An inherited lethal mitochondrial disorder characterized by fetal growth restriction (GR), aminoaciduria (A), cholestasis (C), iron overload (I), lactacidosis (L), and early death (E).

Summary:
Epidemiology
The typical GRACILE syndrome is prevalent in Finland, where it has an incidence of about 1/50,000 births. It has also rarely been found in Sweden and the U.K.
Clinical description
Fetal growth restriction appears early during the pregnancy without signs of chronic hypoxia. Because of small fetal size, the pregnancies are usually interrupted a few weeks before the estimated due date (median 38 gestational weeks). The newborn infant is small for gestational age (birth weight approximately 1,700 g) and develops fulminant lactic acidosis (median pH 7.02, lactate 12.8 mmol/l) during the first day of life. In metabolic screening, marked aminoaciduria is found due to renal proximal tubulopathy of Fanconi type. Iron overload is illustrated by increased plasma ferritin and decreased transferrin concentrations and accumulation of iron in the liver. Further signs of hepatopathy are cholestasis with steatosis, fibrosis and cirrhosis. No dysmorphic features are noted. No distinct cerebral abnormalities have so far been found, however in some infants, EEG has been abnormal, maybe as a result of severe metabolic acidosis. The hearing response assessed with BAEP has been abnormal.
Etiology
GRACILE syndrome is caused by a mutation in BCS1L, located on chromosome 2q35, encoding a protein essential in the assembly of complex III in the mitochondrial respiratory chain. In Finnish patients, the disease is caused by one homozygous mutation (c.232A>G) leading to an amino acid change (Serine on position 78 to Glycine) in the BCS1L protein. Several recently discovered mutations in the gene can cause variable phenotypes ranging from neonatal GRACILE-like hepatopathy and tubulopathy to those presenting during infancy or childhood with encephalopathy and psychiatric disorders.
Diagnostic methods
GRACILE syndrome is suspected if an infant is severely small for gestational age, develops hypoglycemia and lactic acidosis, has tubulopathy and increased ferritin levels and shows signs of liver dysfunction. Iron overload is illustrated by increased plasma ferritin and decreased transferrin concentrations and accumulation of iron in the liver. In patients of Finnish descent, the diagnosis is confirmed by assessing the single-nucleotide polymorphism (accredited method in HUS-LAB, Helsinki). In other patients, the entire BCS1L gene should be sequenced. Respirometry should be performed in a mitochondrial laboratory.
Differential diagnosis
Other mitochondrial hepatopathies such as Pearson syndrome should be excluded. Disorders of mitochondrial fatty acid oxidation and Krebs cycle disorders may also mimic GRACILE syndrome.
Antenatal diagnosis
In families with a previous case of GRACILE syndrome or renal tubulopathy, encephalopathy, liver failure, the causative BCS1L mutation can be investigated antenatally.
Genetic counseling
GRACILE syndrome is inherited autosomal recessively so genetic counseling should be offered to affected families. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.
Management and treatment
There is no cure for the disease and treatments are purely symptomatic. Infants require intensive care, including alkali therapy and supplementation of urinary losses. Lactic acidosis responds only slightly to treatment.
Prognosis
The prognosis is life threatening with half of infants decease during the first days of life and the other half not living past 4 months of age, mainly because of energy depletion.

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Pr Vineta FELLMAN


A rare disease that occurs after allogeneic hematopoietic stem cell transplant and is a reaction of donor immune cells against host tissues. Activated donor T cells damage host epithelial cells after an inflammatory cascade that begins with the preparative regimen.

Summary:
Epidemiology
About 35%-50% of hematopoietic stem cell transplant (HSCT) recipients will develop acute Graft versus host disease (GVHD). Given the number of transplants performed, it is estimated that about 5500 patients/year will develop acute GVHD.
Clinical description
Three organs are involved: the skin (rash/dermatitis), liver (hepatitis/jaundice), and gastrointestinal tract (abdominal pain/diarrhea). Either one or more of these organs may be affected.
Etiology
The exact risk is dependent on the stem cell source, age of the patient, conditioning, and GVHD prophylaxis used.
Diagnostic methods
GVHD is a clinical diagnosis that may be supported with appropriate biopsies. The reason to pursue a tissue biopsy is to help differentiate from other diagnoses which may mimic GVHD, such as a viral infection (hepatitis, colitis) or drug reaction (causing skin rash). Acute GVHD is staged and graded (grade 0-IV) by the number and extent of organ involvement.
Management and treatment
Generally the patient is treated by optimizing immunosuppression and adding methylprednisolone to the treatment regimen. About 50% of patients will have a solid response to methylprednisolone. If patients progress after 3 days or show no improvement after 7 days, they should receive a salvage (second-line) immunosuppressive therapy for which there is currently no standard-of-care. Well-organized clinical trials are imperative for better defining second-line therapies for this disease. Additional management issues are attention to wound infections in skin GVHD and fluid/nutrition management in gastrointestinal GVHD.
Prognosis
About 50% of patients with acute GVHD will eventually have manifestations of chronic GVHD. Patients with grade III/IV acute GVHD tend to have a poor outcome.

                            Last update:
                            September 2007

                            - Expert reviewer(s):
                            Dr David JACOBSOHN  - Dr Georgia VOGELSANG


A variant of lichen planopilaris characterized by the clinical triad of progressive cicatricial (scarring) alopecia of the scalp, follicular keratotic papules on glabrous skin, and variable alopecia of the axillae and groin.

Summary:
Epidemiology
It is a very rare disease but the exact prevalence is not known. It mainly affects women during adulthood (30-60 years of age).
Clinical description
Scarring alopecia presents as small confluent patches that are atrophic and cicatricial in the center but erythematous and squamous around the edges. Follicular keratosis presents as pruritic, red-brown, follicular spiny papules on the trunk and extremities. Generally, the three clinical features appear simultaneously but in some cases, scalp alopecia precedes the follicular keratosis.
Etiology
Etiology is unknown.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Stephanie ARNOLD  - Dr Susan COOPER


A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by early onset of hypertension and multifocal stenotic lesions of various arteries (including cerebral, renal, abdominal, and coronary). Variable additional features include learning difficulties, mild facial dysmorphism, anomalies of the fingers and toes, bone fragility, and congenital heart defects.


Grant syndrome is a rare osteogenesis imperfecta-like disorder, described in two patients to date, characterized clinically by persistent wormian bones, blue sclera, mandibular hypoplasia, shallow glenoid fossa, and campomelia. There have been no further descriptions in the literature since 1986.


Type I granular corneal dystrophy (GCDI) is a rare form of stromal corneal dystrophy (see this term) characterized by multiple small deposits in the superficial central corneal stroma, and progressive visual impairment, which may sometimes be severe.

Summary:
Epidemiology
Prevalence of this form of corneal dystrophy is not known. GCDI appears to be more prevalent in Europe than in other regions.
Clinical description
Lesions appear within the first decade of life and may be evident by 3 years of age. Early symptoms include glare and photophobia that usually start before the end of the first decade of life. Visual acuity decreases as opaciﬁcation progresses with age. Recurrent erosions are seen frequently. Homozygotes have more severe manifestations.
Etiology
GCDI is caused by a p. Arg555Trp mutation in the multifunctional TGFBI gene (5q31).
Diagnostic methods
Lesions resemble white, discrete, irregularly-shaped, sharply-demarcated spots in the stroma.
Differential diagnosis
The appearance of the granular deposits in GCDI differs from those in GCDII and unlike GCDII, amyloid deposits do not occur. The features of GCD may be very similar to the corneal features of monoclonal gammopathies (see these terms).
Genetic counseling
Both forms of GCD usually follow an autosomal dominant pattern of inheritance, but sporadic de novo mutations have been reported.
Management and treatment
When indicated, a penetrating keratoplasty is the ideal form of therapy.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Dr Gordon KLINTWORTH


Type II granular corneal dystrophy (GCDII) is a rare form of stromal corneal dystrophy (see this term) characterized by irregular-shaped well-demarcated granular deposits in the superficial central corneal stroma, and progressive visual impairment.

Summary:
Epidemiology
Prevalence of this form of corneal dystrophy is not known. GCDII appears to be more prevalent in Japan, Korea and the USA.
Clinical description
Lesions appear within the first decade of life and may be evident by 3 years of age. Onset is generally earlier in homozygous patients. Pain may accompany mild corneal erosions. Visual acuity usually remains good until late in the course of the condition. The course is slowly progressive but homozygotes may demonstrate more rapid progression.
Etiology
GCDII is caused by a p. Arg124His mutation in the TGFBI gene (5q31).
Diagnostic methods
Opacities are initially small superficial whitish dots. Subsequently, ring or stellate-shaped stromal opacities develop. Final-stage opacities are more superficial and translucent, and may coalesce in the anterior stroma.
Differential diagnosis
Deposits are less numerous than in type I granular corneal dystrophy, and are sometimes lattice-like linear deposits and may superficially resemble lattice corneal dystrophy (see these terms). The features of GCD may be very similar to the corneal features of monoclonal gammopathies (see these terms).
Genetic counseling
Both forms of GCD usually follow an autosomal dominant pattern of inheritance, but sporadic de novo mutations have been reported.
Management and treatment
A penetrating keratoplasty is usually indicated, but superficial stromal opacities can sometimes be ablated without the removal of the entire cornea.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Dr Gordon KLINTWORTH


A rare anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis characterized by necrotizing inflammation of small and medium vessels (capillaries, venules and arterioles), resulting in tissue ischemia.

