
Management and treatment
High dose oral or parenteral 5-formyltetrahydrofolate (5-formylTHF) and oral L-5-methyltetrahydrofolate (L-5-methylTHF) are the two types of reduced folates used to treat HFM. Dosage is monitored and adjusted (individualized for each patient) so that the CSF folate levels remain within the normal range (around 100nM in infants-2 year olds). Folic acid should not be used as it binds to folate receptors and blocks folate transport. If anemia is severe, a transfusion may be necessary. Early treatment with reduced folates before the appearance of symptoms can prevent the metabolic consequences of HFM. Patients should have regular blood tests to monitor complete blood count, serum and CSF folate and homocysteine concentrations and serum immunoglobulin concentrations.
Prognosis
With proper treatment the prognosis is good and reversal of most of the systemic consequences of the disease is usually achieved. Only when untreated is the prognosis poor.

                            Last update:
                            October 2012

                            - Expert reviewer(s):
                            Dr David ROSENBLATT  - Dr David WATKINS


Hereditary fructose intolerance (HFI) is an autosomal recessive disorder of fructose metabolism (see this term), resulting from a deficiency of hepatic fructose-1-phosphate aldolase activity and leading to gastrointestinal disorders and postprandial hypoglycemia following fructose ingestion. HFI is a benign condition when treated, but it is life-threatening and potentially fatal if left untreated.

Summary:
Epidemiology
The estimated prevalence is 1 in 20,000 in Europe and the carrier frequency is about 1 in 70. The prevalence of HFI in adult population is not known.
Clinical description
HFI usually presents in infancy at the time of weaning (when fructose is added to the diet), manifesting with hypoglycemia, lactic acidosis, ketosis with recurrent vomiting, abdominal pain and systemic manifestations following consumption of fructose-containing foods. Persistent ingestion of fructose and related sugars (such as sucrose and sorbitol) may lead to growth retardation, hepatomegaly, proximal tubular dysfunction, liver and renal failure, seizures, coma and risk of death. All patients achieve adulthood, develop a natural aversion to fruit/sweets and report a life long history of vomiting and hypoglycemia following fructose ingestion. Dental caries are absent in a significant proportion of adult population with HFI (which may give a clue to the diagnosis). Sometimes, the diagnosis may be made in an adult who has, owing to his aversion to fructose, excluded all fructose-containing food since childhood.
Etiology
HFI is caused by mutations in the ALDOB (9q22.3) gene, encoding the enzyme aldolase B. Affected individuals fail to metabolize fructose completely in the liver, intestine and kidneys because of fructose-1-phosphate aldolase B deficiency, leading to accumulation of the substrate fructose-1-phosphate and subsequent depletion of adenosine triphosphate.
Diagnostic methods
Early diagnosis is essential, as patients can live a symptom-free life by eliminating fructose from their diet. When clinical features, nutritional and family history are suggestive, HFI is confirmed by molecular diagnosis on DNA from peripheral leucocytes. Very rarely, when no mutation can be found, liver biopsy may be performed to assess aldolase B activity.Early diagnosis is essential, as patients can live a symptom-free life by eliminating fructose from their diet. When clinical features, nutritional and family history are suggestive, HFI is confirmed by molecular diagnosis on DNA from peripheral leucocytes. Very rarely, when no mutation can be found, liver biopsy may be performed to assess aldolase B activity.
Differential diagnosis
Differential diagnoses include pyloric stenosis, gastro-esophageal reflux,galactosemia, tyrosinemia, glycogen storage disease, ornithine transcarbamoylase deficiency, Wilson disease, tumor of hematopoietic and lymphoid tissue (see these terms) and fructose malabsorption.
Antenatal diagnosis
Prenatal diagnosis is technically possible in families with known mutations, but it is not indicated due to the benign nature of this condition.
Genetic counseling
HFI is an autosomal recessive condition.
Management and treatment
Whenever HFI is suspected, fructose should be eliminated from diet. This involves avoiding all types of food in which fructose, sucrose and/or sorbitol is found, either naturally or added during processing, including certain pharmacological preparations and infant formulae. The beneficial clinical and chemical effects of withdrawal are usually seen within a few days. Multivitamin preparation may be prescribed to substitute vitamins, especially vitamin C and folates. Intensive care and supportive measures may be required in case of acute intoxication
Prognosis
HFI prognosis is favorable with normal growth, intelligence and lifespan.

                            Last update:
                            September 2015

                            - Expert reviewer(s):
                            Pr Philippe LABRUNE


Hereditary gastric cancer refers to the occurrence of gastric cancer in a familial context and is described as two or more cases of gastric cancer in first or second degree relatives with at least one case diagnosed before the age of 50. Familial clustering is observed in 10% of all cases of gastric cancer, and includes hereditary diffuse gastric cancer (early onset diffuse-type gastric cancer), gastric adenocarcinoma and proximal polyposis of the stomach (see these terms) and familial intestinal gastric cancer (familial clustering of intestinal type gastric adenocarcinoma). Hereditary gastric cancer can also occur in other hereditary cancer syndromes such as Lynch syndrome, Li-Fraumeni syndrome, familial adenomatous polyposis and juvenile polyposis syndrome (see these terms).


A rare genetic tremor disorder characterized by recurrent episodes of involuntary tremor of the chin and lower lip due to isolated myoclonus of the mentalis muscle. Patients may present more severe symptoms such as tongue biting and psychological distress. Even though neurological abnormalities are not associated, occasional involvement of sleep disorders and other facial muscles have been described. Sporadic cases were also reported.


Hereditary gingival fibromatosis (HGF) is a rare benign, slowly progressive, non-inflammatory fibrous hyperplasia of the maxillary and mandibular gingivae that generally occurs with the eruption of the permanent (or more rarely the primary) dentition or even at birth. It presents as a localized or generalized, smooth or nodular overgrowth of the gingival tissues of varying severity. It can be isolated, with autosomal dominant inheritance, or as part of a syndrome.


An inherited disorder of angiogenesis characterized by mucocutaneous telangiectases and visceral arteriovenous malformations.

