A type of HCD characterized by the production of incomplete monoclonal gamma-heavy chains without associated light chains. The clinical presentation most commonly resembles that of patients with systemic lymphoproliferative/autoimmune diseases.

Summary:
Epidemiology
The prevalence is unknown. There have only been about 120 cases reported in the worldwide literature but this condition is thought to be under-diagnosed.
Clinical description
Disease onset usually occurs between the ages of 40 and 90 years but the disease has also been seen in younger persons. Disseminated lymphoproliferative disease with lymphadenopathy, splenomegaly and hepatomegaly is the most common feature of gamma-HCD. Localized lymphoproliferative disease may be extramedullary (commonly cutaneous involvement) or may be located exclusively in the bone marrow. In other patients the disease can present with no apparent proliferative lymphoplasmacytic disease but instead an underlying autoimmune disorder such as rheumatoid arthritis, autoimmune hemolytic anemia or thrombocytopenic purpura (see these terms).
Etiology
The cause of gamma-HCD is unknown.
Diagnostic methods
The diagnosis of gamma-HCD is based on identification of free gamma-chains without associated light chains by immunofixation of serum and a concentrated urine specimen by using specific antisera. Patients presenting with a lymphoplasma-cell proliferative disorder should be evaluated for gamma-HCD. Immunofixation of serum and urine should be performed on patients with atypical lymphoplasma-cell proliferative disorders.
Management and treatment
Because gamma-HCD is a heterogenous condition, the choice of therapy should rely on the underlying disorder. In an asymptomatic patient with minimal lymphoid proliferation no treatment is recommended. Any associated autoimmune disease should be managed with standard therapy without taking into account the existence of the abnormal monoclonal component. Melphalan and prednisone are used if proliferation is mainly plasmacytic. Chlorambucil, cyclophosphamide and vincristine may be beneficial if there is evidence of a progressive lymphoproliferative process. Radiation therapy and surgical removal of extramedullary plasmacytomas can be curative in some cases.
Prognosis
Gamma-HCD has a highly variable clinical course and ranges from an asymptomatic, benign, or transient process to a rapidly progressive neoplasm leading to a very poor prognosis.

                            Last update:
                            October 2011

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


Gamma-sarcoglycan-related limb-girdle muscular dystrophy R5

A subtype of autosomal recessive limb-girdle muscular dystrophy characterized by a childhood onset of progressive shoulder and pelvic girdle muscle weakness and atrophy frequently associated with calf hypertrophy, diaphragmatic weakness, and/or variable cardiac abnormalities. Mild to moderate elevated serum creatine kinase levels and positive Gowers sign are reported.


A rare, mixed neuronal-glial tumor characterized by slow growth and irregular arrangement of neoplastic ganglion cells (large, multipolar dysplastic neurons) within stroma composed of non-neoplastic glial elements. Most commonly it occurs in temporal lobe, but it can be located throughout central nervous system. Clinical manifestations vary depending on the location and include seizures, increased intracranial pressure, cerebellar signs and focal neurologic deficits. Memory disturbances, cranial nerve palsies and psychiatric symptoms have also been reported.


Ganglioglioma is a rare, usually benign, well-circumscribed, often cystic, mixed neuronal-glial tumor (composed of both neoplastic glial and ganglionic elements) which is typically located in the temporal lobe and rarely invades the surrounding tissue. Patients usually present with seizures refractory to medical treatment. Association with neurofibromatosis type I and tuberous sclerosis has been reported.


Ganglioneuroblastoma is a rare type of primitive neuroectodermal tumor (PNET; see this term), affecting almost exclusively infants and young children under the age of 10, usually occurring in the posterior mediastinum, adrenal medulla and extra-adrenal retroperitoneum (but sometimes in the neck and pelvis), with metastasis most often presenting in the bones, and characterized clinically by pain, stridor, shortness of breath, peripheral neurological signs, superior vena cava syndrome and congenital Horner syndrome (see this term), depending on the location of the tumor.


Ganglioneuroma is a rare tumor of neuroepithelial tissue, a benign and well-differentiated tumor of neural crest origin, arising from the sympathetic nervous system and composed of ganglion cells and stromal Schwann cells. It can arise anywhere from the base of the skull to the pelvis, with the most frequent locations being the adrenal glands, retroperitoneum, posterior mediastinum and the pelvis, or, in rare cases, the central nervous system, heart, bones, intestine or other sites. It may be asymptomatic or present with various symptoms due to mass effect. Association with neurofibromatosis type I, multiple endocrine neoplasia type 2B and Turner syndrome was reported.


A rare, genetic, multiple congenital anomalies syndrome characterized by growth retardation, alopecia, pseudoanodontia and ocular manifestations.

Summary:
Epidemiology
Approximately 60 patients with GAPO syndrome have been reported in literature since the first description in 1947.
Clinical description
Patients have a short stature, growth retardation and a typical facies with high and bossing forehead, hypertelorism, puffy eyelids, midfacial hypoplasia, depressed nasal bridge, anteverted wide nostrils, thick and everted lower lip, micrognathia, protruding, low-set and folded ears, and premature aging appearance mainly due to redundant hyperelastic skin with unusual wrinkles. Scalp hair may be primarily present but disappears after the first months of life resulting in complete or partial alopecia. Eyebrows and/or eyelashes are sparse or in some cases absent. Primary and permanent teeth are formed but fail to erupt. Ocular manifestations may include progressive optic atrophy, glaucoma, strabismus, photophobia, megalocornea, myelinated retinal nerve fiber layer, bilateral keratoconus, nystagmus and ptosis. Otorhinolaryngological features are choanal atresia, deafness and presence of flaccid and pulsatile masses with an audible murmur in the mastoid area associated with dilated and tortuous scalp veins. Patients have a mild intellectual deficit. Some patients have also been reported with umbilical hernia, hyperextensible joints, osseous anomalies (congenital dislocation of hips or delayed bone age) and cutaneous manifestations (hemangioma or depigmented areas). Other manifestations include intracranial hypertension in infancy, hypothyroidism, mitral valve dysfunction or cardiomyopathy, pulmonary diseases, headache, hepatomegaly, renal impairment and altered gonadal functions (irregular periods or amenorrhea, oligoasthenospermia). Cryptorchidism, ankyloglossia and hearing loss is also reported.
Etiology
Homozygous nonsense or splicing mutations in the ANTXR1 gene (2p13.3), encoding anthrax toxin receptor 1, also known as tumor endothelial marker 8 (TEM8) causes GAPO Syndrome.
Diagnostic methods
Diagnosis mostly relies on physical and ophtamologic examination. Additionally skin biopsy, cerebral angiography and magnetic resonance imaging contribute to more specific diagnosis.
Differential diagnosis
The differential diagnosis includes cerebral alterations and cutaneous manifestations such as prominent cortical veins, occluded or absent left transverse sinus and left sigmoid sinus, agenesis of left jugular vein, prominent scalp veins, dermis anomalies including amorphous hyaline substance, and pyoderma vegetans.
Antenatal diagnosis
Prenatal diagnosis is not possible from fetal ultrasound (US). In utero growth retardation may be observed on US but is not specific.
Genetic counseling
The pattern of inheritance is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of that the risk of having an affected child at each pregnancy is 25%.
Management and treatment
There is no curative treatment. Management mostly relies on ophthalmologic surveillance and symptomatic treatment of the multiple health problems.
Prognosis
GAPO patients are reported to have a reduced lifespan (until the fourth to sixth decade of life).

                            Last update:
                            October 2020

                            - Expert reviewer(s):
                            Dr Márcia Maria CASTANHOLE-NUNES  - Dr Ana Lívia GALBIATTI-DIAS  - Pr Eny Maria GOLONI-BERTOLLO  - Dr Érika Cristina PAVARINO


Gardner syndrome is a severe form of familial adenomatous polyposis characterized by multiple adenomas in the colon and rectum associated with prominent extracolonic features including osteomas and multiple skin and soft tissue tumors.


Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is a rare hereditary gastric cancer characterized by proximal gastric polyposis and increased risk of early-onset, intestinal-type adenocarcinoma of the gastric body, with no duodenal or colorectal polyposis.


Gastric linitis plastica (gastric LP) is a malignant, diffuse, infiltrative gastric adenocarcinoma.

Summary:
Epidemiology
Gastric LP accounts for about 10% of all gastric cancers but the exact prevalence in the general population is unknown. Gastric LP predominantly affects individuals of Asian origin (Korean, Chinese, Taiwanese and Japanese populations) but it is becoming more frequent in Europe. Females are slightly more frequently affected than males.
Clinical description
The age of onset is lower than that of classical gastric carcinoma, with onset frequently before 40 years of age, sometimes in very young patients (20 to 25 years of age). Signs and symptoms are nonspecific: satiety, nausea and vomiting, epigastric pain, and weight loss. Patients may present progressive dysphagia. Gastric LP is characterized by malignant glandular proliferation of independent cells (signet-ring cells) in the fibrous stroma leading to thickening and rigidity of the gastric wall. The most common sites of gastric LP are the antral and pyloric regions. Unlike other stomach cancers, gastric LP frequently extends into the peritoneum and lymphatic system. Gastric LP may be primary or occur secondary to infiltrating lobular carcinoma of the breast.
Etiology
LP is generally a sporadic disease but familial cases have been described. Etiology is unknown. The PSCA gene, that appears to be involved in regulating gastric epithelial cell proliferation, may be a susceptibility gene for diffuse-type gastric cancers. Mutations in E-cadherin gene (CDH1, 16q22.1) were detected in several affected members from one family with gastric LP.
Diagnostic methods
Diagnosis is often problematic as the gastric mucosa is frequently spared from malignant invasion. It requires morphologic studies revealing an infiltrating stomach tumor, and is based on histopathologic findings including signet-ring cells and a fibrous stroma. Multiple endoscopic biopsies are needed. Endoscopic ultrasonography shows a thickening of the submucosal layer of the tumoral wall (up to 10 to 20 mm). CT scan and endoscopic ultrasound may be useful for the diagnosis and for evaluation of local extension.
Differential diagnosis
The differential diagnosis should include malignant diseases (adenocarcinoma and lymphoma) and some benign diseases with thickening of the gastric wall (Menetrier's disease, lymphoid hyperplasia and amyloidosis; see these terms).
Management and treatment
Treatment options include surgical resection (mainly total gastrectomy) for localized disease. However, surgery with curative intent is possible in only 20% to 25% of cases due to the very high incidence of peritoneal and distant lymph node involvement. In these cases, chemotherapy provides the only alternative treatment but its efficacy is often limited in this form of cancer. The beneficial effects of adjuvant radiochemotherapy after complete excision of the primary tumour seem to be less pronounced for gastric LP than those observed for the classical form of gastric adenocarcinoma.
Prognosis
Gastric LP has a very poor prognosis due to the frequent occurrence of peritoneal dissemination, lymphatic invasion and extension toward neighboring organs. The 5-year survival rate is around 10-20% in Japan and Europe.