Summary:
Epidemiology
The prevalence is estimated between 1/6,400 - 42,000 worldwide with annual incidence between 1/84,000-475,000. There is geographic and/or ethnic variation, with a higher incidence in colder regions and among Caucasians. Childhood-onset disease is characterized by female predominance, and adult-onset by a slight male predominance.
Clinical description
The average age of onset is 45 years but the disease may manifest at any age including childhood. The disease may present with various organ manifestations. Ear, nose and throat symptoms are present in 50-95% (persistent nasal obstruction, destructive sinusitis, crusting and/or hemorrhagic rhinitis, nasal septum deformity, saddle nose deformity, and otitis media), bronchopulmonary symptoms in 60-80% (nodules, alveolar hemorrage, bronchial and/or subglottic stenosis), and renal disease (typically extra-capillary necrotizing glomerulonephritis) in 60-80% of affected individuals. General signs (fever, arthralgia, myalgia, weight loss) are common. Skin lesions (purpura and cutaneous nodules) are observed in 10-50%, peripheral neuropathy (multineuritis) in 25%, central nervous system manifestations (headaches, sensorimotor deficit, hemiplegia and epilepsy) in 10%, and ocular anomalies (scleritis and orbital tumors) in 7-8% of patients.
Etiology
The pathogenesis of GPA is still under study. Genetic susceptibility factors, environmental agents, infectious episodes and anomalies in innate and adaptive immunity seem to play a role in the development of all ANCA-associated vasculitides. Genetic variants appear to correlate with antineutrophil cytoplasmic antibody (ANCA) antigen specificity rather than with clinical phenotype. Thus, cytoplasmic-ANCAs directed to proteinase 3 (PR3-ANCA), found in 60-80% of GPA cases, are associated with genetic variants in HLA-DP1A and HLA-DP1B (6p21.32) which encode a class II major histocompatibility complex, SERPINA1 (14q32.13) encoding alpha-1 antitrypsin, and PRTN3 (19p13.3) encoding the autoantigen proteinase 3.
Diagnostic methods
Diagnosis relies on clinical findings, imaging studies and biochemical testing, and detection of ANCAs in the serum, principally PR3-ANCAs. Histological analysis of biopsy specimens from affected organs confirms the diagnosis, showing necrotizing vasculitis and granulomatous inflammation.
Differential diagnosis
Differential diagnoses include other ANCA-associated vasculitides such as microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis.
Management and treatment
Induction therapy comprises steroid pulses combined with either intravenous Rituximab or Cyclophosphamide. Disease remission is achieved in more than 80% of patients with these protocols. In cases of lacking or insufficient response, plasma exchange can be considered. Azathioprine and Methotrexate are efficacious agents for maintenance immunosuppression whereas Mycophenolate-Mofetil is less effective. Leflunomide is an alternative option for individuals intolerant to Azathioprine or Methotrexate. Anti-TNF antibodies (e.g. Infliximab and Adalimumab) have shown promising results in clinical trials as steroid-sparing agents.
Prognosis
While remission is achieved with treatment in 70-100% of cases, the disease relapses in more than 80% of patients within 10 years. Significant morbidity may emerge both from the disease and its treatment. Ten-year patient survival is around 75%.

                            Last update:
                            January 2019

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

                                * European Reference Network


A rare gynecologic or obstetric disease characterized by a painful, palpable breast mass with relative sparing of the subareolar regions, often associated with inflammation of the overlying skin and accompanied by axillary lymphadenopathy. It usually occurs in young parous women with a history of breast-feeding. The diagnosis of idiopathic granulomatous mastitis requires that other granulomatous lesions in the breast be excluded.


Granulomatous slack skin (GSS) is a variant of mycosis fungoides (MF; see this term), a form of cutaneous T-cell lymphoma, and is characterized by the presence of circumscribed areas of pendulous lax skin.

Summary:
Epidemiology
Less than 50 cases have been reported in the literature so far. GSS predominantly affects males (sex ratio: 2.9:1).
Clinical description
Onset usually occurs in adulthood. The disease is characterized by the slow development of large areas of pendulous, lax skin in the major skin folds (axillae and groins). Although GSS is considered as a variant of MF, an association with Hodgkin lymphoma was observed in approximately one-third of the reported patients.
Etiology
The etiology is unknown. A chromosomal translocation, t(3;9)(q12;p24), was found in one case.
Diagnostic methods
The diagnosis is based on typical clinical findings and on histologic features revealing a dermal infiltrate of T-cells (with a CD3+, CD4+ and CD8- phenotype) with granulomatous features and the presence of multinucleated giant cells. Molecular analyses reveal a monoclonal rearrangement of the T-cell receptor genes.
Differential diagnosis
Acquired cutis laxa (see this term) can be differentiated from granulomatous slack skin by histological examination.
Management and treatment
No reliable treatment exists. Surgical excision of the pendulous skin folds is usually performed, but is only palliative and recurrence is the rule. Radiotherapy has been used in some patients. A variety of other therapies (mostly treatments for MF) have been tested in anecdotal cases with variable success.
Prognosis
Most patients have an indolent clinical course.

                            Last update:
                            June 2009

                            - Expert reviewer(s):
                            Pr Lorenzo CERRONI


Gray platelet syndrome (GPS) is a rare inherited bleeding disorder characterized by macrothrombocytopenia, myelofibrosis, splenomegaly and typical gray appearance of platelets on Wright stained peripheral blood smear.

Summary:
Epidemiology
Exact prevalence of the disorder is not known. About 60 cases from various populations around the world have been described in the literature to date. It affects males and females equally.
Clinical description
Onset of clinical symptoms is generally in the neonatal period or in early childhood while age of diagnosis is variable. Presenting features include low platelet counts, easy bruising (petechiae), prolonged bleeding and epistaxis. Patients often have myelofibrosis and splenomegaly. Bleeding tendency is usually mild to moderate in GPS patients with mild thrombocytopenia. However, thrombocytopenia and myelofibrosis in GPS are progressive in nature; GPS may result in fatal hemorrhage especially in adulthood when platelet counts are further decreased. Female patients may develop menorrhagia.
Etiology
GPS is caused by mutations in the NBEAL2 gene. Absence or marked reduction of alpha-granules in platelets underlie the disorder. Alpha-granules are the most abundant vesicles in platelets and store proteins that promote platelet adhesiveness and wound healing when secreted during platelet activation.
Diagnostic methods
Diagnosis is based on clinical findings and requires demonstration of absence or marked reduction of alpha-granules by electron microscopy (EM). Absence of alpha-granules is an isolated finding in GPS; dense bodies and other platelet organelles and polymorphonuclear leukocytes are normal on EM. Peripheral smears show typical large, pale gray platelets. Most patients also have high serum vitamin B12 levels. Bone marrow sampling is not required for diagnosis of GPS, but might be needed to evaluate myelofibrosis occurring in GPS and to exclude other disorders.
Differential diagnosis
Differential diagnosis includes other platelet disorders such as macrothrombocytopenias (Bernard-Soulier syndrome, MYH9-related thrombocytopenia, macrothrombocytopenia with mitral valve insufficiency, Mediterranean macrothrombocytopenia), idiopathic thrombocytopenic purpura (ITP) (see these terms), as well as other disorders with hypogranular or gray platelets such as myelodysplastic syndrome (MDS, see this term), myocardial infarction, other causes of hypersplenism, and congenital conditions such as alpha-delta granule deficiency, white platelet syndrome and Quebec platelet disorder (see these terms). Electron microscopy of platelets differentiates GPS from the autosomal dominant variant and from the X-linked variant described as X-linked thrombocytopenia with thalassemia, caused by mutations in GATA1 gene (see this term). These variants display abnormalities not limited to alpha-granules.
Antenatal diagnosis
Prenatal diagnosis is possible if the NBEAL2 mutation has been identified in the family.
Genetic counseling
GPS is inherited in an autosomal recessive manner (autosomal dominant inheritance has been reported in only 1 family). Siblings of an affected patient are at 25 % risk for GPS, while the risk for offspring of a GPS patient is not significantly higher than for the general population.
Management and treatment
There is no specific treatment but management involves anticipating and preventing risks of bleeding (e.g. possible platelet transfusions before surgery). Treatment may include administration of desmopressin. Splenectomy should be considered to increase the platelet counts in patients whose platelet counts decrease to approximately 30,000/microliter.
Prognosis
Prognosis is generally good early in life when thrombocytopenia is mild. GPS patients with platelet counts less than 30,000/microliter are at risk for life-threatening bleeding.

                            Last update:
                            October 2011

                            - Expert reviewer(s):
                            Dr William GAHL  - Dr Meral GUNAY-AYGUN


Grayson-Wilbrandt corneal dystrophy (GWCD) is an extremely rare form of corneal dystrophy characterized by variable patterns of opacification in the Bowman layer of the cornea which extend anteriorly into the epithelium with decreased to normal visual acuity.

Summary:
Epidemiology
Prevalence of this form is unknown and the existence of GWCD as a distinct entity is questionable. Only one incompletely studied family has been reported.
Clinical description
Onset is in the first to second decade of life. Patients develop painful erosions that are less severe than those in Reis-Bücklers corneal dystrophy and Thiel-Behnke corneal dystrophy (see these terms). Visual acuity is normal or sometimes slightly decreased. The condition has a progressive course.
Etiology
The etiology is unknown but is thought to be genetic.
Diagnostic methods
On slit-lamp examination, Bowman layer demonstrates variable patterns of opacification from diffuse mottling to diffuse gray-white opacities, which extend anteriorly into the epithelium. The cornea between the deposits is clear.
Genetic counseling
An autosomal dominant pattern of inheritance has been reported.
Management and treatment
A superficial keratectomy or penetrating keratoplasty can improve vision.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Dr Gordon KLINTWORTH


Greenberg dysplasia is a very rare lethal skeletal dysplasia characterized by fetal hydrops, short limbs and abnormal chondro-osseous calcification. The disease is characterized by early in utero lethality and affected fetuses are considered as nonviable.