Summary:
Epidemiology
The prevalence is approximately 1/6,000
Clinical description
The most common clinical signs of hereditary hemorrhagic telangiectasia (HHT) include recurrent epistaxis (nosebleeds), frequently from childhood, and cutaneous or mucosal telangiectases generally presenting later, and increasing with age, where anemia may become an important part of the disease. Visceral arteriovenous malformations (AVMs) are usually asymptomatic but can lead to complications that produce highly variable manifestations. The age of onset of AVM-related complications is variable, ranging from childhood to geriatric age, with a few cases reported during the neonatal period. Pulmonary AVMs may manifest with brain abscesses, strokes, transient ischemic attacks, signs of chronic hypoxaemia or, rarely, haemorrhagic rupture. AVMs of the central nervous system can be haemorrhagic or, rarely, produce signs of slow compression. Hepatic AVMs, which can remain latent for a long time, in a limited proportion of patients become severe leading to high-output cardiac failure, portal hypertension, pulmonary hypertension or ischemic cholangitis. Hemorrhagic digestive telangiectases increase with age and can worsen chronic anemia.
Etiology
This genetic disorder is due to pathogenic variants primarily in ENG (9q34.11) or ACVRL1 (12q13.13), encoding proteins involved in vascular development and angiogenic homeostasis of capillaries. Mutations in SMAD4 (18q21.2) occur in rare cases (1-3%) and result in HHT associated with juvenile polyposis. In a small proportion of HHT families, the pathogenic gene variant has not yet been identified.
Diagnostic methods
The diagnosis is clinical and/or molecular. The clinical diagnosis is based on having at least three of the four Curaçao criteria: recurrent epistaxis, cutaneous/mucosal telangiectases, visceral involvement, and a first line family member with HHT. Genetic testing can be used to screen, to confirm a diagnosis, or to rule out the diagnosis if the pathogenic variant is known in the family.
Differential diagnosis
The differential diagnosis includes limited cutaneous systemic sclerosis, digestive angiodysplasias, isolated sporadic AVMs in the lungs, liver and brain, other vascular anomaly syndromes that cause AVMs; benign hereditary telangiectasia; and other causes of recurrent epistaxis (coagulation disorders or other local nasal factors).
Antenatal diagnosis
Prenatal genetic testing is possible in families where the pathogenic variant has been identified in the family, but is not necessary for proper pregnancy and delivery management. Decisions about prenatal genetic testing are the choice of the parents, but discussion of all related issues is appropriate. The usual antenatal scans will be offered, and sonographers aware of the presence of HHT in the family will detect most major AVMs.
Genetic counseling
Transmission is autosomal dominant. Penetrance is age dependent, the majority having symptoms before 50 years of age. The phenotype is highly variable, even between members of the same family.
Management and treatment
Disease management includes prevention and treatment of epistaxis and anaemia, screening for AVMs, and guidance regarding pregnancy-related issues. The management of pulmonary AVM(s) relies on early detection, occlusion where feasible, and ongoing care in cases of persistent pulmonary AVMs. For severe liver involvement, multidisciplinary patient assessment in a center with expertise in HHT is recommended. Usually, cerebral AVMs that have not bled are not treated, whereas cerebral AVMs that have already bled or have become symptomatic usually require treatment. Gastrointestinal telangiectases may sometimes be the cause of significant anemia, especially in older patients, and need specific management. Awareness of the possibility of AVMs/HHT is important for optimal management of diverse medical states. HHT due to a SMAD4 pathogenic variant requires polyposis screening and aortic follow up.
Prognosis
Life expectancy is reduced in unscreened patients. In patients assessed and treated for pulmonary AVMs in an HHT Center, life expectancy is comparable to the general population. Pregnancy-related death has been reported, and is a particular risk for women with pulmonary arteriovenous malformations.

                            Last update:
                            January 2019

                            - Expert reviewer(s):
                             HHT WORKING GROUP | VASCERN*

                                * European Reference Network


Hereditary hypercarotenemia and vitamin A deficiency is an extremely rare metabolic disorder characterized clinically by skin discoloration, elevated levels of carotene and low levels of vitamin A described in fewer than 5 patients to date.


Hereditary hyperekplexia is a hereditary neurological disorder characterized by excessive startle responses.

Summary:
Epidemiology
To date about 150 cases have been reported in the literature.
Clinical description
Hereditary hyperekplexia manifests shortly after birth with violent jerking to noise and touch, and massive and sustained stiffening of the trunk and limbs, clenching fists, and attacks of a high-frequency trembling. Newborns are at risk for sudden infant death due to laryngospasm and cardiorespiratory failure. Stiffness attacks may resemble epileptic seizures, although sleep can reduce or even abolish stiffness and jerking and EEG is normal. In the months after birth, muscle stiffness subsides, but excessive jerking to external stimulation or excitement persists. Motor milestones are often mildly delayed, but intellectual development is usually normal. Affected children walk toddling, and often seek assistance or a hold. Gait disturbance increases when in a hurry, amongst a crowd, or if forced. Stumbling or an unexpected jolt may induce uncontrolled falls (''like a log'') with the risk of serious injuries.
Etiology
Mutations in the GLRA1 gene (5q32) are found in about 30% of patients with hereditary hyperekplexia (and a considerable number of patients without an obviously affected parent). These mutations are transmitted as an autosomal dominant or recessive trait. The GLRA1 gene encodes the alpha1 subunit of the juvenile neuronal receptor for the inhibitory neurotransmitter, glycine. Mutations of this subunit cause a variety of dysfunctions of the neuronal chloride (Cl-) channel, and therefore hereditary hyperekplexia is regarded as a channelopathy. Mutations in the GLRB, GPHN and SLC6A5 genes (4q31.3, 14q24 and 11p15.2-p15.1) have also been observed.
Diagnostic methods
Diagnosis is based on the clinical signs, molecular genetic testing and electrophysiology.
Differential diagnosis
Differential diagnoses include symptomatic hyperekplexia and spasticity, and epilepsy in perinatal brain damage and metabolic brain diseases, which can be excluded by normal EEG and reduction or abolition of stiffness and jerking with sleep.
Management and treatment
Symptomatic treatment in adults involves clonazepam (1mg per day). In children lower doses are required. Vigabatrin is ineffective. Children gain benefit from repeated trials of physical exercise rather than from established physiotherapies or from resolute or demanding training. Extensive activities on soft or sandy ground are particularly effective. Intervention against incomprehension, mockery or pressure from uninformed teachers, relatives and friends may be required.
Prognosis
In most patients, fear of falling and the toddling gait normalizes in adolescence. However, brisk startle and jerkiness to unexpected stimulation persist lifelong, and a minority of patients suffer phobic anxiety of crossing open spaces and an insecure and hesitating gait disorder.

                            Last update:
                            August 2010

                            - Expert reviewer(s):
                            Pr Hans-Michael MEINCK


A rare genetic disease characterized by the association of early onset cataract with persistently raised plasma ferritin concentrations in the absence of iron overload.