                            Last update:
                            January 2011

                            - Expert reviewer(s):
                            Pr Michel DUCREUX


A rare, syndromic, hyperpigmentation of the skin characterized by multiple lentigines and café-au-lait spots associated with hiatal hernia and peptic ulcer, hypertelorism and myopia. There have been no further descriptions in the literature since 1982.


Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal (GI) tract, typically presenting in adults over the age of 40 (mean age 63), and only rarely in children, in various regions of the GI tract, most commonly the stomach or small intestine but also less commonly in the esophagus, appendix, rectum and colon. GISTs can be asymptomatic or present with various non-specific signs, depending on the location and size of tumor, such as loss of appetite, anemia, weight loss, fatigue, abdominal discomfort or fullness, nausea, vomiting, as well as an abdominal mass, blood in stool, and intestinal obstruction. GISTs can also be seen in familial syndromes such as Carney triad and neurofibromatosis type 1.


A rare abdominal wall malformation characterized by the bowel protruding from the fetal abdomen on the right lateral base of the umbilical cord, and without a covering sac.

Summary:
Epidemiology
In Europe, the average recorded prevalence of gastroschisis is 1/6,000 births with an increasing trend.
Clinical description
The disorder occurs around the tenth week of gestation, and results in bowel protruding, without a covering sac. If the defect is large enough, other viscera (stomach, bladder and gonads) might be exteriorized in some cases by the end of gestation. The liver always remains intra-abdominal. Intestinal damage, bowel atresia and even bowel perforation may occur as a result from the primary defect. When the hernia ring is tight or decreasing in size, necrosis or progressive ischemia of the protruding intestines may be observed, resulting in some cases with poorer prognosis. Intestinal lesions are linked to the quality of the mesenteric vascularization more than to the contact between intestinal loops and amniotic fluid. Other malformations are only exceptionally associated.
Etiology
Gastroschisis is believed to be a defect of the umbilical cord and ring, but the exact etiology remains unknown. Maternal age ( less than 20 years old) and maternal exposure to cigarette smoke could be risk factors. Genetic mutations and maternal genitourinary tract infections have been associated with an increased risk, but the exact pathological mechanisms remain elusive. Few familial cases have been reported.
Diagnostic methods
Diagnosis is usually made before birth during prenatal ultrasound (US) in the first trimester, allowing the birth to be arranged in a specialized unit where surgery can be performed immediately and intensive neonatal support is available.
Differential diagnosis
The only differential diagnosis is omphalocele which is more frequent, occurs earlier in embryonic development, and is associated in half of the cases with other malformations.
Antenatal diagnosis
Prenatal diagnosis is nowadays made in the first trimester, and relies on the picture of intestinal loops floating freely outside the abdominal cavity, to the right of the cord. Fetal karyotype is not mandatory. Later in gestation, the US scan focuses on fetal growth, amniotic fluid amount, thickness and diameter of both intra and extra abdominal loops.
Management and treatment
Gastroschisis is a surgical emergency. Primary abdominal closure is not always possible and different techniques of delayed management may be resorted to. Neonatal nutritional support is paramount. Early delivery is often proposed when intestinal complication is suspected.
Prognosis
Prognosis is linked to the functional quality of the intestinal loops, but is excellent in more than 90% of cases.

                            Last update:
                            March 2020

                            - Expert reviewer(s):
                            Dr Sylvie BEAUDOIN


A rare genetic primary immunodeficiency characterized by profound circulating monocytopenia, B- and NK-cell lymphopenia and severe dentritic cell decrease, which manifests clinically with disseminated mycobacterial and viral infections, as well as opportunistic fungal and parasitic infections and frequent pulmonary alveolar proteinosis. Predisposition to developping myeloid neoplasms is associated.


Gaucher disease type 1 is the chronic non-neurological form of Gaucher disease (GD; see this term) characterized by organomegaly, bone involvement and cytopenia.

Summary:
Epidemiology
It represents around 90% of all cases of GD with an estimated prevalence of 1/100,000 in the general population.
Clinical description
Although the disease can be diagnosed at any age, half of patients are under the age of 20 at diagnosis. The clinical presentation is heterogeneous with occasional asymptomatic forms. It is characterized by the association of frequent asthenia, growth retardation or delayed puberty, splenomegaly (90% of cases) that may be complicated by splenic infarctions (sometimes superinfected), hepatomegaly (80% of cases) and in rare cases can progress towards fibrosis followed by cirrhosis. Bone anomalies are present in 80% of cases. They manifest as deformations, osteopenia that sometimes causes pathological fractures or vertebral compression, bone infarctions or even aseptic osteonecrosis. Involvement of other organs (rarely symptomatic pulmonary, renal and cardiac involvement) is less common. Pancytopenia is frequent and is associated with various degrees of thrombocytopenia (sometimes severe), anemia and, less frequently, leukoneutropenia. Polyclonal hypergammaglobulinemia is often present and is sometimes complicated by monoclonal gammapathy.
Etiology
GD type 1 is a lysosomal storage disease caused by a mutation in the GBA gene (localized to 1q21) that codes for the lysosomal enzyme, glucocerebrosidase. The deficiency in glucocerebrosidase leads to the accumulation of glucosylceramidase (or beta-glucocerebrosidase) deposits in the cells of the reticuloendothelial system of the liver, of the spleen and the bone marrow (Gaucher cells).
Diagnostic methods
Diagnostic methods involve ultrasound and magnetic resonance imaging (MRI) for the initial evaluation and subsequent monitoring of hepatosplenomegaly, radiography and bone scintigraphy to detect bone lesions and complications, osteodensitometry for the evaluation of osteopenia of the lumbar spine and femoral neck, and cardiac ultrasound for the detection of pulmonary arterial hypertension. An increase in certain biological markers, that are important both for the initial diagnosis and monitoring with or without treatment, is also observed: chitotriosidase, angiotensin converting enzyme, ferritin and tartrate-resistant acid phosphatases. Diagnosis can be confirmed by demonstrating a deficit in the enzymatic activity of glucocerebrosidase. In rare cases, genotyping may be of prognostic value: a patient with a homozygous N370S mutation in the GBA gene will not develop neurological disease.
Differential diagnosis
Differential diagnoses include other lysosomal storage disorders. The presence of Gaucher-like cells can be found in certain hematologic diseases (lymphoma, Hodgkin's lymphoma and chronic lymphocytic leukemia; see these terms).
Genetic counseling
The transmission is autosomal recessive
Management and treatment
The standard treatment for GD type 1 is enzyme substitution therapy, administered intravenously (e.g.: imiglucerase with European marketing authorization (MA) since 1997 and velaglucerase with a MA since 2010). Substrate reduction therapy (miglustat), administered orally, provides an alternative second-line treatment when enzyme substitution therapy is not suitable. Bisphophonates can also be proposed to prevent bone complications.
Prognosis
GD type 1 is not usually life-threatening. The functional prognosis, on the other hand, can be affected by sometimes serious bone complications.

                            Last update:
                            February 2012

                            - Expert reviewer(s):
                            Dr Nadia BELMATOUG  - Dr Jérôme STIRNEMANN


Gaucher disease type 2 is the acute neurological form of Gaucher disease (GD; see this term). It is characterized by early-onset and severe neurological involvement of the brainstem, associated with an organomegaly and generally leading to death before the age of 2.

Summary:
Epidemiology
The annual incidence of GD in the general population is around 1/60,000 and the prevalence is approximately 1/100,000. GD type 2 is very rare, with an incidence of approximately 5% of all GD patients and has a prevalence of virtually zero, taking into account its severity and early death.
Clinical description
The disease usually presents in infants aged 3 to 6 months with systemic manifestations of hepatosplenomegaly and an early onset and severe neurological syndrome. The first signs are oculomotor paralysis or bilateral fixed strabismus associated with bulbar signs, in particular severe swallowing difficulties, progressive spasticity and dystonic movements. Seizures occur later and manifest as myoclonic epilepsy that is refractory to treatment with antiepileptics.
Etiology
GD type 2 is a lysosomal storage disease caused by a mutation in the GBA gene (1q21) that codes for the lysosomal enzyme, glucocerebrosidase. The deficiency in glucocerebrosidase leads to the accumulation of glucosylceramidase (or beta-glucocerebrosidase) deposits in the cells of the reticuloendothelial system of the liver, of the spleen and the bone marrow (Gaucher cells).
Diagnostic methods
A definite diagnosis requires the demonstration of a deficit in the enzymatic activity of glucocerebrosidase.
Antenatal diagnosis
Biochemical prenatal diagnosis can be proposed to couples who have already had a child with GD type 2. It can be carried out by measuring the enzyme activity in chorionic villus samples at 10-12 weeks of pregnancy or in amniocytes in culture towards 16 weeks of pregnancy.
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
The treatment does not seem to have an effect on neurological manifestations and is therefore not indicated for patients with GD type 2.
Prognosis
Prognosis is poor with most patients dying before the age of 2.

                            Last update:
                            February 2012

                            - Expert reviewer(s):
                            Dr Nadia BELMATOUG  - Dr Jérôme STIRNEMANN


Gaucher disease type 3 is the subacute neurological form of Gaucher disease (GD; see this term) characterized by progressive encephalopathy and associated with the systemic manifestations (organomegaly, bone involvement, cytopenia) of GD type 1 (see this term).