Summary:
Epidemiology
Less than ten cases have been published so far.
Clinical description
The main features include fetal hydrops, severe short-limbed dwarfism and a marked disorganization of chondro-osseous calcification. Unusual facial features, cystic hygroma, incomplete lung lobation, pulmonary hypoplasia, extramedullary hematopoiesis, intestinal malrotation and polydactyly may occur.
Etiology
The causative gene has been recently identified as that encoding the lamin B receptor (LBR gene), a member of the sterol reductase family. Mutations in LBR have also been reported to cause Pelger-Huët anomaly (PHA), but in this case transmission occurs in an autosomal dominant manner. PHA is characterized by hypolobulated granulocyte nuclei and abnormal chromatin structure in granulocytes. It has been suggested that homozygous LBR mutations result in distinct mild (PHA homozygosity) or severe (Greenberg skeletal dysplasia) phenotypes based on allelic heterogeneity.
Diagnostic methods
Radiologic abnormalities include a distinctive 'moth-eaten'' appearance of the long bones, marked platyspondyly with multiple abnormal ossification centers, ectopic ossification of the ribs, sternum, pelvis and epiphysis, and deficient ossification of the skull. Histological characterization shows marked disorganization of the cartilaginous architecture, with absence of cartilage column formation, nodular calcifications in cartilage and islands of cartilage surrounded by bone. Greenberg dysplasia has been shown to be associated with an abnormality of cholesterol biosynthesis.
Differential diagnosis
Greenberg dysplasia should be considered in differential diagnosis of cases with severe fetal hydrops (see this term) and phokomelia on antenatal sonography.
Antenatal diagnosis
Prenatal ultrasound diagnosis at 20 weeks of gestation will usually reveal the polyhydramnios, hydrops fetalis, severely short limbs, and cystic hygroma. Sterol profile analysis may be a useful diagnostic tool and can be used for prenatal diagnosis, as can molecular analysis if the mutation in the family is known.
Genetic counseling
It is inherited as an autosomal recessive trait.

                            Last update:
                            November 2007

                            - Expert reviewer(s):
                            Pr Raoul HENNEKAM


A rare developmental defect during embryogenesis with digit duplication, polydactyly, syndactyly, and/or hyperphalangy characterized by multiple congenital anomaly syndrome.

Summary:
Epidemiology
The precise estimates of birth prevalence are difficult to determine, as ascertainment is erratic (estimated range 1-9/1,000,000).
Clinical description
The primary findings include widely spaced eyes, macrocephaly with frontal bossing, and pre- or post-axial polydactyly and cutaneous syndactyly. The polydactyly is most commonly preaxial in the feet and postaxial in the hands, with variable cutaneous syndactyly, but the limb findings vary significantly. Other low frequency findings include central nervous system (CNS) anomalies, hernias, and cognitive impairment.
Etiology
GCPS is caused by loss of function on chromosome 7p14.1 in the transcription factor gene GLI3.
Diagnostic methods
Clinical diagnosis is challenging because the findings of GCPS are relatively non-specific, and no specific and sensitive clinical criteria have been delineated. A presumptive diagnosis of GCPS can be made if the patient has the classic triad of preaxial polydactyly with cutaneous syndactyly of at least one limb, hypertelorism, and macrocephaly. Individuals with a phenotype consistent with GCPS (but which may not manifest all three attributes listed above) and a GLI3 pathogenic variant may be diagnosed definitively with GCPS. In addition, individuals with a GCPS-consistent phenotype who are related to a definitively diagnosed family member in a pattern consistent with autosomal dominant inheritance may also be diagnosed definitively.
Differential diagnosis
Differential diagnoses include preaxial polydactyly type 4, the GCPS contiguous gene syndrome, acrocallosal syndrome, Gorlin syndrome, Carpenter syndrome, and Teebi syndrome. The disorder is allelic to Pallister-Hall syndrome and one form of the acrocallosal syndrome.
Antenatal diagnosis
Antenatal molecular diagnosis is technically feasible.
Genetic counseling
The disorder is inherited in an autosomal dominant manner. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the pathogenic variant to offspring.
Management and treatment
Treatment of the disorder is symptomatic, with plastic or orthopedic surgery indicated for significant limb malformations.
Prognosis
The prognosis for is generally excellent. There may be a slight increase in the incidence of developmental delay or cognitive impairment. Patients with large deletions that include GLI3 may have a poorer prognosis.

                            Last update:
                            January 2020

                            - Expert reviewer(s):
                            Dr Leslie BIESECKER


GRFoma is a type of pancreatic endocrine tumor (see this term) that hypersecretes growth hormone-releasing factor (GRF or GHRH) and that clinically resembles a pituitary adenoma (see this term) as patients present with acromegaly. In addition to the pancreas, this tumor can also occur in the lungs or small intestine, are usually large > 6cm and approximately 1/3 have metastasized at the time of diagnosis. It often co-occurs with Zollinger-Ellison syndrome or multiple endocrine neoplasia type 1 (MEN 1; see these terms).


GRIN2B-related developmental delay, intellectual disability and autism spectrum disorder

A rare genetic syndromic intellectual disability characterized by infantile or childhood onset of mild to profound developmental delay and intellectual disability in all affected individuals, as well as variable occurrence of epilepsy, autism spectrum disorder / behavioral issues, microcephaly, muscle tone abnormalities such as hypotonia and spasticity, dystonic, dyskinetic, or choreiform movement disorder, and cortical visual impairment. Brain MRI may reveal abnormal cortical development, hypoplastic corpus callosum, enlarged/dysplastic basal ganglia, and hippocampal dysplasia.


A rare subtype of Griscelli syndrome characterized by pigmentary dilution in skin and hair with irregular clumps of pigment in hair shafts resulting in silvery hair, in association with increased susceptibility to recurrent infections and immunological abnormalities, in particular impairment of T-cell and natural killer cytotoxic activity eventually leading to hemophagocytic lymphohistiocytosis. Patients may present neurological manifestations related to infiltration of the central nervous system in the context of the hemophagocytic syndrome. The disease is mostly fatal in the first decade of life.


Griscelli syndrome (GS) is a rare cutaneous disease characterized by a silvery-gray sheen of the hair and hypopigmentation of the skin, which can be associated to primary neurological impairment (type 1), immunologic impairment (type 2) or be isolated (type 3).

Summary:
Epidemiology
To date, approximately 150 cases have been reported, predominantly in Turkish and Mediterranean populations. GS type 2 appears to be the most common of the three known types, while GS type 3 is the least common.
Clinical description
GS occurs in infancy to childhood. In addition to the silvery-gray sheen of the hair and the light-colored skin, GS type 1 patients present with delayed motor development, intellectual disability and hypotonia. GS type 2 patients have the same hypopigmentation features but in association with immune pathology. Patients exhibit a lymphocyte cytotoxic defect resulting in an uncontrolled T-lymphocyte and macrophage-activation syndrome, also known as hemophagocytic syndrome (HLH), in which activated T cells and macrophages infiltrate the lymph nodes and other organs (including the brain), producing hemophagocytosis. Patients with GS type 2 can present neurological symptoms due to brain infiltration by the activated hematopoietic cells. In GS type 3 patients, hypopigmentation of the skin and hair is the only feature.
Etiology
GS type 1 is caused by a mutation in the myosin Va (MYO5A) gene located on chromosome 15q21 and likely corresponds to Elejalde disease. GS type 2 is caused by mutations in the RAB27A encoding gene. Myosin-5a and RAB27A genes have been localized to the same chromosomal 15q21 region and encode for proteins which are key effectors of intracellular vesicular transport. Myosin Va regulates organelle transport in both melanocytes and neuronal cells, whereas RAB27A, regulates exocytic pathways, especially the cytotoxic granule exocytosis. The cytotoxic defect caused by RAB27A mutations is responsible for the hemophagocytic syndrome observed. GS type 3 is due to mutations in the MLPH gene, a gene encoding melanophilin, which forms a protein complex with Rab 27a and myosin Va, and participates in melanosome transport in melanocytes.
Diagnostic methods
The diagnosis of the three types of GS can be established by the clinical signs and light microscopic examination, evidencing large clumps of pigment in hair shafts and the accumulation of mature melanosomes in melanocytes. A decrease in T and NK lymphocyte degranulation and cytotoxicity characterize GS type 2. No immunological or cytotoxic defects have been observed in GS type 1 or 3. Thus, based on the patient's clinical and biological features, sequencing of the corresponding causative gene allows confirmation of the type of GS.
Differential diagnosis
GS can be distinguished from Chediak-Higashi syndrome by the lack of giant granules in granulocytes of GS patients. The differential diagnosis of GS type 1 also includes Elejalde disease.
Antenatal diagnosis
Antenatal diagnosis of GS type 1 and 2 can be performed through chorionic villus sampling by the sequencing of the MYO5A or RAB27A gene, respectively.
Genetic counseling
GS is an autosomal recessive disorder and genetic counseling informing affected couples of a 25% risk of having an affected child is possible.
Management and treatment
Treatment for GS type 1 is only symptomatic. In GS type 2, the hemophagocytic syndrome is often fatal and the only cure is hematopoietic stem cell transplantation (HSCT). Currently there is no specific management for GS type 3.
Prognosis
If not treated by HSCT, the prognosis for long-term survival in GS type 2 is relatively poor, with many patients not surviving the first decade. The prognosis of GS type 1 is good. GS type 3 should be better considered as a pigmentation phenotype rather than a pathology with a prognosis similar to the control population.