Summary:
Epidemiology
The exact worldwide prevalence of hereditary hyperferritinemia-cataract syndrome (HHCS) remains unknown. It is estimated to be at least 1/200,000 in Australia.
Clinical description
The single clinical presentation of the disease is bilateral cataract that usually manifests after birth, as early as infancy, but also in adolescence or in early adulthood. Age of diagnosis ranges from 6 to 40 years old. Cataracts are described as numerous, pulverulent (dust-like) opacities of the lens causing glare and decreasing visual acuity. HHCS is characterized by variable severity of ocular involvement, and variable serum ferritin levels without iron overload. Ophthalmologic follow-up studies indicate an age-related evolution of lens opacities that might be related to the progressive accumulation of insoluble L-ferritin aggregates. The recognition of HHCS as a distinct disease is important for two main reasons: 1) to enable early detection of cataract even in asymptomatic patients, allowing adequate follow-up and scheduled surgical removal; 2) to avoid misdiagnosis that can lead to useless diagnostic procedures and inadequate treatment.
Etiology
The disease is caused by a mutation in a translational regulatory element, a stem-loop structure called iron responsive element (IRE), in the 5' non-coding region of the light ferritin (FTL) gene located on 19q13.4-qter. In the absence of iron, the iron regulatory protein (IRP) binds to IRE and represses ferritin synthesis. Mutations affecting the IRE loop, bulge, and two partial deletions affecting either part of the IRE, have been reported. The most widely accepted pathophysiological mechanism is accumulation of insoluble crystalline aggregates of iron-poor L-ferritin protein causing cataract formation, which was demonstrated by immunohistochemical analysis and transmission electron microscopy of HHCS patients' lens aspirate. Age of onset and severity of lens damage vary in patients with the same mutations, even within one family, which suggests that other factors, acquired or genetic, may modulate clinical presentation.
Diagnostic methods
Diagnosis is suspected in patients presenting with isolated hyperferritinemia in the absence of other evident cause of hyperferritinemia and iron overload. A personal or family history of early onset cataract should be investigated. Given that the cataract may not immediately be symptomatic, and that cases of de novo mutations have been reported, a comprehensive eye exam including a visual acuity test and a slit lamp examination may be recommended.
Differential diagnosis
Acquired causes of isolated hyperferritinemia should be evaluated and excluded. They include infections and inflammatory diseases, acute and chronic liver diseases, high alcohol intake, metabolic disorders, fatty liver disease, and hypothyroidism. Other inherited diseases may be considered such as genetic hyperferritinemia without iron overload, ferroportin disease, aceruloplasminemia, and Gaucher disease.
Genetic counseling
The disorder is autosomal dominant, with only few reports of spontaneous cases. Genetic counselling should be offered to affected individuals informing them that one of the parents is likely affected and there is a 50% risk of having an affected child at each pregnancy.
Management and treatment
Patients are treated by cataract surgery when they suffer visual impairment due to cataracts formation. Hyperferritinemia is not associated with iron overload and doesn't require treatment. Thus, venesections should be avoided as they could induce iron deficiency and iron deficient anemia without significant change of ferritin level.
Prognosis
Besides cataracts, there is no other clinical manifestation associated with this disease and the prognosis is good.

                            Last update:
                            April 2023

                            - Expert reviewer(s):
                            Pr Alberto PIPERNO | EuroBloodNet*

                                * European Reference Network


Hereditary hypophosphatemic rickets with hypercalciuria

A rare hereditary disorder of renal phosphate wasting characterized by hypophosphatemia and hypercalciuria associated with rickets and/or osteomalacia. Other features include slow growth, short stature, skeletal deformities, muscle weakness and bone pain that are associated with normal or elevated plasma levels of calcitriol and hyperphosphaturia.


Hereditary hypotrichosis with recurrent skin vesicles is a very rare inherited hair loss disorder described in a family and characterized by sparse, fragile or absent hair on the scalp, eyebrows, eyelashes, axillae and rest of the body, associated with vesicle formation on various parts of the scalp and body which regularly burst and release watery fluid.


Hereditary inclusion body myopathy type 4 is a rare non-dystrophic myopathy characterized by slowly progressive muscular weakness and atrophy initially involving proximal lower limbs and hip girdle and later on shoulder girdle, proximal upper limbs and axial muscles. Ambulation is usually preserved. Congophilic inclusions with cytoplasmic inclusions of 15-21 nm filaments on electron microscopy are revealed in muscle biopsy.


Hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome

A rare genetic neuromuscular disease characterized by early onset of proximal or generalized muscle weakness, external ophthalmoplegia with or without ptosis, and joint contractures. Hypotonia, neonatal respiratory distress necessitating ventilation, and severe dysphagia have also been reported. The disease is of variable severity and non- or slowly progressive. Patients typically remain ambulatory. Muscle biopsy may show predominance of type 1 fibers, marked variability in fiber size, increased internal nuclei, and proliferation of perimysial and endomysial connective tissue.


Hereditary isolated aplastic anemia is a rare, genetic, constitutional aplastic anemia disorder characterized by severe peripheral blood pancytopenia and bone marrow hypoplasia in multiple individuals of a family, in the absence of any somatic symptoms. Abnormal bleeding, as well as erythrocyte macrocytosis, is reported and patients usually become transfusion-dependent.


Hereditary late-onset Parkinson disease (LOPD) is a form of Parkinson disease (PD), characterized by an age of onset of more than 50 years, tremor at rest, gait complaints and falls, bradykinesia, rigidity and painful cramps. Patients usually present a low risk of developing non motor symptoms, dystonia, dyskinesia and levodopa-induced dyskinesia (LID).

Summary:
Epidemiology
Prevalence of LOPD is unknown. The prevalence of PD is estimated at about 1% in people over 60 years of age in the general population in Europe and only 10% of the reported PD has shown to be hereditary.
Clinical description
Onset of LOPD is > 50 years with predominant symptoms including tremor at rest (70% of cases), gait complaints and falls (20%), bradykinesia (20%), rigidity and painful cramps (8%). Compared to young onset PD (YOPD; see this term), a higher risk of developing gait freezing and falls but a lower risk of developing dystonia, dyskinesia and LID have been reported. Patients with hereditary LOPD are also more affected by severe diplopia, cognitive impairment, and gastrointestinal and urinary disorders. LOPD patients report a lower prevalence of non-motor symptoms such as depression, hallucinations, behavioral disturbances (i.e. agitation or impulse control disorder), dementia and apathy.
Etiology
The exact etiology of hereditary LOPD is still unknown but mutations in the genes SNCA (4q21.3-q22), LRRK2 (12q12), and VPS35 (16q12) have been implicated in its pathogenesis. Heterozygous mutations in GBA (1p22; glucocerebrosidase) are the most common risk factor for PD.
Genetic counseling
Transmission is autosomal dominant. Genetic counseling should be offered to the affected families informing them of the 50% risk the offspring has of inheriting the disease-causing mutation and therefore being affected with the disorder.

                            Last update:
                            January 2015

                            - Expert reviewer(s):
                            Dr Coro PAISAN-RUIZ


Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a hereditary cancer syndrome characterized by a predisposition to cutaneous and uterine leiomyomas and, in some families, to renal cell cancer.