Summary:
Epidemiology
The annual incidence of GD is about 1/60,000 and the prevalence is approximately 1/100,000. GD type 3 accounts for 5% of all patients with GD.
Clinical description
The clinical presentation is very heterogeneous. Neurological disease appears in childhood or adolescence, a much later onset than in GD type 2 (see this term). Encephalopathy can be the presenting sign of the disease or may occur later in the disease course. Some patients have moderate systemic involvement associated with ophthalmoplegia as the only neurological symptom. For the more severe forms, the neurological signs encountered are variable: supranuclear horizontal ophthalmoplegia, progressive myoclonic epilepsy, cerebellar ataxia, spasticity and dementia. GD type 3 is also associated with the clinical and biological signs of ''systemic'' disease, such as frequent asthenia, growth retardation or delayed puberty, splenomegaly and hepatomegaly. Bone anomalies may also be present and manifest as deformations, osteopenia, which sometimes leads to pathological fractures or vertebral compression, bone infarctions or even aseptic osteonecrosis. Involvement of other organs (rarely symptomatic pulmonary, renal and cardiac) is less common. Pancytopenia is frequent and involves varying degrees of thrombocytopenia (sometimes severe), anemia and, less frequently, leukoneutropenia. Polyclonal hypergammaglobulinemia is often present and is sometimes complicated by monoclonal gammapathy.
Etiology
GD type 3 is a lysosomal storage disease caused by a mutation in the GBA gene (1q21) that codes for the lysosomal enzyme, glucocerebrosidase. The deficiency in glucocerebrosidase leads to the accumulation of glucosylceramidase (or beta-glucocerebrosidase) deposits in the cells of the reticuloendothelial system of the liver, spleen and the bone marrow (Gaucher cells).
Diagnostic methods
Diagnostic methods involve ultrasound and magnetic resonance imaging (MRI) for initial evaluation and subsequent monitoring of hepatosplenomegaly, radiography and bone scintigraphy to detect bone lesions and complications, osteodensitometry for the evaluation of osteopenia of the lumbar spine and femoral neck, and cardiac ultrasound for the detection of pulmonary arterial hypertension. An increase in certain biological markers that are important both for the initial diagnosis and monitoring with or without treatment, is also observed: chitotriosidase, an angiotensin converting enzyme, ferritin and tartrate-resistant acid phosphatases. Diagnosis can be confirmed by demonstrating a deficit in the enzymatic activity of glucocerebrosidase in circulating leukocytes. In rare cases, genotyping may be of prognostic value: a patient with a homozygous L444P mutation in the GBA gene has a very high risk of developing neurological disease.
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
The treatment for patients with GD type 3 exhibiting clinically significant non neurological manifestations is enzyme substitution therapy (imiglucerase with marketing authorization (MA) since 1997). It appears to slow progression of the neurological symptoms and is effective against the systemic manifestations.
Prognosis
In the absence of treatment, clinical progression leads to death within a few years.

                            Last update:
                            February 2012

                            - Expert reviewer(s):
                            Dr Nadia BELMATOUG  - Dr Jérôme STIRNEMANN


Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome

Gaucher disease - ophthalmoplegia - cardiovascular calcification is a variant of Gaucher disease, also known as a Gaucher-like disease that is characterized by cardiac involvement.

Summary:
Epidemiology
This syndrome is rare with less than 30 cases reported in the literature.
Clinical description
The principle manifestation is progressive calcification of the aorta, and of the aortic and/or mitral valves. Other common features include mild splenomegaly, corneal opacities, and supranuclear ophthalmoplegia.
Etiology
The disease is caused by homozygous D409H (1342G to C) mutations in the GBA gene (1q21) that encodes the lysosomal membrane-associated glycoprotein, glucosylceramidase. The enzyme deficiency resulting from the mutation leads to accumulation of glucosylceramide (GL1) and other glycolipids in the cells of the reticuloendothelial system.
Diagnostic methods
The diagnosis can be made by measuring glucosylceramidaseactivity and is confirmed by identification of the D409H GBA gene mutation.
Antenatal diagnosis
Prenatal diagnosis is possible through detection of the glucosylceramidase deficiency in amniocytes or chorionic villus samples, or through screening for the GBA gene mutation in families in which the D409H allele has been identified in both parents or an affected brother or sister.
Genetic counseling
The syndrome is transmitted in an autosomal recessive manner.
Management and treatment
Patients with this syndrome require close monitoring by echocardiography as the cardiac complications require aortic and mitral valve replacement. Enzyme substitution therapy, involving regular intravenous infusions of the recombinant glucosylceramidase enzyme, imiglucerase, has been used successfully in the treatment of this disorder following surgery.
Prognosis
The prognosis for patients depends on the outcome of the heart surgery.

                            Last update:
                            February 2012

                            - Expert reviewer(s):
                            Dr Nadia BELMATOUG  - Dr Jérôme STIRNEMANN


Gaucher disease (GD) is a lysosomal storage disorder encompassing three main forms (types 1, 2 and 3), a fetal form and a variant with cardiac involvement (Gaucher disease - ophthalmoplegia - cardiovascular calcification or Gaucher-like disease).

Summary:
Epidemiology
The prevalence is approximately 1/100,000. The annual incidence of GD in the general population is about 1/60,000, but it can reach up to 1/1,000 in Ashkenazi Jewish populations.
Clinical description
The clinical manifestations of this disease are highly variable. GD type 1 (90% of cases) is the chronic and non-neurological form associated with organomegaly (spleen, liver), bone anomalies (pain, osteonecrosis, pathological fractures) and cytopenia. Type 2, the acute neurological form, is characterized by early onset, rapidly progressing brainstem dysfunction, associated with organomegaly and leading to death before the age of 2. Type 3, the subacute neurological form, affects children or adolescents and is characterized by progressive encephalopathy (oculomotor apraxia, epilepsy and ataxia) with the systemic manifestations seen in type 1. The fetal form manifests with a decrease or absence of fetal movements or anasarca. Gaucher-like disease presents with progressive calcification of the aorta and the aortic and/ or mitral valves as its main feature.
Etiology
GD is due to mutations in the GBA gene (1q21) that codes for a lysosomal enzyme, glucocerebrosidase, or in very rare cases the PSAP gene that codes for its activator protein (saposin C). The deficiency in glucocerebrosidase leads to the accumulation of glucosylceramide (or beta-glucocerebrosidase) deposits in the cells of the reticuloendothelial system of the liver, the spleen and the bone marrow (Gaucher cells).
Diagnostic methods
Formal diagnosis of the disease is determined by the measurement of glucocerebrosidase levels in circulating leukocytes. Genotyping confirms the diagnosis.
Differential diagnosis
Differential diagnoses include other lysosomal storage disorders. The presence of Gaucher-like cells can be found in certain hematologic diseases (lymphoma, Hodgkin's lymphoma and chronic lymphocytic leukemia; see these terms).
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
There are two available treatments for GD type 1 and 3: enzyme substitution therapy (using imiglucerase or velaglucerase) and substrate reduction therapy (miglustat). These treatments are ineffective for GD type 2.
Prognosis
The prognosis is good in GD type 1. In type 2, death usually occurs before the age of 2. Without specific treatment, GD type 3 progresses to death within a few years.

                            Last update:
                            February 2012

                            - Expert reviewer(s):
                            Dr Nadia BELMATOUG  - Dr Jérôme STIRNEMANN


A rare tumor of pancreas caused by mutations in the GCGR gene characterized by pancreatic alpha cell hyperplasia, pancreatic neuroendocrine tumors and markedly increased serum glucagon levels in the absence of a glucagonoma syndrome. Clinical manifestations may include abdominal pain, pancreatitis, fatigue, diarrhea, and diabetes mellitus.


Gelatinous drop-like corneal dystrophy (GDCD) is a form of superficial corneal dystrophy characterized by multiple prominent milky-white gelatinous nodules beneath the corneal epithelium, and marked visual impairment.

Summary:
Epidemiology
Worldwide prevalence of this form of corneal dystrophy is not known. Cases have been reported in patients from India, Tunisia, Vietnam, Turkey, the USA and other countries, but most cases seem to be in Japan where prevalence is estimated to be 1/300,000.
Clinical description
Lesions generally develop in the first or second decade of life. The clinical features include severe photophobia, tearing, a corneal foreign body sensation and severe progressive loss of vision.
Etiology
Gelatinous drop-like corneal dystrophy is mostly caused by mutations in the TACSTD2 gene (1p32) encoding tumor-associated calcium signal transducer 2. More than 20 mutations have been reported but some patients have been found not to have a mutation in this gene, which suggests genetic heterogeneity.
Diagnostic methods
Fusiform deposits similar to those in lattice corneal dystrophy (LCD, see this term) in the deeper stroma may be found by light microscopy.
Genetic counseling
An autosomal recessive pattern of inheritance has been reported.
Management and treatment
An unsatisfactory response has been observed to both lamellar keratoplasty (LKP) and penetrating keratoplasty (PK), as well as to a superficial keratectomy, since amyloid recurs in the graft within about 5 years.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Dr Gordon KLINTWORTH


A rare skeletal dysplasia characterized by short stature, prominent abnormalities in hands and feet, and a characteristic facial appearance (described as "happy'').

Summary:
Epidemiology
Fewer than 30 cases have been reported to date.
Clinical description
The characteristic facial appearance (''happy'' face) consists in a shortened nose, full cheeks, hypertelorism, long flat philtrum, and a thin upper lip. Additional clinical features include progressive cardiac valvular thickening often leading to an early death, contractions of the gastrocnemius muscle and Achilles tendon leading to tip toe walking, tracheal stenosis, bronchopulmonary insufficiency, and liver enlargement. Radiological manifestations include delayed bone age, cone-shaped epiphyses, shortened long tubular bones and ovoid vertebral bodies.
Etiology
Mutations have been found in the ADAMTSL2 and FBN1 genes which appear to induce microfibrillar network disorganization and enhanced TGF-beta signaling. FBN1 encodes fibrillin-1 and ADAMTSL2 (Disintegrin And Metalloproteinase with Thrombospondin repeats- like 2) encodes a glycoprotein of unknown function.
Genetic counseling
Transmission is autosomal recessive in the cases with ADAMTSL2 gene mutations and autosomal dominant in the cases with FBN1 mutations.

                            Last update:
                            June 2012

                            - Expert reviewer(s):
                            Pr Valérie CORMIER-DAIRE


Gemignani syndrome is a rare neurodegenerative disease characterized by slowly progressive ataxia, amyotrophy of the hands and distal arms, spastic paraplegia, progressive sensorineural hearing loss, hypogonadism and short stature. Additional features include generalized cerebellar atrophy and peripheral nervous system anomalies. Small cervical spinal cord, intellectual/language disability and localized vitiligo have also been reported. There have been no further descriptions in the literature since 1989.


Generalized arterial calcification of infancy

A rare genetic vascular disease characterized by early onset (between in utero to infancy) of extensive calcification and stenosis of the large and medium sized arteries. Presentation is typically with respiratory distress, congestive heart failure and systemic hypertension.