                            Last update:
                            November 2018

                            - Expert reviewer(s):
                            Dr Geneviève DE SAINT-BASILE - CHAZELAS


A rare neoplastic disorder characterized by benign metastatic masses increasing in size and number after chemotherapy for non-seminomatous germ cell tumors of testis or ovary. It may present at any time after chemotherapy, with a median occurrence within 24 months after treatment completion. Per definition, the resected specimen exclusively contains mature teratoma components, and serum tumor markers have normalized. The retroperitoneum is the most common site, although almost any other localization has been reported. Increased tumor size may cause mechanical compression of vital organs, with renal dysfunction, bowel ischemia, and biliary obstruction as major complications.


Growth and developmental delay-hypotonia-vision impairment-lactic acidosis syndrome

A rare, genetic, mitochondrial oxidative phosphorylation disorder characterized by intrauterine growth retardation, microcephaly, hypotonia, vision impairment, speech and language delay and lactic acidosis with reduced respiratory chain activity (typically complex I). Additonal features may include macrocytic anemia, tremor, muscular atrophy, dysmetria and mild intellectual disability.


Growth delay due to insulin-like growth factor I resistance

Growth delay due to IGF-I resistance is characterised by variable intrauterine and postnatal growth retardation and elevated serum IGF-I levels. Addition features include variable degrees of intellectual deficit, microcephaly and dysmorphism (broad nasal bridge and tip, smooth philtrum, thin upper and everted lower lips, short fingers, clinodactyly, wide-set nipples and pectus excavatum).

Summary:
Epidemiology
Prevalence is unknown.
Etiology
IGF-I resistance may be caused by a variety of genetic defects: ring chromosome 15, distal heterozygous 15q deletions encompassing the IGF1R gene (15q26.3), or IGF1R gene mutations. Intellectual deficit is pronounced in patients with ring chromosome 15 but varies depending on the size of the deletion and on the functions of other deleted genes in patients with 15q deletions. Partial IGF-I insensitivity due to IGF1R haploinsufficiency has been reported in one patient with a small deletion encompassing one allele of the IGF1R gene and was characterised by small size for gestational age, persistent growth failure that improved considerably with GH therapy, and the absence of intellectual deficit. IGF1R mutations have been described in six patients so far and were associated with variable growth delay and degrees of intellectual deficit.
Diagnostic methods
Diagnosis relies on karyotyping for detection of ring chromosome 15, detection of small deletions encompassing IGF1R and detection of IGF1R mutations by sequence variation screening methods or by direct sequencing of the 21 IGF1R exons and their intron-exon junctions.
Differential diagnosis
The differential diagnosis should include bio-inactive IGF-I resulting in IGF-I deficiency (see this term). Measurement of IGF-I levels can be used for diagnosis but circulating levels of IGF-I may vary over time for the same patient and may not be elevated in case of poor nutritional status.
Antenatal diagnosis
Prenatal diagnosis has not been reported and is complicated by the variable expressivity (even within the same family) of some of the reported mutations, especially in terms of their impact on intellectual development.
Genetic counseling
In all but one of these patients, the mutations were heterozygous and transmitted as an autosomal dominant trait. Affected families should be offered genetic counselling and informed of a 50% risk of recurrence for dominant inheritance and of a 25% risk of recurrence for recessive transmission.
Management and treatment
Management involves nutritional and developmental support. Although deafness has not yet been reported in patients with IGF-I resistance, it is present in some patients with IGF-I deficiency (caused by mutations in the gene encoding the IGF1R ligand, IGFI). As a result, screening for deafness should be proposed for all patients with IGF-I resistance. Some patients with IGF-I resistance show increased growth velocity with recombinant GH therapy while others show no response.
Prognosis
Prognosis varies depending on the underlying molecular anomaly.

                            Last update:
                            May 2008

                            - Expert reviewer(s):
                            Pr Yves LE BOUC  - Pr Irène NETCHINE


Growth delay due to insulin-like growth factor type 1 deficiency

Growth delay due to insulin-like growth factor I deficiency is characterised by the association of intrauterine and postnatal growth retardation with sensorineural deafness and intellectual deficit.

Summary:
Epidemiology
The syndrome is extremely rare and only four cases have been reported in the literature so far.
Clinical description
Addition clinical features include microcephaly, adiposity, and insulin resistance. Partial gonadal dysfunction and osteoporosis may also be present. A case of partial IGF-I deficiency has also been described and was associated with pre- and postnatal growth retardation and microcephaly but the developmental delay was mild and hearing tests were normal.
Etiology
IGF-I deficiency is caused by homozygous mutations in the insulin-like growth factor 1 gene (IGFI; 12q22-q24.1). IGF-I is essential for foetal and postnatal growth, brain development and metabolism.
Diagnostic methods
Diagnosis relies on direct sequencing of the five IGF1 exons and of the intron-exon junctions. Measurement of IGF-I levels can be used for diagnosis but the circulating levels of IGF-I vary between patients (ranging from undetectable, low to very high) depending on the molecular defect present and on the immunoassay used.
Differential diagnosis
The differential diagnosis should include growth hormone deficiency and growth hormone resistance (caused by GH receptor or STAT5b anomalies), growth delay due to insulin-like growth factor I resistance and primary acid-labile subunit (ALS) deficiency syndrome (see these terms), as well as secondary IGF-I deficiency due to nutritional problems.
Antenatal diagnosis
Prenatal diagnosis is feasible for families with an identified IGF1 mutation proven to be responsible for the disease phenotype of intrauterine and postnatal growth delay associated with intellectual deficit.
Genetic counseling
IGF-I deficiency is transmitted as an autosomal recessive trait. Affected families should be offered genetic counselling and informed of a 25% risk of recurrence.
Management and treatment
Management involves nutritional and developmental support, together with screening for deafness. Growth velocity in patients with partial IGF-I deficiency can be increased by recombinant growth hormone (GH) therapy. Recombinant IGF-I therapy can be used in patients with complete IGF-I deficiency or those showing an insufficient response to recombinant GH treatment.

                            Last update:
                            April 2008

                            - Expert reviewer(s):
                            Pr Yves LE BOUC  - Pr Irène NETCHINE


Growth delay-hydrocephaly-lung hypoplasia syndrome

Growth delay - hydrocephaly - lung hypoplasia, also named Game-Friedman-Paradice syndrome, is a rare developmental disorder described in 4 sibs so far and characterized by delayed fetal growth, hydrocephaly with patent aqueduct of Sylvius, underdeveloped lungs and various other anomalies such as small jaw, intestinal malrotation, omphalocele, shortness of lower limbs, bowed tibias and foot deformities.


Growth delay-intellectual disability-hepatopathy syndrome

A rare, genetic, syndromic intellectual disability disease characterized by severe intrauterine and post-natal growth delay, moderate to severe intellectual disability, and neonatal-onset hepatopathy with fibrosis, steatosis, and/or cholestasis, occasionally leading to liver failure. Additional variable manifestations include muscular hypotonia, zinc deficiency, recurrent infections, diabetes mellitus, joint contractures, skin and joint laxity, hypervitaminosis D, and sensorineural hearing loss.


Growth hormone insensitivity syndrome (GHIS) is a group of diseases characterized by marked short stature associated with normal or elevated growth hormone (GH) concentrations, which fail to respond to exogenous GH administration. GHIS comprises growth delay due to IGF-1 deficiency, growth delay due to IGF-1 resistance, Laron syndrome, short stature due to STAT5b deficiency and primary acid-labile subunit (ALS) deficiency (see these terms).

Summary:
Epidemiology
A few cases of IGF-1 deficiency, IGF-1 resistance, STAT5B and ALS deficiencies, and more than 250 cases of Laron syndrome have been reported in the literature so far. Males and females are equally affected.
Clinical description
Intrauterine growth and birth size are usually subnormal. Postnatal growth is slowed. Facial dysmorphism is common and includes microcephaly, thin upper and everted lower lips and small chin. Disproportional growth, delayed motor development and delayed puberty have been described in some cases and relative obesity may occur in young adults. Intellectual development varies from normal intelligence to intellectual deficiency. Despite sharing short stature and the classical biochemical features of GH insensitivity, affected individuals present heterogeneous clinical features depending on the genetic condition. Immune deficiency has been described in some cases of STAT5b deficiency. Hearing loss has been described in some cases of IGF-1 deficiency.
Etiology
GHIS is due to mutations in the growth hormone receptor (GHR) gene (Laron syndrome) or to post receptor defects due to mutations in the IGF-1 (IGF-1 deficiency and IGF-1 resistance), IGFALS (short stature due to primary ALS deficiency) or STAT5B genes (STAT5b deficiency). Transmission is autosomal recessive.
Diagnostic methods
The diagnosis is based on clinical and biological findings. Hormonal tests reveal normal or high serum concentrations of GH. IGF-1 and growth hormone binding protein (GHBP) levels depend on the disease-causing mutations. IGF-1 levels are low in cases ofGHR defects, STAT5b, IGF-1 and ALS deficiencies, and high in cases of IGF-1 resistance. GHBP levels are low in cases of mutations in the extracellular domain of GHR and normal in cases of mutations in the intracellular domain of GHR or post receptor defects. IGF-BP 3 levels are low in cases of GHR, STAT5b, and ALS deficiencies, normal in cases of IGF-1 deficiency. ALS levels are low in cases of ALS deficiencies. Genetic tests should be performed to make a precise etiological diagnosis.
Differential diagnosis
The differential diagnosis should include secondary IGF-1 deficiency due to nutritional problems or chronic pediatric diseases.
Genetic counseling
Genetic counseling should be proposed to parents of an affected individual before any further pregnancy, informing them of the risks and the available diagnostic methods.
Management and treatment
Management aims at improving growth and, except for IGF-1 resistance, includes treatment with daily subcutaneous injections of mecasermin, a recombinant human IGF-1, and diet with adequate caloric intake. In August 2005, mecasermin was granted EC orphan drug designation. Growth hormone treatment may partially improve growth in cases of IGF-1 resistance. There is no treatment that cures or prevents the disease.
Prognosis
With age, osteoporosis can become apparent. Patients may develop obesity, hypercholesterolemia, insulin resistance, glucose intolerance and even type II diabetes.