Summary:
Epidemiology
The prevalence is unknown. Over 200 families with HLRCC have been reported.
Clinical description
Disease onset can occur at any age, but is more common in young adults and elderly patients. Multiple or single benign cutaneous leiomyomas are common and usually present at around the age of 25 (range from 10-47 years) as firm papules or nodules that are skin colored to light brown. They are usually localized to the trunk and extremities but sometimes on the face. They tend to increase in size and number with age and are usually sensitive to touch and/or cold temperature and, in some, are painful. Uterine leiomyomas (present in 77% of women with HLRCC), also known as fibroids, usually appear around the age of 30 but age at diagnosis can range from 18-52 years. Symptoms of pelvic pain and irregular or heavy menstrual bleeding often occur before they are discovered. Renal tumors (mean age of presentation: 44) are less commonly seen in this syndrome (10-16% of cases) and may present with back pain, although some may be asymptomatic. They are mainly papillary type II renal cell carcinoma and are usually aggressive, often rapidly progressing to metastatic disease and death.
Etiology
HLRCC is caused by a mutation in the FH gene (1q42.1),which is thought to act as a tumor suppressor gene, encoding the enzyme fumarate hydratase (FH) that metabolizes the fumarate produced during the purine nucleotide cycle and arginine synthesis in the cytoplasm. It is still unclear how a deficiency in FH is involved in oncogenesis.
Diagnostic methods
Diagnosis of HLRCC is based on either the presence of multiple cutaneous leiomyomas with at least 1 histologically confirmed leiomyoma (interlacing bundles of smooth muscle fibers with centrally located long blunt-edged nuclei, occasional multinucleated cells, and no mitotic figures) or the presence of a single leiomyoma with a positive family history of the disease. Reduced enzymatic activity of FH is found in all patients and can be measured in cultured skin fibroblasts or lymphoblastic cells. MRI is the most accurate imaging technique for visualizing uterine leiomyomas. Molecular genetic testing can identify mutations in the FH gene, confirming diagnosis.
Differential diagnosis
Differential diagnoses include familial renal cancer syndromes such as Von Hippel-Lindau syndrome, Birt-Hogg-Dubé syndrome and hereditary papillary renal cancer (see these terms), as well as uterine fibroids and cutaneous lesions.
Antenatal diagnosis
Prenatal testing is possible in families with a known disease causing mutation.
Genetic counseling
HLRCC is inherited autosomal dominantly and genetic counseling is recommended.
Management and treatment
Management and treatment are multidisciplinary. Cutaneous leiomyomas can be treated by botulinum toxin type A injections, cryoablation and lasers. Solitary painful lesions can be surgically removed. Medications given to reduce pain include alpha blockers, calcium channel blockers (ex. nifedepine), antiepileptic drugs, nitroglycerine and antidepressants. Uterine fibroids can be treated with gonadotropin-releasing hormone agonists, pain relievers and antihormonal medications or surgically with a myomectomy. In some severe cases a hysterectomy may be necessary. As renal tumors associated with HLRCC are highly aggressive, a total nephrectomy is recommended for those with a renal mass. Adjuvant therapy (i.e. VEGF inhibitors) may be necessary in advanced cases. Annual clinical examinations and imaging assessments are recommended to monitor any changes. Family members of patients with HLRCC should equally be screened for the presence of lesions.
Prognosis
The prognosis of HLRCC is poor but treatments with new molecular targets may improve survival in the future.

                            Last update:
                            July 2014

                            - Expert reviewer(s):
                            Dr Maria MERINO


A rare red cell disorder classified principally into two clinical phenotypes: autosomal recessive congenital (or hereditary) methemoglobinemia types I and II (RCM/RHM type 1; RCM/RHM type 2).

Summary:
Clinical description
In RCM type 1, cyanosis from birth is the only symptom. It is well-tolerated and is associated with mild complaints of headaches, fatigue and shortness of breath upon exertion. RCM type 2 is much more severe; the cyanosis is accompanied by neurological dysfunction (with intellectual deficit, microcephaly, growth retardation, opisthotonus, strabismus and hypertonia), which usually becomes evident during the first four months of life. Two additional forms of RCM have also been reported. RCM type 3 was the term used to define a phenotype with cyanosis but without neurological abnormalities in which Cb5R deficiency was identified in leucocytes and platelets as well as erythrocytes. This distinction has been largely ignored in subsequent reports of other CYB5R3 variants, so the term RCM type 3 is rarely used. RCM type 4 is a very rare disease associated with chronic cyanosis caused by mutations in the CYB5A gene (18q23) encoding cytochrome b5. In addition, there have been two reports of NADPH reductase deficiency, but in one case (identified though an inability to metabolize methylene blue) methemoglobinemia was not present suggesting that this pathway has limited physiological importance. It is also possible that mutations of the substrate of NADPH reductase, which remains to be identified, could have a minor effect on the reduction of methemoglobin.
Etiology
RCM type 1 is caused by mutations of the CYB5R3 gene (22q13.31-qter) encoding the NADH-cytochrome b5 reductase (Cb5R) and Cb5R deficiency is limited to the erythrocytes. RCM type 2 is caused by global loss of Cb5R function. Over 40 different CYB5R3 mutations have been identified so far, some of which have been identified in both types. RCM type 1 is generally associated with missense mutations, whereas RCM type 2 is more commonly associated with truncating mutations, splicing errors or mutations that lead to disruption of the active site.
Management and treatment
Treatment of methemoglobinemia revolves around administration of methylene blue and/or ascorbic acid. Although ascorbic acid alone is sufficient to alleviate the cyanosis in milder cases, the reaction rate is slower than that of the combined treatment. However, these treatments have no effect on the neurological dysfunction in RCM type 2.

                            Last update:
                            November 2008

                            - Expert reviewer(s):
                            Pr Terry LAPPIN  - Dr Melanie PERCY


Hereditary mixed polyposis syndrome (HMPS) describes an autosomal dominantly inherited large-bowel disease characterized by the presence of a mixture of hyperplastic, atypical juvenile and adenomatous polyps that are associated with an increased risk of developing colorectal cancer if left untreated.


Hereditary motor and sensory neuropathy type 5 is a rare axonal hereditary motor and sensory neuropathy characterized by slowly progressive distal muscle weakness and atrophy with or without sensory loss resulting in difficulty in walking, foot drop and pes cavus, that may be associated with pyramidal signs (extensor plantar responses, mild increase in tone, brisk tendon reflexes), muscle cramps, pain and spasticity.


Hereditary motor and sensory neuropathy type 6

A rare axonal hereditary motor and sensory neuropathy disease characterized by progressive, peripheral, axonal sensorimotor neuropathy (of variable severity), affecting predominantly the distal lower limbs, associated with progressive, variably severe, optic atrophy, which frequently leads to visual loss. Patients typically present distal limb muscle weakness and atrophy, hypo/areflexia, foot deformities, poor visual acuity (often with a central scotoma), nystagmus, and reduced peripheral and nocturnal vision. Additional reported manifestations include sensorineural hearing loss, major joint contractures, anosmia, scoliosis/lumbar hyperlordosis, cognitive impairment and vocal cord paresis.


Hereditary motor and sensory neuropathy with acrodystrophy is a rare axonal hereditary motor and sensory neuropathy characterized by progressive axonal neuropathy with limb weakness and severe distal sensory loss in all limbs and acrodystrophic changes leading to painless non-healing ulcers, osteomyelitis, contractures and mutilating lesions with loss of terminal phalanges. One family with three affected siblings is described and there have been no further descriptions in the literature since 1999.