Summary:
Epidemiology
Approximately 300 cases have been reported worldwide in the medical literature. The prevalence is unknown; however, based on carrier frequency of the recognized pathogenic variants, the frequency of 1/566,000 has been suggested.
Clinical description
Disease onset is either early (in utero to within the first week of life) or late (median age three months). Early-onset disease presents variably with fetal distress, heart failure, polyhydramnios, hypertension, respiratory distress, hydrops fetalis, edema, visceral effusions, cyanosis, cardiomegaly, and ascites. Presentation of late-onset disease variably includes respiratory distress, cyanosis, feeding difficulties, congestive heart failure, vomiting, irritability, failure to thrive, fever, hypertension, and edema. Additional findings can include extravascular calcifications (particularly periarticular), typical skin and retinal manifestations of pseudoxanthoma elasticum, hearing loss, and development of rickets after infancy. Pathologically, the condition is characterized by deposition of calcium along the internal elastic membrane of arteries, accompanied by fibrous thickening of the intima, which causes luminal narrowing.
Etiology
Causal mutations have been identified in the genes ENPP1 (chromosome 6q23.2) and ABCC6 (chromosome 16p13.11) respectively encoding ectonucleotide pyrophosphatase/ phosphodiesterase 1 and multidrug resistance-associated protein 6, a transmembrane protein belonging to the family of ATP-binding cassette (ABC) transport proteins. Pathological variants lead to aberrant tissue mineralization, and the subsequent luminal narrowing invariably leads to coronary arterial occlusion and myocardial ischemia or stenoses of different arteries leading to end-organ damage. ENPP1 mutations also cause autosomal recessive hypophosphatemic rickets, which is associated with longer survival.
Diagnostic methods
Diagnosis of is made by the combination of clinical, imaging or histopathological findings, together with genetic results. The preferred imaging modality to assess calcifications extension is whole-body computed tomography combined with CT angiography.
Differential diagnosis
Differential diagnosis includes endocardial fibroelastosis, myocardititis, storage disorders, infarction, anomalous insertion of the coronary arteries, cardiac anomalies, metastatic calcification due to renal disease, hypervitaminosis D, infections, and non-immune fetal hydrops, Takayasu arteriitis.
Antenatal diagnosis
Antenatal diagnosis has been reported, with findings of arterial calcifications, hydrops, abnormal cardiac contractility, and hyperechoic kidneys. The diagnosis is essential for genetic counseling, and for screening of siblings at risk for developing the disease.
Genetic counseling
The pattern of inheritance is autosomal recessive. The sibling-recurrence risk is 25%. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants in the family are known.
Management and treatment
Use of bisphosphonates appears to significantly increase survival. Aspirin therapy is warranted in those with severe coronary stenosis who are at increased risk for coronary thrombosis. Anti-hypertensive therapy is warranted for hypertension. Treatment of hypophosphatemic rickets involves calcitriol and oral phosphate supplements. It seems prudent to avoid the use of warfarin if possible. Where endotracheal intubation is required, lateral cervical spine x-ray is recommended to evaluate for cervical spine fusion, and thereby avoid secondary complications.
Prognosis
Prognosis is poor; most infants die from myocardial infarction within the first year of life, with the greatest number of deaths occurring within the first six months. Nevertheless, long-term survival into the second and third decade has been reported.

                            Last update:
                            April 2019

                            - Expert reviewer(s):
                            Dr Yvonne NITSCHKE  - Pr Frank RUTSCH


Generalized basaloid follicular hamartoma syndrome is a rare, genetic skin disease characterized by multiple milium-like, comedone-like lesions and skin-colored to hyperpigmented, 1 to 2 mm-sized papules, associated with hypotrichosis and palmar/plantar pits. Lesions are usually first noticed on cheeks or neck and gradually increase in size and number to involve the scalp, face, ears, shoulders, chest, axillas, and upper arms. In severe cases, lower back, lower arms, and back of the legs can be involved. Mild hypohidrosis has also been reported.


Generalized epilepsy-paroxysmal dyskinesia syndrome is characterised by the association of paroxysmal dyskinesia and generalised epilepsy (usually absence or generalised tonic-clonic seizures) in the same individual or family. The prevalence is unknown. Analysis in one of the reported families led to the identification of a causative mutation in the KCNMA1 gene (chromosome 10q22), encoding the alpha subunit of the BK channel. Transmission is autosomal dominant.


A rare non-Langerhans cell histiocytosis characterized by rapid onset of crops of asymptomatic small red to brown papules, typically distributed symmetrically over the face, trunk, and proximal extremities, occasionally with mucous membrane involvement. The lesions resolve spontaneously without scarring after a variable time span and do not recur in most cases. Histopathology reveals diffuse, uniform dermal infiltration with non-xanthomatous histiocytes staining positive for CD68 and Ki-M1p. Multinucleate giant cells may occasionally be found.


Generalized eruptive keratoacanthoma (GEKA) is rare variant of keratoacanthoma (KA) that affects the skin and mucous membranes and which is characterized by a sudden generalized eruption of severely pruritic, hundreds to thousands of small follicular papules, often with a central keratotic plug.


A rare skin disease characterized by widespread cutaneous telangiectases usually ﬁrst appearing on the lower limbs and slowly progressing upwards to involve the trunk and arms. The lesions can be diffuse, localized, macular, plaque-like, discrete, or conﬂuent. Recurrent bleeding from the skin and mucous membranes is not a common feature. Likewise, co-existing epidermal or dermal abnormalities, like atrophy, depigmentation, or purpura, are absent. The condition is non-hereditary, and to establish the diagnosis, other primary and secondary telangiectases must be excluded.


Generalized glucocorticoid resistance syndrome

A rare, adrenogenital syndrome characterized by generalized, partial tissue insensitivity to glucocorticoids leading to variable phenotype, including asymptomatic individuals with only biochemical alterations or patients with ambiguous genitalia at birth in females, hypertension, acne, hirsutism, precocious puberty, male-pattern hair loss, anxiety and depression in both sexes, menstrual irregularities in women, and oligospermia in men.


A form of peeling skin syndrome characterized by a generalized distribution. It comprises two sub-types: the non-inflammatory (PSS type A) and the inflammatory (PSS type B) form. PSS type A is characterized by generalized white scaling with superficial non-inflammatory peeling of the skin, while PSS type B is characterized by superficial patchy peeling of the entire skin with underlying erythroderma, pruritus, and atopy.


Generalized pseudohypoaldosteronism type 1

A severe form of pseudohypoaldosteronism type 1 characterized by salt wasting in multiple organs including the kidney, colon, and sweat and salivary glands. Presentation is in the first few weeks of life with severe dehydration, vomiting and failure to thrive in association with hyponatremia, hyperkalemia and metabolic acidosis as well as elevated aldosterone and renin levels. No remission is reported and patients suffer from recurrent life-threatening episodes of salt loss.


Generalized pustular psoriasis is a severe inflammatory skin disease that can be life-threatening and that is characterized by recurrent episodes of high fever, fatigue, episodic erythematous cutaneous eruptions with sterile cutaneous pustules formation on various parts of the body, and neutrophil leukocytosis.


Genetic epilepsy with febrile seizure plus

Generalized epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome in which family members display a seizure disorder from the GEFS+ spectrum which ranges from simple febrile seizures (FS) to the more severe phenotype of myoclonic-astatic epilepsy (MAE) or Dravet syndrome (DS) (see these terms).

Summary:
Epidemiology
Prevalence is unknown but hundreds of cases have been described in the literature.
Clinical description
Phenotypes in patients can be variable, ranging from simple FS to epileptic encephalopathies including MAE and DS. Disease onset is variable. FS plus (FS+) is the characteristic phenotype seen in most GEFS+ families, described as febrile seizures that persist beyond the age of 6 or that occur with other afebrile seizure types including generalized tonic-clonic seizures, myoclonic, or absence seizures that usually remit by late childhood or early adolescence. Occasional seizures in adulthood are possible. Partial seizure types can also be observed.
Etiology
Mutations in SCN1A (2q24.3) (most commonly) and SCN1B (19q13.12) have been identified as causal in several families with GEFS+. These genes encode two subunits of the neuronal sodium channel. Other causal mutations include those in the gamma 2 subunit (GABRG2) gene (5q34). SCN2A (2q24.3), SCN9A (2q24), and GABRD (1p36.3) have been suggested as possible susceptibility genes for GEFS+.
Diagnostic methods
GEFS+ is diagnosed clinically through the seizure type of the patient and the family history. Molecular genetic testing can confirm the diagnosis.
Differential diagnosis
Differential diagnoses include other genetic epilepsies such as benign familial infantile seizures (due to PRRT2 mutations) or encephalopathy due to GLUT1 deficiency (see these terms) or a sporadic epilepsy caused by injury or infections.
Antenatal diagnosis
Given the broad phenotypic range of known GEFS+ mutations, prenatal diagnosis is usually not performed.
Genetic counseling
In most large families, GEFS+ is inherited in an autosomal dominant manner, often with incomplete penetrance. In other families it follows complex inheritance where several genes or environmental factors are thought to be involved. Genetic counseling is possible in families with a known disease causing mutation. However, precise phenotypes cannot be predicted as wide phenotypic variability is seen within families.
Management and treatment
As most patients with GEFS+ have a mild phenotype, treatment may not be necessary. Seizure control with antiepileptic drugs is essential in patients with recurrent seizures. The drugs mainly used include valproic acid, benzodiazepines (i.e. clobazam), ethosuximide, levetiracetam and topiramate. Given the relatedness to DS, lamotrigine and phenytoin may not be considered. Temporal lobe surgery resulted in a positive outcome in two patients with GEFS+. Regular follow-up and neuropsychological evaluations are recommended along with electroencephalographic monitoring when a new seizure pattern is suspected. In patients with active epilepsy, activities where a seizure could lead to injury or death should be avoided.
Prognosis
The overall prognosis depends on the exact phenotype within the GEFS+ spectrum. In patients with mild phenotypes (FS, FS+) seizures often remit by adolescence. Patients with more severe phenotypes may require life-long treatment and may have lasting neurocognitive sequelae.

                            Last update:
                            May 2014

                            - Expert reviewer(s):
                            Pr Ingo HELBIG


Genetic hyperferritinemia without iron overload is a rare biological anomaly defined as high serum ferritin levels without elevations of transferrin saturation, tissue or serum iron and characterized by an apparently asymptomatic clinical phenotype.


A rare genetic disease characterized by early-onset severe obesity due to mutations in single genes acting on the development and function of the hypothalamus or the leptin-melanocortin pathway, leading to disruption of energy homeostasis and endocrine dysfunction. Patients present with a body mass index over three standard deviations above normal at less than five years of age, accompanied by a variety of signs and symptoms according to the mutated gene, including hyperphagia, insulin resistance, reduced basal metabolic rate, or hypogonadism, among others.


Genetic recurrent myoglobinuria is an inborn error of metabolism characterized by abnormal urinary excretion of myoglobin due to acute destruction of skeletal muscle fibers.