                            Last update:
                            November 2009

                            - Expert reviewer(s):
                            Pr Juliane LEGER


Growth retardation-mild developmental delay-chronic hepatitis syndrome is a rare, genetic, parenchymatous liver disease characterized by pre- and postnatal growth retardation, mild global developmental delay, chronic hepatitis with hepatosplenomegaly, Hashimoto thyroiditis, thrombocytopenia, anemia, and B-precursor acute lymphoblastic leukemia.


Grubben-de Cock-Borghgraef syndrome is a rare intellectual disability syndrome characterized by pre- and postnatal growth deficiency, generalized muscular hypotonia, developmental delay (particularly of speech and language), hypotrophy of distal extremities, small and puffy hands and feet, eczematous skin and dental anomalies (i.e. small, widely-spaced teeth). Partial agenesis of the corpus callosum and a selective immunoglobulin IgG2 subclass deficiency have also been reported in some patients.


GTP-cyclohydrolase I deficiency, an autosomal recessive genetic disorder, is one of the causes of malignant hyperphenylalaninemia due to tetrahydrobiopterin deficiency. Not only does tetrahydrobiopterin deficiency cause hyperphenylalaninemia, it is also responsible for defective neurotransmission of monoamines because of malfunctioning tyrosine and tryptophan hydroxylases, both tetrahydrobiopterin-dependent hydroxylases.

Summary:
Clinical description
When left untreated, the deficiency causes neurological signs at age 4 or 5 months, although clinical signs are often obvious from birth. The principal symptoms include: psychomotor retardation, tonicity disorders, convulsions, drowsiness, irritability, abnormal movements, hyperthermia, hypersalivation, and difficulty swallowing.
Diagnostic methods
GTP-cyclohydrolase I deficiency should be suspected in all infants with a positive neonatal screening test for phenylketonuria, especially when hyperphenylalaninemia is moderate. The most effective way to diagnose the disorder is to measure pteridine levels in urine and to confirm the result by measuring neurotransmitters (5-hydroxyindolacetic acid, homovanillic acid) in cerebrospinal fluid and with an oral tetrahydrobiopterin-loading test (20 mg/kg).
Management and treatment
The treatment attempts to bring phenylalaninemia levels back to normal (diet with restricted phenylalanine intake or prescription of tetrahydrobiopterin) and to restore normal monoaminergic neurotransmission by administering precursors (L-dopa/carbidopa and 5-hydroxytryptophane).

                            Last update:
                            February 2005

                            - Expert reviewer(s):
                            Pr Jean-Louis DHONDT


Guanidinoacetate methyltransferase (GAMT) deficiency is a creatine deficiency syndrome characterized by global developmental delay/intellectual disability (DD/ID), prominent speech delay, autistic/hyperactive behavioral disorders, seizures, and various types of pyramidal and/or extra-pyramidal manifestations.

Summary:
Epidemiology
Less than 100 patients are known worldwide.
Clinical description
Onset of manifestations of GAMT deficiency occurs between 3 months and 3 years of age. Affected individuals have mild to severe intellectual disability with a distinctive deficit in expressive language, regardless of the degree of the intellectual deficit. Seizures, of different types, are observed in most individuals and are often intractable. Behavioral disorders such as hyperactivity and autistic features are also frequent. Patients may also have movement disorders which mainly affect the extra-pyramidal system and manifest as chorea, athetosis and ataxia.
Etiology
GAMT deficiency is due to mutations in the GAMT gene (19p13.3). Different mutations (missense, nonsense, splice site, insertions, deletions) have been identified, located on various exons of the GAMT gene. The most frequently identified mutation, c.327G>A (p.K109K, splice site exon 2), is present in at least one allele in over 50% of families. c.59G>C is most frequently encountered in Portuguese patients. To date no genotype phenotype correlation has been established.
Diagnostic methods
The diagnosis is clinically suspected in children with DD/ID, speech/language delay, autistic behavior and seizures. Diagnosis is based on the presence of high levels of guanidinoacetate (GAA) in the urine/blood and low levels of creatine in the brain. Diagnosis is confirmed by genetic testing for mutations in the GAMT gene. In case of unknown significance of a gene variant, measurement of GAMT enzyme catalytic activity helps to confirm a functional deficiency. Methods for newborn screening have been established and pilot projects are currently being conducted in various newborn screening programs.
Differential diagnosis
The differential diagnosis in children with a cerebral creatine deficiency includes L-Arginine:glycine amidinotransferase (AGAT) deficiency and X-linked creatine transporter deficiency. In the case of a partial cerebral creatine deficiency, argininosuccinic aciduria, citrullinemia type I, and gyrate atrophy of the choroid and retina (see these terms) should be considered.
Antenatal diagnosis
Preimplantation or prenatal genetic diagnosis is possible for at risk couples.
Genetic counseling
Transmission is autosomal recessive. In case of family history, genetic testing for the family of the proband and genetic counseling with regards to family planning is recommended.
Management and treatment
Treatment consists of oral high dose creatine monohydrate, in combination with ornithine supplementation (100-800mg/kg/day given in 3-6 doses daily) and/or dietary restriction of arginine (15-25mg/kg/day). Management of GAMT deficiency involves regular measurement of plasma guanidinoacetate and ornithine levels. Treatment improves seizures and behavioral and movement disorders, but it cannot reverse intellectual disability and developmental delay incurred before diagnosis. Early detection is essential in avoiding irreversible brain damage.
Prognosis
GAMT deficiency is a treatable disease and is not life threatening, however life expectancy is limited, particularly in those who have multiple disabilities and severe seizures.

                            Last update:
                            December 2014

                            - Expert reviewer(s):
                            Dr Sylvia STOCKLER


A clinically heterogeneous spectrum of rare post-infectious neuropathies that usually occur in otherwise healthy patients and encompasses acute inflammatory demyelinating polyradiculoneuropathy (AIDP), acute motor axonal neuropathy (AMAN) and acute motor-sensory axonal neuropathy (AMSAN), Miller-Fisher syndrome (MFS) and some other regional variants.

Summary:
Epidemiology
The overall annual incidence of GBS varies between 1/91,000 and 1/55,000. In Europe and North America, AIDP is the most frequent form of GBS (accounting for around 90% of cases) and thus the term GBS in general is synonymous with AIDP in Western countries. The axonal forms account for only 3-5% of cases in Western countries but are much more frequent (30%-50% of GBS cases) in Asia and Latin America.
Etiology
In the majority of cases, an infectious disease precedes the onset of limb weakness with Campylobacter jejuni infection being the most frequently identified initiating event. GBS has also been reported to occur after vaccination or following a surgical intervention.
Management and treatment
Treatment consists of rapid administration of intravenous immunoglobulin (IVIg) or plasma exchange (PE). Physiotherapy and rehabilitation are also important.
Prognosis
The prognosis is variable depending on the form of GBS and ranges from patients with complete recovery, to those who are unable to walk 6 months after disease onset, and to patients in whom the disease has a fatal outcome.

                            Last update:
                            December 2009

                            - Expert reviewer(s):
                            Pr P.A. [Pieter] VAN DOORN


Guttmacher syndrome is an extremely rare syndrome characterized by hypoplastic thumbs and halluces, 5th finger clinobrachydactyly, postaxial polydactyly of the hands, short or uniphalangeal 2nd toes with absent nails and hypospadias.

Summary:
Epidemiology
It has been described in a father and his son and daughter.
Clinical description
The affected patients have normal mental development. Except for postaxial polydactyly of the hands and uniphalangeal 2nd toes with absent nails, features are in common with hand-foot-genital syndrome (HFGS, see this term) caused by mutations in the HOXA13 gene.
Etiology
In all three affected individuals with Guttmacher syndrome, two different sequence alterations were identified in HOXA13 gene: a de novo missense mutation and a deletion in the promoter region of the gene, inherited from an unaffected parent, which may contribute to the phenotype in the affected individuals.
Genetic counseling
The condition is inherited in an autosomal dominant manner.

                            Last update:
                            January 2011


Gyrate atrophy of the choroid and retina (GACR) is a very rare, inherited retinal dystrophy, characterized by progressive chorioretinal atrophy, myopia and early cataract.