Hereditary motor and sensory neuropathy, Okinawa type is a rare, genetic, axonal hereditary motor and sensory neuropathy characterized by the adult-onset of slowly progressive, symmetric, proximal dominant muscle weakness and atrophy, painful muscle cramps, fasciculations and distal sensory impairment, mostly (but not exclusively) in individuals (and their descendents) from the Okinawa region in Japan. Absent deep tendon reflexes, elevated creatine kinase levels and autosomal dominant inheritance are also characteristic.


A rare, genetic, immune deficiency with skin involvement characterized by clinical triad of non-scarring alopecia affecting mainly the scalp, well-demarcated mucosal erythema and psoriasiform erythematous intertriginous plaques. Follicular keratosis, keratoconjuctivitis, cataracts, angular cheilitis, fissured tongue, and recurrent infections are additional clinical features. Histopathology of mucosal lesions show characteristic findings of dyskeratotic keratinocytes, vacuolated basal cells, lack of epithelial maturation and decreased number of desmosomes.


Hereditary myopathy with early respiratory failure

A rare genetic neuromuscular disease characterized by adult onset of slowly progressive distal and/or proximal muscle weakness in the upper and lower extremities, and early involvement of respiratory muscles leading to respiratory failure. Additional features are neck flexor weakness, foot extensor weakness, and, in rare cases, mildly impaired cardiac function. Muscle biopsy shows eosinophilic myofibrillar inclusions referred to as cytoplasmic bodies, as well as fiber size variation, increased internal nuclei and connective tissue, fiber splitting, and rimmed vacuoles.


Hereditary myopathy with lactic acidosis due to ISCU deficiency

A rare disorder of energy metabolism characterized clinically by myopathy with severe exercise intolerance, and biochemically by deficiencies of skeletal muscle mitochondrial respiratory chain enzymes, succinate dehydrogenase and aconitase.

Summary:
Epidemiology
ISCU myopathy is an ultra-rare disease reported in approximately 20 individuals in the world. Most patients are of Swedish heritage, though patients from other ethnic backgrounds have also been identified.
Clinical description
The cardinal feature of this condition is childhood-onset exercise intolerance, with muscle fatigue, pain, tachycardia and dyspnea occurring within a few minutes of mild physical activity. More prolonged or substantial exertion can result in an episode of profound muscle weakness associated with lactic acidosis and severe rhabdomyolysis. Cardiomyopathy has also been reported in patients of non-Swedish ancestry.
Etiology
This genetic condition occurs due to bi-allelic variants in the gene ISCU (autosomal recessive inheritance). There is one report of a patient with a de novo heterozygous variant in ISCU, but thus far no other cases support an autosomal dominant inheritance pattern. The ISCU protein acts as a scaffold for iron-sulfur cluster assembly. Iron-sulfur clusters are essential components of various proteins, including some involved in mitochondrial function. Dysfunction of ISCU prevents mitochondria (particularly in muscle) from generating energy efficiently, resulting in exercise intolerance. All Swedish patients described to date are homozygous for the same genetic change in ISCU (c.418+382G>C).
Diagnostic methods
ISCU myopathy should be considered in patients with the above clinical features. High blood lactate levels are usually present at baseline: with exercise physiology testing, further elevations in lactate and pyruvate occur, significantly limiting VO2 max. Confirmation of the diagnosis is now primarily via molecular (genetic) testing: possibilities include targeted sequencing for the Swedish variant, a gene panel for myopathy, or a broader test such as whole exome sequencing. Specialized biochemical testing can add confidence to the diagnosis, especially if the molecular testing identifies variants of uncertain significance. Most patients have high plasma fibroblast growth factor 21 levels. Analysis of muscle biopsy specimens can identify deficiency of mitochondrial aconitase, succinate dehydrogenase and specific respiratory chain complexes (I, II and III), as well as histochemical evidence of mitochondrial iron accumulation.
Differential diagnosis
The differential diagnosis includes other mitochondrial disorders, muscle-specific glycogen storage diseases, fatty acid oxidation disorders, glycolytic pathway defects (eg. phosphoglycerate kinase deficiency), TANGO2 deficiency and other genetic myopathies.
Antenatal diagnosis
Antenatal diagnosis is possible if the disease-causing variants have been previously identified in an affected family member. The decision to undertake testing should be discussed with the couple with input from genetic counseling and obstetric teams.
Genetic counseling
Because this is a recessive condition, couples where each partner carries a pathogenic variant in ISCU have a 25% chance of having an affected child with each pregnancy. Specialized genetic counseling can help such couples contextualize this risk and understand their reproductive options.
Management and treatment
Currently, the focus of treatment for this condition is supportive management during episodes of rhabdomyolysis and a specialized exercise program to maintain muscle function without precipitating symptoms. Antisense oligonucleotide therapy has been trialled in vitro on patient myotubular cell lines. It appeared to correct the c.418+382G>C splicing abnormality, leading to improvements in biochemical abnormalities. However, there have been no subsequent clinical trials or other studies of such a treatment in humans.
Prognosis
Most patients live well into adulthood, with preserved quality of life despite their limited exercise tolerance. Acute decompensations with rhabdomyolysis and lactic acidosis can be fatal in rare instances, especially if supportive management is not initiated in these situations.

                            Last update:
                            July 2024

                            - Expert reviewer(s):
                            Dr Parayil Sankaran BINDU  - Dr Arthavan SELVANATHAN


A rare genetic vascular anomaly characterized by the presence of angiomatous lesions affecting the skin, brain, and spinal cord. Lesions of the central nervous system have a marked tendency to bleed. There have been no further descriptions in the literature since 1988.


Hereditary neuroendocrine tumor of small intestine

A rare inherited cancer-predisposing syndrome characterized by occurrence of multiple synchronous primary carcinoids of the small intestine. Clinical presentation is otherwise indistinguishable from sporadic carcinoids and includes abdominal pain, flushing, and diarrhea, often becoming manifest only after a long asymptomatic period. Most patients present with low grade tumors. Occurrence of pulmonary carcinoids has also been reported.


A rare neurologic disease characterized by recurrent mononeuropathies usually triggered by minor physical activities innocuous to healthy people.