Summary:
Epidemiology
The exact prevalence remains unknown.
Clinical description
In the majority of cases, the disease manifests in childhood and is often triggered by exertion or infection (febrile illness). Hypertonia, muscle stiffness and muscle pain, impaired kidney function and elevated levels of serum creatine kinase are common clinical features.
Etiology
Mutations in the mitochondrial DNA-encoded cytochrome C oxidase genes (MT-CO1 and MT-CO2) should be considered in patients with recurrent myoglobinuria. Recently, mutations in the LPIN1 gene (chromosome 2p21) have been reported to have a causative role in three patients with recurrent episodes of myoglobinuria, originating from consanguineous families.
Genetic counseling
The disorder may occur sporadically, or be inherited in either a recessive or dominant manner.

                            Last update:
                            March 2010


Genetic steroid-resistant nephrotic syndrome

A rare, hereditary nephrotic syndrome characterized by proteinuria, hypoalbuminemia, edema, and hyperlipidemia, with an absence of response to an initial trial of corticosteroids (i.e. steroid-resistant nephrotic syndrome; SRNS) and a generally complicated course.

Summary:
Epidemiology
The annual incidence is 1/ 200,000- 500,000 children.
Clinical description
Disease onset may occur anywhere between birth and adulthood but predominantly presents in younger populations. The nephrotic syndrome is defined by severe proteinuria (Urinary Protein/Creatinine ration > 200 mg/mmol) with low serum albumin (<30 g/l) and possible edema. Biopsy shows minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS) or, more rarely, diffuse mesangial sclerosis (DMS), and podocyte foot process effacement by electron microscopy. It is multi-drug resistant and usually progresses to end-stage kidney failure; however, patients have a very low risk of recurrence after kidney transplantation.
Etiology
Causative pathogenic variants are identified in approximately 10-15% of young adults presenting with SRNS, 30% of children and at least 66% in congenital and infantile cases. Among these genes, NPHS1 (19q13.12) and NPHS2 (1q25.2) are by far the two main autosomal recessive genes implicated in SRNS while INF2 (14q32.33) and WT1 (11p13) are the leading cause of autosomal dominant SRNS. COQ8B (19q13.2) biallelic variants are commonly found in patients of Asian descent. So far, more than 60 single gene causes of SRNS have been reported, however most novel gene variants are rare and involve few families.
Diagnostic methods
Comprehensive gene panels to include all currently known SRNS genes; alternatively cascade testing starting with screening for pathogenic variants in NPHS2 and WT1, the most commonly mutated genes in children, can be performed at the initial stage and if negative expanded to large next generation sequencing based test.
Differential diagnosis
A number of hereditary renal disorders might present with persistent proteinuria, the hallmark of SRNS. These include defects in ciliary (eg. TTC21B) or tubular (eg. CLCN5, Dent disease) genes or atypical hemolytical syndrome (DGKE). There is also a number of syndromic (i.e. multiorgan) forms associated with defects in WT1, LMX1B, LAMB2, PAX2, etc.
Antenatal diagnosis
The decision regarding preimplantation genetic diagnosis and prenatal genetic testing should be discussed with the family in light of the local financial, social, and legal settings.
Genetic counseling
Recurrence risk counseling should be provided in all cases. Family members who are candidates for living-related kidney donation have to undergo genetic testing as part of evaluation; only heterozygous carriers of a recessive SRNS genetic variant may be considered as a potential donor, while a family member having a variant associated with a dominant inheritance should be dissuaded from kidney donation.
Management and treatment
International Pediatric Nephrology Association 2020 guidelines recommend discontinuing ineffective immunosuppressive therapies, and continuing non -immunosuppressive management, including RAASi and other supportive measures in patients with diagnosis of a hereditary nephrotic syndrome. There is high risk of progression to end-stage kidney disease; however, recurrence of the disease in the grafted kidney after transplantation is exceptional.
Prognosis
Life expectancy is not dramatically affected in SRNS patients, however individual outcome depends on prompt management and access to specific procedures, i.e. dialysis and kidney transplantation.

                            Last update:
                            January 2021

                            - Expert reviewer(s):
                            Pr Olivia BOYER | ERKNet* - Pr Beata LIPSKA-ZIETKIEWICZ | ERKNet*

                                * European Reference Network


Genetic transient congenital hypothyroidism is a rare, thyroid disease characterized by a gene mutation induced, temporary deficiency of thyroid hormones at birth, which later reverts to normal with or without replacement therapy in the first few months or years of life.


A rare, multiple congenital anomalies/dysmorphic syndrome characterized by male, 46,XY gonadal dysgenesis, cleft palate, micrognathia, conotruncal heart defects and unspecific skeletal, brain and kidney anomalies.


A rare congenital patellar anomaly syndrome characterized by patellar aplasia or hypoplasia associated with microcephaly, characteristic coarse facial features (microcephaly, bitemporal narrowing, large, broad nose with high nasal bridge, prominent cheeks and micro/retrognathia or prognathism), arthrogryposis of the hips and knees, urogenital abnormalities and intellectual deficiency.


A rare disorder characterized by chondromatosis, typically involving the clavicles, upper end of the humerus, and lower end of the femur. Lesions are bilateral and symmetrical. The clinical course is benign.


Genochondromatosis type 2 is a rare genetic bone development disorder characterized by normal clavicles and symmetrical, generalized metaphyseal enchondromas, particularly in the distal femur, proximal humerus, and bones of the wrists, hands, and feet. Lesions regress later in life with growth cartilage obliteration. Clinical examination is normal and the course of the disease is benign.


German syndrome is an autosomal recessive arthrogryposis syndrome, described in 5 cases. Three of the four known families with affected children were Ashkenazi Jews. German syndrome is characterized by arthrogryposis, hypotonia-hypokinesia sequence, and lymphedema. Patients present distinct craniofacial appearance (tall forehead and ''carp''-shaped mouth, cleft palate), contractures, severe hypotonia manifesting as motor delay, and swallowing difficulties. The disease has a severe morbidity and mortality rate and survivors present a small stature, hypotonia, frequent upper respiratory infections, and psychomotor delay. There have been no further descriptions in the literature since 1987.


A rare primary germ cell tumor of central nervous system characterized by a space-occupying lesion usually arising in structures around the third ventricle, most commonly the region of the pineal gland and the suprasellar compartment. It is composed of uniform cells resembling primitive germ cells. Clinical manifestations depend on the tumor site and include hydrocephalus, visual disturbances, and endocrine abnormalities. Prognosis is favorable in pure germinomas due to high radiosensitivity.


Geroderma osteodysplastica (GO) is characterized by lax and wrinkled skin (especially on the dorsum of the hands and feet and abdomen), progeroid features, hip dislocation, joint laxity, severe short stature/dwarfism, severe osteoporosis, vertebral abnormalities and spontaneous fractures, and developmental delay and mild intellectual deficit.

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
The severe osteoporosis and early spontaneous fractures, together with the absence of large, open fontanels are usually distinguishing features of GO.
Etiology
Although the etiology in some cases remains unknown, mutations in the GORAB gene (1q24.2) have been identified in some families. Mutations in the PYCR1 gene (17q25.3) have recently been identified in patients with the clinically overlapping phenotypes (wrinkly skin, osteopenia and progeroid features) of GO, autosomal recessive cutis laxa type 2 (ARCL2), wrinkly skin syndrome (WSS), and De Barsy syndrome (DBS; see these terms).
Genetic counseling
GO is transmitted in an autosomal recessive manner.
Management and treatment
Bisphosphonates can be successfully used in cases with severe osteopenia.
Prognosis
Patients with GO have a normal life expectancy and, in most cases, normal intelligence. There is a spontaneous improvement in the disease course. Bone fractures become less frequent with age.

                            Last update:
                            July 2010

                            - Expert reviewer(s):
                             M GUILLARD  - Pr D.J. [Dirk] LEFEBER  - Pr Eva MORAVA-KOZICZ  - Pr R.A. [Ron] WEVERS


Gerstmann syndrome is a very rare neurological disorder characterized by the specific association of acalculia, finger agnosia, left-right disorientation, and agraphia, which is supposed to be secondary to a focal subcortical white matter damage in the parietal lobe.


A rare inherited human prion disease characterized by adult onset of slowly progressive cerebellar ataxia, with dementia developing relatively late in the disease course (classic ataxic phenotype). Patients may present with gait disturbances and frequent falls, dysarthria, dysphagia, nystagmus, dysmetry, and eventually pancerebellar syndrome, myoclonus, spasticity, severe dementia, and mutism. The disease is invariably fatal after five years on average. Neuropathological hallmark is the presence of numerous multicentric prion protein plaques in the cerebral and cerebellar cortex.


A form of gestational trophoblastic neoplasia characterized histologically by trophoblast proliferation, absence of chorionic villi (except in cases of intraplacental choriocarcinoma) and tissue necrosis with bleeding. The tumor occurs secondary to pregnancy (ectopic or normal), miscarriage, voluntary termination of pregnancy (VTP) or a hydatidiform mole. Indicative signs are persistent unexplained metrorrhagia or secondary increase, stagnation, or non-normalization at 6 months of total serum chorionic gonadotropin (hCG) levels after removal of a hydatidiform mole; persistent unexplained metrorrhagia following spontaneous abortion or VTP; occasionally unexplained metrorrhagia in the weeks or months following normal childbirth or an ectopic pregnancy. Occasionally, metastases (lung, liver, brain, kidneys, vagina) are indicative signs in women of childbearing age.


A rare, malignant group of gestational trophoblastic diseases always following pregnancy, most often molar pregnancy (hydatidiform mole). Four histological forms are described: invasive mole, gestational choriocarcinoma, placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT).