Summary:
Epidemiology
Prevalence has been estimated to be 1/50,000 in Finland. More than 200 biochemically-confirmed cases have been reported in the international literature. Cases have also been reported from Canada, Germany, Italy, Israel, Japan, the Netherlands and the USA.
Clinical description
Age at diagnosis is highly variable (1 month - 44 years). High phenotypic variability is noted among patients even within the same family, as well variable disease progression. The first complaints of the patients are night blindness (nyctalopia) and constriction of the visual field caused by multiple round areas of chorioretinal atrophy in the periphery. Over the years, the atrophic areas increase, coalesce and spread towards the macula leading to central visual loss in the 4th to 7th decade of life. Other ocular manifestations include myopia with marked astigmatism, early posterior subcapsular cataract, and cystoid macular edema.
Etiology
GACR is caused by homozygous or compound heterozygous mutations in the ornithine aminotransferase OAT gene (10q26) which codes for the ornithine-degrading, pyridoxal phosphate-dependent enzyme ornithine aminotransferase. More than 60 OAT mutations have been identified to date. Deficient OAT enzyme activity results in hyperornithinemia. The exact mechanism leading to chorioretinal atrophy is still unknown.
Diagnostic methods
Diagnosis is based on ophthalmological examination showing the typical sharply demarcated round patches of chorioretinal atrophy located circumferentially in the periphery, and the other clinical manifestations such as myopia and early cataract. Cystoid macular edema can be detected with optical coherence tomography. Fundus autofluorescence is absent in the atrophic areas. The full-field electroretinogram shows severely reduced or undetectable amplitudes even at an early stage of the disease. Serum, urine, and spinal fluid ornithine levels are 10 to 20 times higher than those in healthy subjects. The diagnosis can be confirmed by molecular genetic testing of the OAT gene.
Differential diagnosis
Careful fundoscopy, fundus autofluorescence images and pointed family history help to delimit autosomal recessive GACR from X-chromosomal choroideremia. At the slightest suspicion of GACR, serum ornithine levels should be measured to detect hyperornithinemia.
Genetic counseling
GACR follows an autosomal recessive pattern of inheritance. Genetic counseling should be provided to affected families.
Management and treatment
Patients with GACR should be referred to a diet expert, because several studies report that an arginine-restricted diet (precursor of ornithine) or a low-protein diet may reduce the ornithine serum level and may slow the progression of chorioretinal atrophy and visual loss. Pyridoxine (vitamin B6) supplementation may also be given but most patients appear to be non-responsive. Cataract surgery may be required. In late stages with visual loss, magnifying visual devices should be provided.
Prognosis
The ocular prognosis is poor because constriction of the visual field and visual loss are progressive and can cause blindness. Early diagnosis and successful diet treatment are important prognostic factors.

                            Last update:
                            May 2015


A rare neurocutaneous syndrome characterized by the association of cerebellum (rhombencephalosynapsis), cranial nerves (trigeminal anesthesia), and scalp (alopecia) abnormalities. Other features observed in patients were craniosynostosis, midfacial hypoplasia, bilateral corneal opacities, low-set ears, short stature, moderate intellectual impairment and ataxia. Hyperactivity, depression, self-injurious behaviour and bipolar disorder have also been reported.


A rare cutaneous disease and a systemic inherited histiocytosis mainly characterized by hyperpigmentation, hypertrichosis, hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism, low height, and occasionally, hyperglycemia/diabetes mellitus. Due to overlapping clinical features, it is now considered to include pigmented hypertrichosis with insulin dependent diabetes mellitus syndrome (PHID), Faisalabad histiocytosis (FHC) and familial sinus histiocytosis with massive lymphadenopathy (FSHML). Some cases of dysosteosclerosis may also represent the syndrome.

Summary:
Epidemiology
To date, around 130 patients have been described in the world literature.
Clinical description
H syndrome becomes clinically apparent mostly during childhood, but cases during infancy and late-onset cases have been reported too. Cutaneous features are the most prevalent. Hyperpigmentation, associated with induration and hypertrichosis, usually appears initially on the medial thighs and shins, but may be more extensive. Sensorineural hearing loss is the second most common manifestation. Additional features include heart anomalies, hepatosplenomegaly, lymphadenopathy, insulin dependent diabetes mellitus, hypogonadism (short stature, gynecomastia, delayed puberty, primary amenorrhea), angiopathy (varicosities, dilated lateral scleral vessels, and facial telangiectasias) and genital masses. Exophthalmos (with normal thyroid function), malabsorption (due to pancreatic exocrine insufficiency), renal anomalies, flexion contractions of interphalangeal joints and hallux valgus (with fixed flexion contractures of the toe), and lytic bone lesions as well as osteosclerosis are also seen. Early-onset recurrent febrile episodes, lateral tibial torsion, and hypertriglyceridemia may be observed. Various hematological abnormalities have been described, including microcytic anemia, myelofibrosis and pure red cell aplasia.
Etiology
H syndrome is caused by mutations in SLC29A3 (10q22.2) (encoding a nucleoside transporter, hENT3), which result in defective nucleoside transport functions of hENT3. This leads to histiocytic infiltration of numerous organs. There are no clear genotype-phenotype correlations for SLC29A3 mutations. Four allelic disorders have been described: PHID, FHC, FSHML and dysosteosclerosis. However, since H syndrome encompasses the clinical features of the first three allelic disorders, and all share identical mutations in SLC29A3, these disorders are now considered as the same entity.
Diagnostic methods
Diagnosis is suspected by the pathognomonic cutaneous features. If these are lacking, the constellation of additional findings such as hearing loss, fixed flexion contractures of fingers and toes, short stature and hepatosplenomegaly should raise suspicion for H syndrome. Laboratory tests show extremely elevated erythrocyte sedimentation rate, mild microcytic anemia, and elevated liver enzymes. Hypogonadism (hyper- or hypogonadotropic) and azoospremia may be observed. Histopathological examination of involved skin shows a characteristic dermal and subcutaneous interstitial mononuclear infiltrate, composed mainly of small to medium-sized CD68+S100+CD1a- histiocytes (occasionally with emperipolesis) and fibrosis. Diagnosis is confirmed by genetic screening of SLC29A3.
Differential diagnosis
Differential diagnosis includes Torg-Winchester syndrome, hemochromatosis, POEMS syndrome and Rosaï-Dorfman disease.
Antenatal diagnosis
Prenatal molecular diagnosis is feasible by DNA testing in chorionic villi or amniotic cells.
Genetic counseling
Transmission is autosomal recessive and genetic counseling should be offered to at-risk couples, informing them of the 25% risk to transmit the causal mutation to their offspring. The clinical picture is highly variable, even within affected families.
Management and treatment
Management is mainly supportive. Oral steroids may temporarily improve cutaneous changes in some patients, but are inappropriate for long term use due to side effects. Tocilizumab has been found to be effective in a number of patients. Early screening for sensorineural hearing loss and diabetes mellitus should be performed.
Prognosis
The disease usually runs a variable but progressive course, and early-death has been described.

                            Last update:
                            June 2019

                            - Expert reviewer(s):
                            Pr Abraham ZLOTOGORSKI


Haddad syndrome is a rare congenital disorder in which congenital central hypoventilation syndrome (CCHS), or Ondine syndrome, occurs concurrently with Hirschsprung disease (see these terms).

Summary:
Epidemiology
Birth incidence of Ondine syndrome is 1 in 200,000 live-births and Hirschsprung disease occurs concurrently in 16% of cases.
Clinical description
Intestinal aganglionosis is more extensive, and the gender ratio is 1:1, unlike in classical Hirschsprung disease.
Etiology
Mutations in the PHOX2B gene are found in a significant number of patients with Haddad syndrome.

                            Last update:
                            November 2010


A rare, genetic, chronic epidermal disorder characterized by diffuse bilateral (or, rarely, localized segmental) erythematous plaques with blistering, erosions, maceration, and frequent secondary infection involving the flexural areas.

Summary:
Epidemiology
The prevalence of familial benign chronic pemphigus (FBCP) is unknown, but no significant difference in sex or ethnic frequency has been noted.
Clinical description
Skin lesions starting as flaccid vesicles on erythematous to normal skin, appear during adolescence or more commonly between the age of 20 and 40 years. Large, macerated, exudative plaques of superficial erosions with crusting are usually seen at the time of diagnosis. Further progression to large, vegetative, malodorous plaques with painful fissures can occur. Involvement sites consist of areas of friction and intertriginous regions (including the neck, axillae, groin, perineum, and the submammary area), affected in a symmetric fashion. Additional feature, observed in approximately 70% of patients, is the presence of longitudal white bands in the fingernails. Segmental forms of the disease present as unilateral, linear, patchy or otherwise confined involvement, often in relation to the Blashko lines. FBPC has a chronic course of repeated remissions and relapses. Triggering or exacerbating factors include sweating, friction, ultraviolet radiation, and secondary infections. Postinflammatory hyperpigmentation is a common sequela.
Etiology
FBCP is caused by heterozygous, loss-of-function mutations in the ATP2C1 gene (3q22.1) which encodes the calcium(Ca2+)-transporting ATPase type 2C member 1 protein, an adenosine triphosphate (ATP)-powered, magnesium-dependent Ca2+ pump involved in Ca2+ sequestering inside the Golgi apparatus. The exact mechanism is unknown, but mutations in ATP2C1 result in altered cellular connections within desmosomes and adherens junctions of the epidermis, secondary to high cytosolic Ca2+ levels.
Diagnostic methods
Histopathological analysis of the lesions shows a widespread and often incomplete acantholysis in the suprabasal layer, which produces a characteristic "dilapidated brick wall" appearance. Direct immunofluorescence staining is negative. Family history and molecular analysis of the ATP2C1 can contribute to confirming the diagnosis.
Differential diagnosis
Differential diagnosis includes intertrigo, candidiasis, inverse psoriasis, lichen simplex chronicus, other subtypes of pemphigus (such as pemphigus vegetans), tinea corporis, and Darier disease.
Antenatal diagnosis
Prenatal testing is possible when the pathogenetic variant has been identified in the family, but is a subject of ethical consideration.
Genetic counseling
FBCP is inherited in an autosomal dominant manner with full penetrance and variable expressivity. About one third of cases occur de novo. Somatic mutations underlie segmental forms of the disease. Genetic counseling can inform the affected individuals of the 50% risk of disease occurrence in their children.
Management and treatment
There is no specific therapy, but drying the affected areas and avoiding friction is essential as well as employing measures to prevent bacterial, fungal and viral infections. Topical medical treatment (including antimicrobials, corticosteroids, calcineurin inhibitors and botulinum toxin injections) may alleviate milder symptoms. There is no strong evidence to support the use of systemic therapies although doxycycline and low-dose naltrexone may provide some benefit. For those with refractory disease, more aggressive treatment with laser ablation, dermabrasion and/or surgery may be considered.
Prognosis
The quality of life in patients with FBCP is significantly impaired, but they have a normal life expectancy, and the intensity of the disease usually diminishes with age.