Summary:
Epidemiology
Hereditary neuropathy with liability to pressure palsies (HNPP) actual prevalence is unknown due to under-diagnosis but estimates range between 1/50,000 -1/20,000 worldwide. In Finland, the prevalence is reported to be 1/6250.
Clinical description
Disease onset usually occurs in the 2nd to 3rd decade of life, but may present in childhood. Some patients are asymptomatic and never diagnosed. The most common presenting symptom is the sudden onset of focal sensory loss and muscle weakness in the distribution of a single nerve. In many cases, these acute focal symptoms are triggered by mechanical stresses to the nerve, such as compression, repetitive movement or stretching of the affected limbs. Commonly affected nerves include the peroneal nerve at the fibular head, ulnar nerve at the elbow, median nerve at the wrist, brachial plexus and radial nerve. Clinical manifestations caused by these mononeuropathies include foot drop, hand numbness and weakness, arm weakness, and sensory loss over the index finger and thumb or lateral aspect of the hand. In 50% of cases, patients recover from these episodes within a few days to months but others have incomplete recovery and suffer from recurrent focal sensory and motor deficits. In rare cases, brachial plexopathy with unilateral painless arm paralysis and sensory loss may be a presenting symptom. Occasionally, mild impairments of cranial nerve functions may be seen. Absent deep tendon reflexes and pes cavus foot deformity are seen in some patients but not in others. The phenotype of HNPP often evolves into a symmetric sensory motor polyneuropathy in aged patients. Many patients with HNPP complain of diffuse pain and severe fatigue. HNPP may cause severe limb paralysis when asymptomatic patients with unknown diagnosis of HNPP are challenged by strenuous physical activities. This imposes a catastrophic risk in a fraction of patients with HNPP.
Etiology
HNPP is due to a mutation in the chromosome 17p12 containing PMP22 and other genes. PMP22 encodes the peripheral myelin protein-22 (PMP22) that is predominantly expressed in the compact myelin of the peripheral nervous system. In 80% of cases, a 1.4Mb deletion at 17p11.2 that includes the PMP22 gene is found, and in the remaining 20%, patients may carry a point mutation or small deletion in PMP22 or mutations in as yet unidentified genes.
Diagnostic methods
Diagnosis of HNPP is typically suggested by the presence of recurrent focal mononeuropathies and the evidence of a family history. Electrophysiologic testing shows prolonged distal latency at the sites susceptible to mechanical stress. Conduction velocities out of these sites are often either normal or only mildly slowed. Tomacula (focal thickening of the myelin sheath) is the characteristic histological finding in sural nerve biopsies. It may however be seen in other types of neuropathies. A DNA test showing the PMP22 heterozygous deletion confirms the diagnosis.
Differential diagnosis
Differential diagnosis includes both compression induced mononeuropathies and generalized polyneuropathies. HNPP can sometimes be mistaken for neuralgic amyotrophy, stroke or multiple sclerosis.
Antenatal diagnosis
Prenatal testing is theoretically possible in families where the disease causing gene has been identified.
Genetic counseling
The disorder is inherited autosomal dominantly. Genetic counseling should be done for individuals having the disease and informing them that there is 50% risk of passing the mutation to offspring.
Management and treatment
Consultation should be provided to the patient about physical activities that may trigger the sensory/motor deficits. Those with foot drop or wrist drop may benefit from an ankle-foot orthosis or a wrist splint. Protective pads for the elbows and knees can alleviate nerves from mechanical stresses. Activities that involve prolonged sitting with crossed legs, leaning on elbows and repetitive movements of the wrists, as well as rapid weight loss should be avoided. Vincristine should equally be avoided. Cautions should be taken when new medications are prescribed with potential side-effect to the peripheral nerves.
Prognosis
HNPP is not life threatening and does not appear to affect longevity. However, many patients may have incomplete recovery in their sensory moto deficits. In some cases, severe and prolonged limb paralysis can occur, particularly after strenuous physical activities. Many patients with HNPP suffer from pain and fatigue. Unfortunately, these issues have not been well studied and should be addressed in future investigations.

                            Last update:
                            March 2020

                            - Expert reviewer(s):
                            Pr Jun LI


A rare, genetic, immune disease characterized by chronic neutrophilia, increase in the percentage of circulating CD34+ cells in peripheral blood, increase in granulocyte precursors in bone marrow and splenomegaly. Patients are predominantly asymptomatic, but may present with systemic inflammatory response syndrome with fever, dyspnea, tachycardia, pleural and pericardial effusion, or myelodysplastic syndrome.


A cancer-predisposing condition characterized by the development of colorectal cancer not associated with colorectal polyposis, endometrial cancer, and various other cancers (such as malignant epithelial tumor of ovary, gastric, biliary tract, small bowel, and urinary tract cancer) that are frequently diagnosed at an early age.


Hereditary North American Indian childhood cirrhosis is a severe autosomal recessive intrahepatic cholestasis that has only been described in aboriginal children from northwestern Quebec. Manifesting first as transient neonatal jaundice, the disease evolves into periportal fibrosis and cirrhosis during a period ranging from childhood to adolescence.


A rare genetic disorder of pyrimidine metabolism characterized by early onset of megaloblastic anemia, global developmental delay, and failure to thrive, associated with massive urinary overexcretion of orotic acid (sometimes with orotic acid crystalluria). Patients without megaloblastic anemia, but with additional manifestations such as epilepsy, have also been reported.


A rare focal palmoplantar keratoderma disorder characterized by the development of thick, painful, non-erythematous, nummular keratotic lesions over pressure points of feet and possibly hands. Occasionally, knee and shin involvement, periungual/subungual hyperkeratoses, and blistering at the edge of the calluses, may be observed.


Hereditary palmoplantar keratoderma, Gamborg-Nielsen type is characterised by the presence of diffuse palmoplantar keratoderma without associated symptoms. The syndrome has been described in multiple families from the northernmost county of Sweden (Norrbotten). The palmoplantar keratoderma found in the Gamborg-Nielsen type disease is milder than that found in Mal de Meleda but more severe than that found in Thost-Unna palmoplantar keratoderma (see these terms). Transmission is autosomal recessive.


Hereditary papillary renal cell carcinoma

A rare familial renal cancer syndrome characterized by a predisposition for developing bilateral and multifocal classic type papillary renal cell carcinomas (formerly known as type 1 papillary renal cell carcinoma until the 2022 WHO classification of renal tumors).