Summary:
Epidemiology
Gestational choriocarcinoma is the most frequent form of gestational trophoblastic neoplasia (GTN); whilst epidemiological data is limited, in the Netherland incidence is estimated at 1/33,000 deliveries and in the USA 1/41,000 pregnancies. This disease appears to be more frequent amongst the Asian population. The PSTT and ETT occur less frequently, with a reported incidence in the Netherlands of approximately 1/100,000 and 1/1,000,000, respectively.
Clinical description
Indicative signs of GTN are an absence of normalization or a secondary elevation of total serum chorionic gonadotropin (hCG) levels after evacuation of a hydatidiform mole (more than 60% of cases), persistent unexplained metrorrhagia following spontaneous miscarriage or voluntary termination of pregnancy (about 30% of cases) and very occasionally, unexplained metrorrhagia in the weeks or months following normal childbirth or ectopic pregnancy (about 10% of cases). Exceptionally, metastasis may be a sign of the disease in women of childbearing age.
Etiology
The etiology of GTN is not known. Identification of a GTN is based on a total serum hCG assay, which is recommended following hydatidiform moles in patients with metrorrhagia persisting for more than six weeks after pregnancy, and in any patient of childbearing age who has metastasis (lung, liver, brain, kidney, vagina) with no known primary tumor.
Diagnostic methods
Diagnosis of a post-molar GTN relies on one of the following four criteria: stable hCG levels (variation of less than 10%) with at least four weekly assays over a period of at least three weeks (days 1, 7, 14, 21), increase of at least 10% in hCG with at least three weekly assays over at least two weeks (days 1, 7, 14), persistence of detectable hCG values for more than six months following mole evacuation or based on histological diagnosis of a choriocarcinoma.
Differential diagnosis
GTNs must not be confused with hydatidiform moles and, for choriocarcinomas, with non-gestational choriocarcinomas, which are most often ovarian.
Antenatal diagnosis
Diagnosis of hydatidiform mole is often by ultrasound and hCG concentration.
Genetic counseling
In extremely rare cases, recurrent molar pregnancy with or without post-molar GTN can have a genetic cause (NLRP7 mutation) with an autosomal recessive pattern of inheritance (familial recurrent hydatidiform mole).
Management and treatment
As soon as the diagnosis is made, staging must be performed to identify frequent metastases. Staging involves pelvic ultrasound, pelvic and cerebral MRI, and abdominal/chest CT. A lung X-ray must be performed to calculate the FIGO 2000 score (International Federation of Obstetrics and Gynecology). This score makes it possible to distinguish between low-risk GTNs (score of 6 or lower) and high-risk GTNs (score of 7 or higher). Management should be multidisciplinary and must be discussed by a panel of physicians, preferably in a specialized center. Low-risk tumors are treated by systemic single-agent chemotherapy, e.g. methotrexate or dactinomycin. High-risk tumors are treated first line with systemic multi-agent chemotherapy. Hysterectomy can of course not be considered for first-line treatment in women who wish to become pregnant, unless there is no other option, but can be considered for older women or women who do not wish to bear children. Placental site trophoblastic tumors and epithelioid trophoblastic tumors are special cases: the FIGO score is not appropriate and total hysterectomy is the standard treatment as these tumors are usually chemo-resistant. For advanced stage disease, multi-agent chemotherapy is indicated. hCG levels should be surveyed during and following treatment.
Prognosis
The overall recovery rate for low-risk GTN is around 99%. The prognosis is very closely related to the FIGO score and, in case of PSTT and ETT, FIGO stage.

                            Last update:
                            May 2022

                            - Expert reviewer(s):
                            Dr Baljeet KAUR | EURACAN* - Dr Christianne LOK

                                * European Reference Network


Ghosal hematodiaphyseal dysplasia syndrome (GHDD) is a rare disorder characterized by increased bone density (predominantly diaphyseal) and aregenerative corticosteroid-sensitive anemia.

Summary:
Epidemiology
The exact prevalence is unknown. GHDD has been reported in unrelated families of Indian and Middle East origin.
Etiology
GHDD is associated with mutations in the TBXAS1 gene (which encodes thromboxane synthase).
Genetic counseling
GHDD is transmitted as an autosomal recessive trait.

                            Last update:
                            March 2008


Giant adenofibroma of the breast is a rare, benign, fibroepithelial tumor which usually manifests as a unilateral, painless, firm, mobile, slow-growing mass in the breast that measures more than 5 cm. It can be associated with significant asymmetry and/or deformity of the breast and hormonal changes (e.g. puberty, pregnancy, oral contraceptives) can lead to its marked enlargement.


Giant axonal neuropathy (GAN) is a severe, slowly progressive neurodegenerative disorder characterized by progressive motor and sensory peripheral neuropathy, central nervous system involvement (including pyramidal and cerebellar signs), and characteristic kinky hair in most cases.

Summary:
Epidemiology
The prevalence is unknown, but to date approximately 50 families have been reported. The frequency of this disease however, is likely to be underestimated, due to patients with incomplete phenotypes and high level of consanguinity among some populations. It occurs equally in both sexes.
Clinical description
Onset of GAN ranges from early infancy to late childhood. Clinical hallmarks include progressive gait disturbance (frequent falls due to muscle weakness, sensory neuropathy and ataxia), everted feet, crouched gait, tightly curled hair, and early-onset central nervous system (CNS) involvement, including pyramidal and cerebellar signs that, when present together almost clinch the diagnosis. Patients usually present with intellectual disability, epilepsy, nystagmus and dysarthria that worsens in the second decade of life, and mortality typically occurs in the third decade. Other clinical signs include facial weakness, optic atrophy, ophthalmoplegia, skeletal deformations (e.g. foot deformities, scoliosis) and tremor. Clinically heterogeneous cases, with GAN presenting with a mild Charcot-Marie-Tooth (CMT)-like phenotype or manifesting with a later age of onset, absence of kinky hair, and slower progression, have recently been documented.
Etiology
GAN is associated with more than 50 different causative mutations in GAN gene (16q24.1), encoding the ubiquitously expressed cytoskeletal protein gigaxonin.
Diagnostic methods
Diagnosis is based on clinical findings and imaging. Cerebellum abnormalities, demyelination in white matter and glial proliferation in white and gray matter are shown by magnetic resonance imaging. Due to the presence of giant axons in other diseases, peripheral nerve biopsy is not sufficient to diagnose GAN. Genetic molecular testing or immunodetection of gigaxonin confirms diagnosis.
Differential diagnosis
Differential diagnosis includes CMT-1F, -2E, -4A, -4B, -4C, -4D and -4E, the classic form of infantile neuroaxonal dystrophy, arylsulfatase A deficiency, spinal muscular atrophy, Friedreich ataxia, globoid cell leukodystrophy, n-hexane toxicity, and acrylamide toxicity.
Antenatal diagnosis
Prenatal diagnosis is possible in families with a known disease-causing mutation.
Genetic counseling
GAN is inherited as an autosomal recessive trait. Parents of an affected child are obligate heterozygotes and asymptomatic. Genetic counseling can inform parents that the risk of having an affected child is 25%. Carrier testing requires the GAN pathogenic variant to have been identified in an affected member of the family.
Management and treatment
Treatment is symptomatic, focusing on stimulating intellectual and physical development, as well as communication skills, through physical, occupational and speech therapy, since the initiation of symptoms. Skeletal deformities and ophthalmoplegia may need surgery. Intrathecal administration of an AAV9-based gene therapy to restore GAN expression is currently being explored.
Prognosis
The prognosis varies but is usually poor. Most patients become wheelchair-dependent in the second decade of life and eventually progress to a bedridden state in early adulthood. Secondary complications, such as respiratory failure, may occur. Life expectancy does not exceed the third decade. Lack of curly hair is correlated with milder disease and slower disease progression, which would suggest a less stark prognosis.

                            Last update:
                            August 2017

                            - Expert reviewer(s):
                            Dr Douglas SPROULE


A rare large vessel vasculitis (LVV) characterized by vasculitis predominantly involving the arteries originating from the aortic arch and the extracranial branches of the carotid arteries. Clinical manifestations are variable, the predominant cranial phenotype is characterized by headache, jaw claudication, scalp tenderness and visual symptoms and the predominant LVV type by constitutional symptoms, polymyalgia rheumatica and occasionally limb ischemia. Overlaps between these two phenotypes are common.

Summary:
Epidemiology
Giant cell arteritis (GCA) is the most common vasculitis in adulthood with an annual incidence of 1/5,000-1/17,000 adults over 50 years old. It is more frequent in populations of northern European background. GCA affects people of more than 50 years of age (median age at diagnosis between 70-75 years old) and occurs twice as frequently in women as in men.
Clinical description
GCA often starts insidiously with constitutional symptoms (fever, weight loss, night sweats, malaise, asthenia), cranial manifestations (headache, jaw claudication, scalp tenderness, visual loss), and, in about 50% of patients, polymyalgia rheumatica. The temporal artery may be swollen and tender. Visual symptoms due to an ischemic optic neuropathy occur in up to 20-30% of patients, and can lead to irreversible blindness if not immediately treated with glucocorticoids. Thoracic aortitis with aneurysms occur in approximately 15% of patients. While aortic complications rarely affect patients at disease onset, they are often a late complication of GCA.
Etiology
The etiology of giant cell arteritis is unknown. Studies have linked genetic factors, infectious agents and a prior history of cardiovascular disease to the development of giant cell arteritis.
Diagnostic methods
The diagnosis of GCA is made in individuals over 50 years of age by a combination of characteristic symptoms as outlined above, increased acute phase reactants (erythrocyte sedimentation rate, C-reactive protein or both) and characteristic imaging findings (ultrasound, magnetic resonance imaging, computerized tomography or 18-fluorodeoxyglucose positron emission tomography) of temporal and/or other large arteries depicting inflammatory wall swelling. In case imaging is either not available or inconclusive, temporal artery biopsy is a valid alternative. In temporal artery biopsy, the most important (and mandatory) histological criterion for the diagnosis of GCA is a mononuclear cell infiltrate predominating at the media-intima junction or involving the entire vessel wall (panarteritis). Response to glucocorticoid treatment is neither sensitive nor specific enough to consider it as a diagnostic criterion.
Differential diagnosis
In elderly patients presenting with constitutional symptoms and elevated inflammatory markers, cancer and infection need to be ruled out. Symptoms of polymyalgia rheumatica can also point towards diagnoses of isolated polymyalgia rheumatica or rheumatoid arthritis. In some instances, biopsy-proven involvement of the temporal arteries can be seen in other systemic vasculitides, e.g. ANCA associated vasculitis or polyarteritis nodosa.
Management and treatment
Glucocorticoids (initial dose 40-60mg/day) are highly effective in GCA but prolonged glucocorticoid therapy is often associated with substantial morbidity in the elderly population. Glucocorticoid pulse therapy (250-1000mg per day for 3 days) may be considered in case of acute visual loss or amaurosis fugax. Tocilizumab, or alternatively methotrexate should be considered in patients with refractory or relapsing GCA as well as in cases with the presence or an increased risk of glucocorticoid related adverse effects or complications. Concomitant prescription of antiplatelet or anticoagulant therapy is not indicated unless required to treat concomitant (e.g. cardiovascular) diseases. Regular monitoring for late vascular complications (e.g. aortic aneurysms) is needed.
Prognosis
The disease is chronic and the clinical course is highly variable. Response to glucocorticoids is usually rapid and complete. However, at least 50% of patients experience subsequent disease flares. Visual loss is the most feared complication but can be prevented by rapid diagnosis and immediate treatment.