                            Last update:
                            July 2024

                            - Expert reviewer(s):
                            Dr Sung Kyung CHO  - Dr Victoria WERTH


Haim-Munk syndrome (HMS) is characterized by palmoplantar hyperkeratosis, severe early-onset periodontitis, onychogryposis, pes planus, arachnodactyly and acroosteolysis.

Summary:
Epidemiology
HMS is rare with less than 100 cases reported in the literature so far. The majority of reported cases are descendants of a few consanguineous families from a religious isolate in Cochin, India. One unrelated Brazilian patient has also been reported.
Clinical description
HMS presents with severe and extensive skin manifestations. In addition to the marked palmoplantar keratosis, patients have scaly erythematous and circumscribed patches on the elbows, knees, forearms, shins and dorsum of the hands. Severe, early-onset progressive periodontitis that affects both the deciduous and permanent dentitions and presents with gingival inflammation and alveolar bone destruction is a hallmark of the disease. Onychogryposis, arachnodactyly, acroosteolysis and pes planus are additional features that help to distinguish HMS from other forms of palmoplantar hyperkeratosis. A peculiar deformity of the fingers (tapered, pointed phalangeal ends and a claw-like volar curve) is typical. Destructive arthritis of the wrist and shoulder joints has been reported in isolated cases. Patients with HMS have increased susceptibility to infections.
Etiology
HMS is caused by germline mutations in the lysosomal protease cathepsin C (CTSC) gene mapped to chromosome 11q14.1-q14.3. Mutations in the same gene cause the clinically related disorders Papillon-Lefèvre syndrome (PLS) and prepubertal periodontitis (see these terms).
Diagnostic methods
Diagnosis is clinical but can be confirmed by detection of the disease-causing mutation.
Differential diagnosis
Differential diagnosis includes the allelic disorder PLS and disorders with palmoplantar hyperkeratosis and prepubertal periodontitis.
Genetic counseling
HMS is transmitted as an autosomal recessive trait.
Management and treatment
Management of the skin manifestations requires topical emollients, keratolytics (including salicylic acid and urea) and oral retinoids (acitretin, etretinate, and isotretinoin). Periodontitis in HMC is usually unresponsive to traditional periodontal therapies. Patients may benefit from extraction of the primary teeth combined with oral antibiotics and professional tooth cleaning. Synovectomy has been shown to alleviate the inflammation associated with destructive arthritis but may lead to loss in the range of the joint motion.

                            Last update:
                            November 2008

                            - Expert reviewer(s):
                            Pr Agnès BLOCH-ZUPAN


A rare, malignant splenic B-cell lymphoma/leukemia characterized by circulating abnormal lymphocytes with intermediate morphology between prolymphocytes and hairy cells with positive expression of CD11c and negative expression of CD25, CD123 and the BRAFV600E mutation. Manifestations include splenomegaly, elevated white blood cell (WBC) count, hyper-cellular bone marrow and anemia/thrombocytopenia, but no monocytopenia.

Summary:
Epidemiology
Hairy cell leukemia variant (HCL-V) constitutes about 10% to 20% of patients with hairy cell leukemia (HCL) and 0.4% of all lymphoid malignancies. There is a slight male predominance (male/female: 1.6).
Clinical description
HCL-V onset is in adulthood, most frequently in the elderly population (median age: 71 years). Initial manifestations are typically of abdominal discomfort or distension, usually related to splenomegaly, hepatomegaly and manifestations derived from cytopenias such as anemia, bleeding and/or infections. HCL-V is more aggressive and resistant to therapy than classical HCL (HCL-C). A disease closely resembling HCL-V has been described in Japan and has been called the HCL Japanese variant (HCL-Jv).
Etiology
The etiology is unknown but there is no evidence of an association between exposure to carcinogens, radiation or viral infections. P53 dysfunction, due to either monosomy, monoallelic deletion or a TP53 mutation (17p13.1), has been reported in many patients (estimate 30% of patients) as well as mutations in the gene  MAP2K1 (15q22.31) (estimate 50%). The VH gene family, IGHV4-34, appears to be over-expressed, but is also found in other B-cell malignancies. HCL-V is not considered to be biologically related to HCL-C, and HCL-V patients are negative for the BRAF-V600E mutation.
Diagnostic methods
Diagnosis is suspected on physical examination, bone marrow biopsy, and abdominal computed tomography (CT) scan, as well as laboratory tests which show raised white blood cell count (>10×109/l). HCL-V cells do not demonstrate reactivity to annexin A1 and are either weakly positive or negative for tartrate-resistant acid phosphatase (TRAP). HCL-V cells are negative for BRAFV600E mutation. The diagnosis of HCL-V is confirmed by flow cytometry immunophenotyping (positive for CD11C, and negative for CD123 and CD25 with variable expression of CD103, CD19, CD20, and CD22).
Differential diagnosis
Differential diagnosis includes splenic marginal zone lymphoma, splenic diffuse red pulp lymphoma (SRPL), HCL-C, mantle-cell lymphoma, and B-cell prolymphocytic leukemia (B-PLL).
Management and treatment
Asymptomatic patients with moderate splenomegaly and no cytopenias may be managed with close monitoring. Therapy is indicated for symptomatic disease (progressive splenomegaly and/or elevated lymphocyte counts with cytopenias). There are no formal guidelines for management and treatment, and information on the efficacy of the various agents is derived from the results on small series of patients or single case reports with limited follow-up. Splenectomy has been utilized in some patients resulting in improvement in anemia and thrombocytopenia; however, the response eventually results in progressive disease. A combination of purine analog (cladribine) and a monoclonal anti-CD20 antibody has resulted in complete remission in patients treated (although follow-up is limited). Immunotherapy alone may be considered and include rituximab (successful treatment in several case reports), and anti-CD22 recombinant immunotoxins (response observed in a limited number of patients but relapse reported). Treatment with interferon alpha and purine analogs alone is unsatisfactory and fails to achieve a durable, high complete remission rate.
Prognosis
HCL-V is an aggressive disorder with a chronic clinical course. The reported survival at five years is approximately 60%; however, complete remission has been reported, in particular with combined purine analog and rituximab treatment or immunotherapy alone. In general, significant anemia, older age, and mutations in TP53 are associated with a worse prognosis.

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Dr Michael GREVER


A rare autosomal dominant skeletal disorder, characterized by progressive bone resorption in the distal phalanges (acro-osteolysis), progressive osteoporosis, distinct craniofacial changes, dental anomalies, and occasional association with renal abnormalities.

Summary:
Epidemiology
Less than 100 cases are confirmed to date.
Clinical description
Whilst affected individuals may appear normal at birth and during infancy, minor facial abnormalities, such as a small mandible, may come to clinical attention in half of affected infants. With age, affected children develop facial dysmorphism (dolicho-bathrocephaly, coarse hair, synophrys, hypertelorism, downslanting palpebral fissures, low set ears, midface flattening, long philtrum, and micrognathia). The fontanels are delayed in closure. Short stature manifests in early childhood and is progressive, presumably due to vertebral compression. Acroosteolysis becomes manifest between preschool age and mid-childhood and clinically presents as short finger tips and nails with pseudoclubbing. Osteoporosis is evident even in childhood, but is conspicuously progressive in late adolescent to adulthood, leading to biconcave codfish vertebrae and kyphoscoliosis. Bone weakness at the craniovertebral junction causes platybasia and basilar invagination, resulting in syringomyelia, hydrocephalus and neurologic deficits. Dental anomalies include severe crowding, periodontitis, and premature loss of teeth. Some patients are at potential risk of renal failure due to multiple renal cysts. Serpentine fibula-polycystic kidney syndrome (SFPKS) is the most severe manifestation of Hajdu-Cheney syndrome, which manifests with bent (serpentine) fibulae and radii as well as congenital renal cysts.
Etiology
The disorder is caused by heterozygous pathogenic variants in the NOTCH2 gene mapped on 1p12 and encoding the neurogenic locus notch homolog protein 2 (Notch2). All known disease-causing variants are located in exon 34, and cause abnormally increased Notch2 signaling (gain-of-function). Of note, pathogenic variants in NOTCH2 also cause a different malformation syndrome, Alagille syndrome type 2.
Diagnostic methods
The diagnosis is made on clinical and radiological grounds, and is confirmed by molecular detection of pathogenic variants in the NOTCH2 gene.
Differential diagnosis
The facial abnormalities are commonly misdiagnosed with Noonan syndrome in infancy and early childhood. The differential diagnosis includes genetic syndromes with pediatric acroosteolysis, such as pyknodysostosis, mandibuloacral dysplasia, as well as congenital insensitivity to pain.
Antenatal diagnosis
Prenatal diagnosis is theoretically possible in affected families in which the causal NOTCH2 variant has been previously identified. The fetal manifestation of SFPKS can be detected on prenatal ultrasonography.
Genetic counseling
The pattern of inheritance is autosomal dominant. The offspring of an affected individual is at a 50% risk of having the pathogenic variant in NOTCH2. However, most cases are sporadic in occurrence.
Management and treatment
Only symptomatic treatment is available for the specific symptoms. Bisphosphonate therapy is beneficial for osteoporosis, though it is not helpful for acroosteolysis. Individuals with renal failure require the standard medical intervention. Regular dental examinations are important.
Prognosis
The life expectancy of patients is not severely impaired. Osteoporosis and associated fractures cause significant morbidity. Basilar invagination occasionally leads to syringomyelia and seldom hydrocephalus. Dental management is important for the quality of life.