Summary:
Epidemiology
Renal cell carcinoma (RCC) accounts for approximately 2% of all malignancies with about 400,000 new cases diagnosed annually worldwide. Papillary RCC, accounting for 15% of cases, is the second most common form of RCC after clear cell RCC (75%). Hereditary cases account for about 5% of all RCC and include a dozen of syndromes with four major conditions: von Hippel-Lindau (VHL), Birt-Hogg-Dubé (BHD), hereditary leiomyomatosis and renal cell cancer (HLRC) and hereditary papillary renal cell carcinoma (HPRC). Less than 60 kindreds with HPRC have been reported to date in the literature and the prevalence is unknown (estimated at 1/500,000).
Clinical description
HPRC is a highly penetrant autosomal dominant disease predisposing to the occurrence of bilateral and multifocal classic papillary RCC. Recently biphasic squamoid alveolar papillary RCC (an emerging variant of papillary RCC) have also been described in association with the disease. Most of the tumors are low-grade, but a small subset of tumors may be high-grade and metastasize. In addition, numerous microscopic papillary adenomas are commonly seen in the background renal parenchyma. In HPRC, renal tumors occur over a wide age range from 19 to 66 years but typically occur later than other forms of hereditary RCC (median age of 41 years). Unlike other major hereditary renal cancer syndromes, there are no extrarenal manifestations in HPRC.
Etiology
HPRC is associated with activating germline mutations in the MET proto-oncogene (7q31) encoding the hepatocyte growth factor-responsive tyrosine kinase receptor. The activation subsequently triggers downstream signaling pathways that promote cell survival, proliferation and inhibition of apoptosis. Tumorigenesis in HPRC patients is most frequently associated with duplication of the chromosome 7 carrying the mutated MET allele (trisomy 7).
Diagnostic methods
Diagnosis is suspected in patients with bilateral or multifocal classic type papillary RCC even in absence of familial history and can be confirmed by detection of a germline mutation in the MET gene. Papillary RCC are classically poorly enhancing on computed tomography (CT) scan and magnetic resonance imaging (MRI) is more performant for their diagnosis.
Differential diagnosis
No other known syndrome predisposes to occurrence of classic type papillary renal cell carcinomas without extrarenal manifestations. In Birt-Hogg Dubé syndrome, such renal tumors can sometimes occur but are associated with other characteristic histologic types (hybrid chromophobe-oncocytomas RCC and chromophobe RCC) as well typical cutaneous and pulmonary lesions. With the advent of multi-gene renal cancer panel tests, the distinction is easily made in case of atypical presentation.
Antenatal diagnosis
There is no indication to prenatal diagnostic testing or preimplantation genetic testing.
Genetic counseling
The transmission is autosomal dominant. At-risk individuals have a 50% chance of transmitting the pathogenic variant to their offspring. Genetic testing is recommended for relatives from the age of 18 years.
Management and treatment
Clinical management should include regular surveillance, preferably by contrast-enhanced MRI, to allow early detection of renal carcinomas. The surveillance should be offered to patients and at-risk relatives, every 1-2 years starting at age 30, until the largest tumor reaches 3 cm, at which time nephron-sparing surgery (tumor excision or partial nephrectomy) is recommended. Percutaneous thermal ablation may provide a safe and alternative treatment to surgery for small tumors.
Prognosis
Compared to other hereditary renal cell carcinomas, HPRC tend to be of indolent nature but patients have a risk of recurrent tumors throughout life with need of often repeated surgeries. In some cases, multiplicity of tumors may ultimately lead to binephrectomy and dialysis. In case of metastatic disease, MET pathway inhibitors have shown promising results.

                            Last update:
                            February 2024

                            - Expert reviewer(s):
                            Pr Stéphane RICHARD


Hereditary persistence of alpha-fetoprotein is a benign genetic condition characterized by persistence of high alpha-fetoprotein (AFP) levels throughout life, with no associated clinical disability and thus no need for specific therapy


Hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome

Hereditary persistence of fetal hemoglobin (HPFH) associated with beta-thalassemia (see this term) is characterized by high hemoglobin (Hb) F levels and an increased number of fetal-Hb-containing-cells.

Summary:
Epidemiology
Prevalence of this form is not known.
Clinical description
The association of HPFH with beta-thalassemia mitigates the clinical manifestations which vary from a normal state to beta-thalassemia intermedia (see this term).
Etiology
HPFH is due to deletions in the beta-globin gene cluster or point mutations in the HBG1 and HBG2 genes (11p15.5).
Diagnostic methods
Diagnosis is based on the presence of a significant elevation in HbF ranging from 10-40% in heterozygotes with normal or near normal red blood cell indices. HbF is homogeneously distributed among the erythrocytes and HbA2 is normal or reduced.
Differential diagnosis
The distinction between HPFH and delta-beta-thalassemia (see this term) is subtle and should be confirmed by alpha-beta-globin chain synthesis ratio and DNA analysis since the distinction between these two conditions is not always possible from routine hematologic analyses.
Genetic counseling
HPFH transmission is co-dominant. Homozygosis for the non-deletional form has to date been reported in rare cases.

                            Last update:
                            May 2011

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


Hereditary persistence of fetal hemoglobin-sickle cell disease syndrome

A rare, genetic, hemoglobinopathy characterized by generally mild clinical phenotype, high fetal hemoglobin levels and mild microcytosis and hypochromia. In some cases, acute sickle cell disease manifestations were reported, namely acute chest syndrome and acute pain crisis. The genotype is characterized by the combination of an HbS and HbF allele; symptoms depend on the degree of HbF:HbS expressivity with patients with more than 35% pancellular HbF expression being asymptomatic. Symptomatic patients have heterocellular expression of HbF.


A rare, hereditary, pheochromocytoma/paraganglioma tumor arising from neuroendocrine chromaffin cells of the adrenal medulla (pheochromocytoma) or from any paraganglia from the skull base to the pelvic floor (paraganglioma). Clinical manifestations are often linked to excess catecholamines production causing sustained or paroxysmal elevations in blood pressure, headache, episodic profuse sweating, palpitations, pallor and apprehension or anxiety. Hereditary pheochromocytoma/paraganglioma tumors tend to present at younger ages, to be multi-focal, bilateral, and recurrent, or to have multiple synchronous neoplasms.


Hereditary progressive mucinous histiocytosis is a rare, benign, non-Langerhans cell histiocytosis characterized by childhood or adolescence onset of multiple, small, asymptomatic, slowly progressing, skin-colored to red-brown papules with predilection for the face, dorsal hands, forearms and legs, without associated mucosal or visceral involvement. Histologically, papules are well-circumscribed, unencapsulated, nodular aggregates of histiocytes with abundant mucin in the upper and middermis.


Hereditary pulmonary alveolar proteinosis

A rare, genetic, interstitial lung disease due to mutations in the CSF2R (colony-stimulating factor 2 receptor) alpha or beta subunits and characterized by alveolar accumulation of pulmonary surfactant, presenting a highly variable clinical presentation, ranging from asymptomatic to severe respiratory failure. Characteristic lung biopsy findings include periodic acid-Schiff-positive, granular eosinophilic material, enlarged foamy alveolar macrophages, and well-preserved alveolar walls. The Granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor function is impaired but GM-CSF receptor autoantibodies are absent.