                            Last update:
                            April 2021

                            - Expert reviewer(s):
                            Pr Christian DEJACO


A rare bone sarcoma characterized by a usually benign space-occupying lesion, which is nevertheless locally aggressive and massively damaging to surrounding bone tissue. The tumor is composed of giant multinucleated cells (osteoclast-like cells), mononuclear macrophages, and mononuclear stromal cells which secrete pro-myeloid and pro-osteoclastic factors. Metastasis and malignant transformation are rare, but the recurrence rate is high.


Gingival fibromatosis-facial dysmorphism syndrome

A very rare syndrome characterized by the association of gingival fibromatosis and craniofacial dysmorphism.

Summary:
Epidemiology
It has been described in two sibs.
Clinical description
Craniofacial dysmorphism consists of relative macrocephaly, bushy eyebrows with synophris, hypertelorism, downslanting palpebral fissures, flattened nasal bridge and high arched palate. The patients have normal intellect.
Genetic counseling
The condition seems to be hereditary, transmitted as an autosomal recessive trait.

                            Last update:
                            October 2010


A rare autosomal dominant disorder characterized by a generalized enlargement of the gingiva occurring at birth or during childhood that is associated with generalized hypertrichosis developing at birth, during the first years of life, or at puberty and predominantly affecting the face, upper limbs, and midback.


Gingival fibromatosis-progressive deafness syndrome

A rare syndrome characterized by gingival fibromatosis associated with progressive sensorineural hearing loss. It has been described in two families (with at least 16 affected members spanning five generations in one of the families, and five affected members spanning three generations in the other family). It is transmitted as an autosomal dominant trait.


A rare syndrome characterized by hypokalemic metabolic alkalosis in combination with significant hypomagnesemia and low urinary calcium excretion.

Summary:
Epidemiology
Gitelman syndrome (GS) prevalence is estimated at 1 to 10 per 40,000 and potentially higher in Asia. GS is arguably the most frequent inherited tubulopathy.
Clinical description
GS presents mainly in adolescents and adults but also encountered in children, as early as in the neonatal period. The diagnosis may be incidental, due to blood tests obtained for unrelated reasons. Clinical symptoms may include salt craving, thirst and nocturia, transient periods of muscle weakness and tetany, sometimes accompanied by abdominal pain. Paresthesias, especially in the face, may occur. Remarkably, some patients are completely asymptomatic. In adulthood, chondrocalcinosis may appear, which can be associated with inflammation over the affected joints. Blood pressure is typically lower than that in the general population, although reports of hypertension in adult patients exist. Sudden cardiac arrest has been described in case reports and long QT syndrome may be present. In general, growth is normal but can be delayed.
Etiology
GS is caused by biallelic inactivating mutations in the SLC12A3 gene encoding the thiazide-sensitive sodium-chloride cotransporter NCC expressed in the apical membrane of cells lining the distal convoluted tubule. At present, more than 350 different NCC mutations throughout the whole protein have been identified.
Diagnostic methods
Diagnosis is based on the clinical symptoms and biochemical abnormalities (chronic hypokalemia, metabolic alkalosis, hypomagnesemia and hypocalciuria) and can be confirmed by genetic testing.
Differential diagnosis
Bartter syndrome (especially type III, caused by mutation in CLCNKB) can be clinically indistinguishable from GS. Mutation in the HNF1B can mimic the electrolyte abnormalities (particularly hypomagnesemia) encountered in GS. Biochemical abnormalities are identical in EAST/SESAME syndrome, but the extra renal features allow it to be distinguished from GS. Chronic thiazide use can cause an acquired GS-like clinical picture.
Antenatal diagnosis
Antenatal diagnosis for GS is technically feasible but not advised because of the good prognosis in the majority of patients.
Genetic counseling
Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
The management of GS should be individualized and at least annual follow-up in a nephrology clinic to monitor potential complications and evolution is advocated. It is recommended to encourage patients to follow their propensity for salt consumption. Lifelong supplementation of salt, potassium (KCl) or magnesium supplementation (magnesium-oxide and magnesium-sulfate) should be considered. Many symptoms are improved by supplementation, but there is no evidence correlating the severity of biochemical abnormalities with the severity of symptoms. Cardiac work-up should be offered to screen for risk factors for cardiac arrhythmias. All GS patients are encouraged to maintain a high sodium and high potassium diet.
Prognosis
To date, there is no evidence that GS affects life expectancy.

                            Last update:
                            March 2020

                            - Expert reviewer(s):
                            Pr Detlef BÖCKENHAUER | ERKNet*

                                * European Reference Network


GJC2-related late-onset primary lymphedema

A rare genetic primary lymphedema characterized by lymphedema of all four limbs with age of onset ranging from birth to adulthood. Manifestations are of variable severity, and upper limb involvement may develop only later in the disease course. Recurrent episodes of cellulitis and skin infections are observed in severe cases. Varicose veins and venous incompetence have been reported in association.


Glanzmann thrombasthenia (GT) is a bleeding syndrome characterized by spontaneous mucocutaneous bleeding and an exaggerated response to trauma due to a constitutional thrombocytopenia.


Glassy cell carcinoma of the cervix uteri is a rare cancer of the uterine cervix, composed of nests of large neoplastic cells with 'ground glass' cytoplasm, surrounded by a stroma with prominent eosinophilic infiltrates. It is a poorly differentiated, aggressive variant of adenosquamous carcinoma that usually affects young women and presents with dysfunctional vaginal bleeding and lower abdominal pain. Distant metastases to the lungs, liver spleen or bones are often present at the time of diagnosis. It is often associated with high-risk HPV-infection (types 18, 16 and 32).


Glaucoma secondary to spherophakia/ectopia lentis and megalocornea is a rare, genetic, non-syndromic developmental defect of the eye disorder characterized by congenital megalocornea associated with spherophakia and/or ectopia lentis leading to pupillary block and secondary glaucoma. Additional features may include flat irides, iridodonesis, axial myopia, very deep anterior chambers, miotic, oval pupils without well-defined borders, ocular pain and irritability manifesting as conjunctival injection, corneal edema and central scarring, as well as a high arched palate.


Glaucoma-ectopia lentis-microspherophakia-stiff joints-short stature syndrome

A rare genetic, syndromic eye disorder characterized by progressive joint stiffness, glaucoma, short stature and lens dislocation. This syndrome shows similarities to Moore-Federman syndrome.


Glaucoma-sleep apnea syndrome is characterized by sleep apnoea associated with glaucoma. It has been described in five members of a family (the mother and four of her children).


Glioblastomas are malignant astrocytic tumors (grade IV according to the WHO classification).

Summary:
Epidemiology
Glioblastomas represent the most frequent brain tumors in adults, with an annual incidence of around 1/33,330. Prevalence is estimated at 1/100,000.
Clinical description
They may occur at any age, but 70% of cases are seen in patients between 45 and 70 years of age. The tumors are usually located in the brain hemispheres, but can be found anywhere in the central nervous system. The disease often progresses rapidly (over 2 to 3 months), except when the glioblastoma develops within a pre-existing low grade astrocytoma (secondary glioblastoma). Neurological signs are nonspecific as they result from intracranial hypertension and include headaches and vomiting, often associated with behavioral changes or focal neurological deficits. Histological variants (gliosarcoma and giant cell glioblastoma) have been described for which the treatment protocols and prognosis are similar to those of glioblastoma.
Etiology
The cause of the disease is unknown, except when it occurs after therapeutic irradiation of the brain for another disease. The genetic abnormalities detected (amplification of the EGFR gene (7p12), mutations in the TP53 gene (17p13.1), loss of chromosome 10) vary depending on the nature of the tumor: primary glioblastoma (de novo) or a secondary glioblastoma (developing from a benign astrocytic tumor).
Diagnostic methods
Radiologic studies, computerized tomography (CT) and magnetic resonance imaging (MRI) demonstrate characteristic features such as an infiltrating tumor associated with heterogeneous contrast enhancement and areas of necrosis.
Differential diagnosis
The differential diagnosis should include infectious and parasitic diseases with central nervous system involvement. Familial forms of glioblastoma are very rare but the tumor may occur as part of a syndrome such as Turcot syndrome, neurofibromatosis type 1 or Li-Fraumeni syndrome (see these terms).
Management and treatment
The first-line treatment is usually surgery, either to confirm the diagnosis with a biopsy or to remove as much of the tumor as possible. Complete resection is rarely feasible, since tumor cells usually infiltrate the surrounding brain. Treatment is then completed with radiotherapy targeted at the tumor bed, combined with chemotherapy (nitrosoureas and temozolomide). In terms of survival, the benefits from adjuvant treatments after surgery are significant, although they remain modest. In case of relapse, second-line chemotherapy or reoperation may be performed. Due to the relative rarity of this tumor, management of glioblastoma patients should be carried out by multidisciplinary teams with expertise in neuro-oncology within prospective studies aiming to improve patient survival and quality of life.
Prognosis
Prognosis is poor, especially in the absence of gross total resection, in older patients and in case of severe neurological deficits.

                            Last update:
                            November 2007

                            - Expert reviewer(s):
                            Dr Jacques GRILL


Glioependymal/ependymal cyst is a rare central nervous system malformation defined as a subarachnoid, supratentorial, interventricular or intraspinal, sometimes intracerebral or intramedullar cyst with an internal ependymal lining, possibly surrounded by glial tissue. It may be an incidental finding or may present at different ages with clinical features depending on its size and location. It may distort adjacent brain structures and cause macrocephaly, ventriculomegaly, hydrocephalus, focal neurological signs and other signs and symptoms. In some cases, it is associated with other cerebral malformations (e.g. corpus callosum agenesis, polymicrogyria, heterotopias).


A rare glial tumor characterized by extensive infiltration of the brain, often extending to infratentorial structures and even the spinal cord. The tumor corresponds to WHO grade III and is composed of elongated glial cells typically resembling astrocytes. Cases in which the predominant cell type is oligodendroglial have also been described. Some tumors develop a circumscribed neoplastic mass in addition to the diffuse lesion, usually showing features of high-grade glioma. Clinical symptoms include dementia, headache, seizures, signs of increased intracranial pressure, and a variety of neurological deficits. Prognosis is generally poor.


Global developmental delay-alopecia-macrocephaly-facial dysmorphism-structural brain anomalies syndrome

A rare disorder of ornithine metabolism characterized by global developmental delay, alopecia, macrocephaly, and dysmorphic facial features (including high and broad forehead, hypertelorism, ptosis, blepharophimosis, downslanting palpebral fissures, deep-set eyes, large ears, and retrognathia or high arched palate). Additional reported manifestations are sensorineural hearing loss, spasticity, hypotonia, hypoplastic nails, cryptorchidism, and clinodactyly, among others. Brain imaging may show white matter abnormalities, periventricular cysts, enlarged lateral ventricles, or prominent perivascular spaces.


Global developmental delay-lung cysts-overgrowth-Wilms tumor syndrome is a rare, genetic, overgrowth syndrome characterized by global developmental delay, macrosomia with subsequent somatic overgrowth, bilateral cystic lung lesions, congenital nephromegaly and bilateral Wilms tumor. Craniofacial dysmorphism includes macrocephaly, frontal bossing, large anterior fontanelle, mild hypertelorism, ear pit, flat nasal bridge, anteverted nares and mild micrognathia. Additional features may include brain and skeletal anomalies, enlarged protuberant abdomen, fat pads on dorsum of feet and toes, and rugated soles with skin folds, as well as umbilical/inguinal hernia and autistic behavior.


Global developmental delay-neuro-ophthalmological abnormalities-seizures-intellectual disability syndrome

A rare genetic neurological disorder characterized by infantile to childhood onset of global developmental delay, hypotonia, seizures, growth delay, and intellectual disability. Additional variable features include strabismus, cortical visual impairment, nystagmus, movement disorder (such as dystonia, ataxia, or chorea), or mild dysmorphic features, among others.


Global developmental delay-osteopenia-ectodermal defect syndrome

A rare genetic disease characterized by global developmental delay with language and cognition deficiencies, behavioral problems, osteopenia, joint laxity, skin defects consisting of hyperkeratosis and sweat gland and melanocyte abnormalities with hypopigmented areas, and abnormal hair structure. Mild facial dysmorphism (prominent forehead, thick eyebrows, epicanthal folds, broad nasal bridge, long philtrum, and micrognathia), abnormalities of the teeth, and skeletal and cardiac anomalies have also been described.


Global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome is a rare, genetic, neurological disorder characterized by mild to severe developmental delay and speech impairment, truncal hypotonia, abnormalities of vision (including cortical visual impairment and abnormal visual-evoked potentials), progressive brain atrophy mainly affecting the cerebellum, and shortened or atrophic corpus callosum. Other clinical findings may include increased muscle tone in the extremities, dystonic posturing, hyporeflexia, scoliosis, postnatal microcephaly and variable facial dysmorphism (e.g. deep-set eyes, gingival hyperplasia, short philtrum and retrognathia).


A rare soft tissue tumor characterized by a nodular lesion composed of cells closely resembling the modified smooth muscle cells of the normal glomus body. The tumors most often arise in the skin or soft tissues of the distal extremities, in particular the subungual region, but have been reported in almost any location. They occur as typical glomus tumors, glomangiomatosis (multiple nodules of solid glomus tumor investing the vascular walls), symplastic (showing striking nuclear atypia without mitotic activity or necrosis) or malignant glomus tumors, and glomus tumors of uncertain malignant potential.


A rare vascular anomaly or angioma characterized by the presence of small, multifocal bluish-purple venous lesions mainly involving the skin.

Summary:
Epidemiology
Glomuvenous malformations (GVMs) prevalence is unknown; over 200 families or cases have been reported in the literature. It is estimated that GVMs account for 70-80% of inherited venous-type malformations ; the rest being cutaneomucosal venous malformations (VMCMs).
Clinical description
GVMs may be present at birth, and slowly expand during childhood. New small lesions appear with time. They are usually hyperkeratotic, raised and nodular with a cobblestone surface. Color varies from pink to purplish-dark blue. However, in some cases (especially in newborns) the lesions may be flat and purple in color; this plaque-like GVM usually darkens with time. GVMs are often painful on palpation and cannot be completely emptied by compression. They are usually multifocal and are located mainly on the extremities, involving the skin and subcutis. They are rarely encountered in mucosae and intestinal hemorrhage is not a feature of this condition. There is significant clinical variation with respect to the size, location and number of lesions, even between affected individuals from the same family. For example, plaque-like GVM-lesions on the thorax can be associated with pleural effusions. Patients with GVMs have normal mental and physical development.
Etiology
GVMs are caused by mutations in the gene encoding glomulin (GLMN; 1p22.1). Inheritance pattern is autosomal dominant. The inherited mutations cause loss-of-function of glomulin. The lesions develop in areas where a double-hit mutation has occurred, indicating that GVM lesions are due to complete localized loss of glomulin. The most frequent somatic second hit is an acquired uniparental isodisomy, which leads to loss of the normal copy, and duplication of the mutated copy in cells within the lesion.
Diagnostic methods
Diagnosis of GVM is based on clinical evaluation of the cutaneous lesions. Confirmation can be obtained via a blood sample for molecular genetic testing. Doppler ultrasound examination and MRI can be used to confirm the venous component and the common superficial extent of the lesions. Histologically, GVMs are characterized by the presence of abnormal mural cells called "glomus cells'' which help differentiate from common venous malformations and VMCM.
Differential diagnosis
The differential diagnosis should include mucocutaneous venous malformations (VMCMs, which are also commonly seen on mucosal membranes, are lighter purple in color than GMVs, and are compressible and generally not painful on palpation, and caused by inherited TIE2/TEK mutations) and Blue rubber bleb nevus syndrome (characterized by the association of cutaneous and mucosal venous-like lesions with gastrointestinal lesions, and caused by somatic TIE2/TEK mutations).
Antenatal diagnosis
Prenatal diagnosis is feasible for affected families in which the disease-causing mutation has been identified, but is not widely available.
Genetic counseling
GVMs are inherited in an autosomal dominant manner. Genetic counseling should be provided for affected families, informing patients of a 50% risk of inheriting the disease-causing mutation and of the variability in clinical expression.
Management and treatment
The most effective treatment is plastic and reconstructive surgery, used depending on the size and location of the lesions. Laser can be effective, especially for small flat lesions as well as plaque-like lesions. Sclerotherapy may be indicated in some cases: the sclerosing agent such as foam aethoxysclerol is associated with less skin necrosis than ethanol (96%). Another sclerosing agent is ethanol (96%) in the form of a gel for injection, which obtained EU orphan drug designation in April 2005 for the treatment of congenital venous malformations.
Prognosis
The prognosis for patients is good, malignant transformation has not been reported and the life expectancy for patients is not reduced.

                            Last update:
                            July 2020

                            - Expert reviewer(s):
                            Pr Laurence BOON  - Pr Miikka VIKKULA


A rare oromandibular-limb hypogenesis syndrome (OLHS) characterised by the presence of an intraoral band of variable thickness attaching the tongue to the hard palate or maxillary alveolar ridge. It may be associated with other abnormalities such as cleft palate (in which case the tongue may be attached to the nasal septum), mandibular hypoplasia, upper-lip hypoplasia, hypodontia and variable limb anomalies (e.g. oligodactyly, syndactyly and polydactyly).


A rare cranial neuralgia characterized by paroxysmal, usually unilateral stabbing pain within the sensory distributions of the auricular and pharyngeal branches of the glossopharyngeal and sometimes the vagus nerve (i. e. the posterior part of the tongue, the tonsillar fossa, oropharynx, larynx, angle of the mandible, and/or ear). The attacks last seconds to minutes with intervals between the paroxysms ranging from a few minutes to a few hours, and appear in clusters lasting weeks to months, again with irregular intervals in between. Pain attacks are usually triggered by a specific stimulus but may also occur spontaneously. The condition can sometimes be associated with bradycardia, syncope, seizures, and even asystole, and is then termed vagoglossopharyngeal neuralgia.


Glucagonoma is a rare, functioning type of pancreatic neuroendocrine tumor (PNET; see this term) that hypersecretes glucagon, leading to a syndrome comprised of necrolytic migratory erythema, diabetes mellitus, anemia, weight loss, mucosal abnormalities, thromboembolism, gastrointestinal and neuropsychiatric symptoms.

Summary:
Epidemiology
The estimated incidence in the general population is 1/20, 000,000.
Clinical description
Glucagonoma usually presents in the fifth decade of life with the initial symptom often being necrolytic migratory erythema. This skin condition is characterized by a red, blistering and migratory rash, associated with an intense pruritus and that is mainly localized to the lower extremities and the groin. Diabetes is present in most cases and requires insulin therapy. Weight loss, anemia, mucosal abnormalities (glossitis, cheilitis, stomatitis), gastrointestinal disturbances, thromboembolism and neuropsychiatric symptoms (depression) are other frequent manifestations. Most glucagonomas have already metastasized by the time that they are diagnosed, mainly to the liver. In some cases glucagonoma may be associated with multiple endocrine neoplasia type 1 (MEN1; see this term). Glucogonoma can be non-functioning in rare cases.
Etiology
The etiology is unknown. These tumors of 2-25 cm mainly occur in the tail of the pancreas. They synthesize and secrete glucagon, which is responsible for balancing the effects of insulin, and is therefore essential in regulating blood sugar levels.
Diagnostic methods
Diagnosis is based on clinical findings and endocrine tests. Serum glucagon levels are markedly elevated (>500 pg/mL) and levels of more than 1000 pg/mL are considered diagnostic if the patient also displays features of glucagonoma syndrome. Other hormones such as insulin, somatostatin and vasoactive intestinal peptide may also be elevated. Levels of blood chromogranin A are increased. Localization of tumors is possible by computed tomography (CT) scan, octreotide scan, magnetic resonance imaging (MRI) and/or endoscopic ultrasound.
Differential diagnosis
Differential diagnoses include familial hyperglucagonemia, autoimmune and hereditary chronic pancreatitis, Mahvash disease, acrodermatitis enteropathica (see these terms) and cirrhosis.
Management and treatment
Somatostatin analogues (octreotide or lanreotide) are usually effective in leading to a remission of rash in most patients as well as improving the symptoms of weight loss, abdominal pain and diarrhea. Glycemia is managed by insulin injections or anti-diabetic drugs. Parenteral nutrition (with essential fatty acids, amino acids, vitamins and minerals) may also be necessary. Surgical resection is the only curative option in localized cases. Surgical debulking followed by chemotherapy may be an option in extensive tumors. Resection of the lymph nodes, spleen and parts of the liver containing metastasized glocagonoma may also be necessary. As thromboembolic complications can occur, blood thinners (antiplatelets and anticoagulants) may be recommended.
Prognosis
The prognosis of glucagonoma is usually poor as most have metastasized by the time that they are discovered. Those associated with MEN1 usually have a fairer prognosis as they are diagnosed sooner.

                            Last update:
                            November 2014

                            - Expert reviewer(s):
                            Dr Run YU