Summary:
Epidemiology
The disease is very rare; it has been suggested to represent between less than 1-6% of the total cases of pulmonary alveolar proteinosis. Most reported cases have mutations due to CSF2RA  mutations rather than CSF2RB mutations. Females are predominantly affected.
Clinical description
The onset of clinical disease is typically insidious, with a subacute, symptom-free period ranging from months to several years. Age of onset is typically in infancy or childhood but may also occur in adulthood, particularly in patients with CSF2RB  mutations. Presenting symptoms include dyspnea (70%), hypoxemia (55%), and cough (56%) and more variably tachypnea (15%) and global respiratory failure (one third). In children and young adults, comorbidities may include failure to thrive, clubbing, pectus excavatum and hepatomegaly. The clinical course may be complicated by respiratory tract infections. Laboratory findings may include elevated serum GM-CSF level (specificity not known) and absence of GM-CSF autoantibodies.
Etiology
Disease is due to disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, which is crucial for clearing of pulmonary surfactant by alveolar macrophages. Causal mutations have been identified in CSF2RA (Xp22.32) and CSF2RB (22q12.2-q13.1), genes encoding for the GM-CSF receptor.
Diagnostic methods
Disease is suspected based on clinical presentation and chest computed tomography findings of diffuse bilateral ground-glass opacifications and a superimposed reticular pattern (crazy paving pattern). Characteristic bronchoalvelolar lavage (BAL) findings indicative of hereditary PAP include a milky fluid with substantial amount of sediment and alveoli filled with numerous foamy, lipid- or surfactant-laden macrophages and secreted functional surfactant debris (staining with periodic acid Schiff). Genetic testing is necessary to establish this diagnosis. Testing of asymptomatic siblings requires genetic counseling.
Differential diagnosis
Differential diagnosis includes Autoimmune PAP, PAP related to the production of surfactant (e.g. due to mutations in SP-B or SP-C,  ABCA3, and NKX2-1), PAP secondary to hematologic disorders and malignancies, toxic dust inhalations, and immune deficiency syndromes, rare infections, mutations affecting functions or numbers of mononuclear phagocytes, and mutations affecting lung development.
Genetic counseling
Autosomal recessive inheritance has been reported for GM-CSF receptor mutations and genetic counseling is recommended for affected families. The disease can also occur from deletion of the GM-CSFR gene in the X chromosome pseudoautosomal region 1. Incomplete penetrance is observed. Due to the insidious nature of hereditary PAP, some vigilance for asymptomatic first-degree relatives for disease is advised.
Management and treatment
Whole lung lavage (WLL) is the only effective therapy, and is indicated when respiratory symptoms impair the quality of life, failure to thrive is observed, or lung function deviates from normal. In cases of severe hypoxemia, patients might be need to be supported by extracorporeal membrane oxygenation, allowing for recovery prior to WLL.
Prognosis
The overall prognosis for hereditary PAP treated by WLL is fair. Sometimes intense WLL treatments are necessary, which may significantly impair quality of life. Patients may be susceptible to opportunistic infections, as GM-CSF receptor has been associated with immune deficiency. Immunosuppressive therapy should be avoided, as it increases the risk of infections. The overall outcome reported so far is favorable, although a significant number will continue to have respiratory symptoms.

                            Last update:
                            January 2020

                            - Expert reviewer(s):
                            Pr Matthias GRIESE


A genetic renal tubular disorder characterized by urinary urate wasting that typically leads to asymptomatic hypouricemia and predisposes to urolithiasis and exercise-induced acute renal failure (EIARF).

Summary:
Epidemiology
Whilst the prevalence is not known in Europe, hereditary renal hypouricemia (RHUC) is reported as common in Japan and South Korea. RHUC is likely underdiagnosed as patients are typically asymptomatic; however, there are increasing reports for European countries and North America.
Clinical description
RHUC may be silent and sometimes the diagnosis is incidental; thus, clinical presentation may be at any age. However, chronic urinary urate wasting predisposes to several complications, such as nephrolithiasis, hematuria, pyelonephrithisis and nephrocalcinosis. In additions, several reports indicate that this disorder increases the risk of EIARF.
Etiology
The disorder is the result of impaired urate reabsorption along the proximal tubule, leading to increased urinary urate excretion and secondary hypouricemia. Two genetic loci have been associates with the disorder: SLC22A12 (11q13.1), encoding the urate transporter 1 (URAT1), and SLC2A9 (4p16.1), encoding for the urate transporter called glucose transporter 9 (GLUT9).
Diagnostic methods
Diagnosis is typically suspected on the incidental finding of low serum uric acid levels (SUA). According to the current clinical practice guideline, diagnosis is confirmed by the presence of the following findings : (1) SUA lower than 2 mg/dl in two consecutive blood examinations, (2) high urinary fractional excretion of urate (greater than 10%) and/or uric acid clearance, (3) in the absence of other causes of hypo-uricemia. Identification of the causative genes, a history of excercise-induced acute kidney injury (EIAKI) or a family history of RHUC is supportive of diagnosis.
Differential diagnosis
The differential diagnosis includes several conditions resulting in (1) increased excretion and (2) reduced uric acid production. The first group of disorders includes Fanconi syndrome, Wilson's disease, syndrome of inappropriate secretion of vasopressin (SIADH), neoplasia, some drugs (as probenecid), diabetes mellitus. The second one includes some rare inherited disorders affecting purine metabolism, as xanthinuria types 1 and 2 and purine nucleoside phosphorylase deficiency (PNP deficiency). In addition, severe liver diseases, malnutrition, some medications (allopurinol) and molybdenum cofactor deficiency may cause urate underproduction.
Genetic counseling
The disorder has both an autosomal recessive and autosomal dominant pattern of inheritance. Biallelic loss-of-function mutations of SLC22A12 and either homozygote and heterozygote SLC2A9 mutations have been described in RHUC patients.
Management and treatment
Complications of RHUC, such as nephrolithiasis and EIAKI, should be treated as in the general population. Asymptomatic patients should be considered at high risk to develop these complications, thus prophylactic measures, such as increased fluid intake and urine alkalization, should be undertaken. There is little consensus on the use of xanthine oxidoreductase inhibitors (XOR) to protect from EIAKI. The rationale to use this medication is to counteract the increased uric acid (UA) production during exercise, reducing the filtered load and lowering the risk of UA precipitation in the tubules. Some reports suggest that XOR might protect from EIAKI onset and/or recurrence, but further studies are required.
Prognosis
RHUC is not lethal and may be asymptomatic. Affected individuals have a higher risk to develop renal complications (renal stones, EIAKI) compared with the general population.

                            Last update:
                            May 2020

                            - Expert reviewer(s):
                            Pr Miriam ZACCHIA | ERKNet*

                                * European Reference Network


Hereditary sclerosing poikiloderma, Weary type

A rare genetic skin disease characterized by generalized poikiloderma with marked accentuation in flexural regions and on extensor surfaces, sclerosis of palms and soles, and linear and reticulated hyperkeratotic and sclerotic bands in the axilla and the antecubital and popliteal fossae. Subcutaneous calcification, finger clubbing, Raynaud phenomenon, and cardiac abnormalities (such as severe aortic stenosis) have also been reported.


Hereditary sensorimotor neuropathy with hyperelastic skin

A rare, genetic, demyelinating hereditary motor and sensory neuropathy disorder characterized by slowly progressive, mild to moderate, distal muscle weakness and atrophy of the upper and lower limbs and variable distal sensory impairment, associated with variable hyperextensible skin and age-related macular degeneration. Hypermobility of distal joints, high palate, and minor skeletal abnormalities (e.g. pectus excavatum, dolichocephaly) may also be associated.


Hereditary sensory and autonomic neuropathy due to TECPR2 mutation

A rare genetic peripheral neuropathy characterized by early hypotonia evolving to spastic paraparesis, areflexia, decreased pain and temperature sensitivity, autonomic neuropathy, gastroesophageal reflux disease, recurrent pneumonia and respiratory problems. Patients also have intellectual disability and dysmorphic features, including mild brachycephalic microcephaly, short broad neck, low anterior hairline and coarse face.