                            Last update:
                            June 2021

                            - Expert reviewer(s):
                            Dr Soren FAERGEMAN | ITHACA* - Dr Pernille GREGERSEN | ITHACA* - Dr Gen NISHIMURA

                                * European Reference Network


Hall-Riggs syndrome is a very rare syndrome consisting of microcephaly with facial dysmorphism, spondylometaepiphyseal dysplasia and severe intellectual deficit.

Summary:
Epidemiology
Eight cases have been reported in the literature in two unrelated families.
Clinical description
Dysmorphic features include hypertelorism, depressed nasal bridge, large nose with a large nasal tip, anteverted nostrils and wide mouth with thick lips. Affected patients do not achieve language ability.
Genetic counseling
The condition is probably hereditary, and transmitted as an autosomal recessive trait.

                            Last update:
                            January 2010


Hallermann-Streiff syndrome is a rare genetic syndrome characterized mainly by head and facial abnormalities such as bird-like facies (with beak-shaped nose and retrognathia), hypoplastic mandible, brachycephaly with frontal bossing, dental abnormalities (e.g. absence of teeth, natal teeth, supernumerary teeth, severe agenesis of permanent teeth, enamel hypoplasia) hypotrichosis, various ophthalmic disorders (e.g. congenital cataracts, bilateral microphthalmia, ptosis, nystagmus) and atrophy of skin (especially around the center of face and nose) as well as telangiectasia and proportionate short stature. Intellectual disability is reported in some cases.


A rare genetic bone development disorder characterized by multiple congenital fractures, slender ribs and long bones, deficient ossification of the skull, and dysmorphic facial features reminiscent of Hallermann-Streiff syndrome (such as high forehead and triangular face with small jaw, deep-set eyes, beaked, narrow nose, downturned mouth, and posteriorly angulated ears). Bilateral microphthalmia, cataracts, and pulmonary hypoplasia have also been reported. The disease is fatal in the neonatal period. There have been no further descriptions in the literature since 1995.


Hallux varus-preaxial polysyndactyly syndrome is a rare, genetic, congenital limb malformation disorder characterized by bilateral medial displacement of the hallux and preaxial polysyndactyly of the first toes. Radiographs show broad, shortened, misshapen first metatarsals and may associate incomplete or complete duplication of proximal phalanges and duplication or triplication of distal phalanges. There have been no further descriptions in the literature since 1980.


An X-linked intellectual disability syndrome (XLMR) characterized by intellectual deficiency, microcephaly and short stature. It belongs to the group of disorders collectively referred to as Renpenning syndrome.

Summary:
Epidemiology
The prevalence is unknown. It has been reported in a family with 2 brothers and their 2 maternal uncles who presented with severe intellectual deficiency.
Clinical description
Marked facial characteristics (abnormal ears, bulbous nose, broad nasal bridge, malar hypoplasia, small mouth, and micrognathia), cleft or highly arched palate, and atrial septal defects were observed. Three out of four patients died in infancy or early childhood. Hamel cerebro-palato-cardiac syndrome represents the more severe phenotypic variant.
Etiology
The syndrome is caused by mutations in the PQBP1 gene. Expansions or reductions in the DR/ER repeat in the polar-amino-acid-rich domain (PRD) are responsible for a truncated protein that is thought to disrupt polyglutamine binding.
Genetic counseling
Hamel cerebro-palato-cardiac syndrome follows an X-linked recessive pattern of inheritance. Genetic testing is possible to identify carrier females and to inform them of the risk of passing on the gene to their offspring.

                            Last update:
                            June 2012

                            - Expert reviewer(s):
                            Pr Vincent DES PORTES


A rare multisystemic disease characterized by small-vessel brain disease, cerebral aneurysm, and extracerebral findings involving the kidney, muscle, and small vessels of the eye.

Summary:
Epidemiology
The prevalence of HANAC syndrome (hereditary angiopathy-nephropathy-aneurysms-muscle cramps syndrome) is not available, but at least six affected families have been reported worldwide to date.
Clinical description
Typical clinical manifestations of HANAC syndrome are the presence of bilateral retinal arteriolar tortuosity (systematically observed), small-vessel brain disease (including porencephaly, leukoencephalopathy, dilated perivascular spaces, lacunar infarcts, and microbleeds, with variable clinical expression), single or multiple intracranial aneurysms (mainly located on the carotid siphon), bilateral cortical and medullary renal cysts, muscle cramps, hematuria, and persistent elevation of serum creatine kinase (CK) concentration. Other eye defects (non-syndromic autosomal dominant congenital cataract, eye anterior segment anomaly of Axenfeld-Rieger type) and glomerular filtration rate decrease have also been reported. More occasional clinical signs include Raynaud phenomenon and supraventricular arrhythmia.
Etiology
The causative gene of HANAC is COL4A1 (13q34) encoding the alpha1 chain of collagen IV, a major component of basement membranes also involved in embryogenesis and cell migration/differentiation. To date, six pathogenic variants have been identified; all localized in exons 24 and 25 within the CB3 [IV] domain of COL4A1. They affect glycine residues localized in a 30-amino acid region of the protein.
Diagnostic methods
The diagnosis is based on the characteristic clinical findings. Testing to establish the diagnosis includes fundoscopic examination (retinal arterial tortuosity), renal ultrasound examination (cysts), and brain MRI (white matter lesion, chronic hemorrhagic foci, cerebral arterial aneurysm). Diagnosis is established in an individual with suggestive features of HANAC and the identification of a heterozygous pathogenic variant in COL4A1 by molecular genetic testing.
Differential diagnosis
The differential diagnosis includes anophthalmia/microphthalmia (A/M), autosomal dominant retinal vasculopathy with cerebral leukodystrophy (RVCL), brain small-vessel with hemorrhage, cerebral autosomal dominant/recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL/CARASIL), COL4A2-related porencephaly and intracerebral hemorrhages, and porencephaly type I.
Antenatal diagnosis
Prenatal diagnosis is possible for pregnancies at increased risk for a COL4A1-related disorder if the COL4A1 pathogenic variant has been identified in an affected family member.
Genetic counseling
The pattern of inheritance of HANAC syndrome is autosomal dominant. Genetic counseling can inform parents that the risk of transmitting the mutation responsible for the disease to their children is 50%. The proportion of HANAC syndrome cases caused by a de novo pathogenic variant has been estimated to be at least 27%.
Management and treatment
There is no effective treatment to date for individuals with COL4A1-related disorders. Possible symptomatic therapies include supportive care (based on individual needs, e.g. cataract surgery for severe lens opacities), treatment of hypertension to reduce risk of stroke and avoiding (unless if absolutely necessary) anticoagulant and platelet anti-aggregant use.
Prognosis
Very rarely, end stage renal disease or hemorrhagic stroke may occur.

                            Last update:
                            May 2019

                            - Expert reviewer(s):
                            Dr Laura CESCA  - Pr Emmanuelle PLAISIER | ERKNet*

                                * European Reference Network


Hand-foot-genital syndrome (HFGS) is a very rare multiple congenital abnormality syndrome characterized by distal limb malformations and urogenital defects.


A rare viral hemorrhagic fever characterized by virus-induced microvascular leakage rapidly leading to a severe illness with diffuse pulmonary edema and respiratory failure. These symptoms set in after a short first disease stage with fever, myalgia, and headache, followed by severe gastrointestinal symptoms such as abdominal pain, vomiting, and diarrhea. The high lethality of the disease is due to the possible development of hypotension and cardiogenic shock.


Hao-Fountain syndrome due to 16p13.2 microdeletion

A partial deletion of the short arm of chromosome 16 characterized by developmental delay, intellectual disability, speech delay, autism spectrum disorder, epilepsy, hypogonadism, and hypotonia. The behavioral profile includes impulsivity, compulsivity, stubbornness, manipulative behaviors, temper tantrums, and aggressive behaviors.


A rare multiple congenital malformation syndrome, characterized by an association of cleft lip and palate, patchy pigmentary retinopathy (cat's paw), obstructive liver disease (cholestasis, portal hypertension etc.) and obstructive renal disease (ectopic ureteric insertion, obstruction, vesicouretral reflux and hydronephrosis). Gastrointestinal tract involvement (malrotation, gastresophageal reflux etc.) and cardiac involvement (coarctation of aorta, pulmonary artery stenosis, etc.) have also been reported. An overlap with Kabuki syndrome is debated.


A rare autosomal recessive congenital ichthyosis characterized at birth by the presence of large, thick, plate-like shell over the whole body associated with severe ectropion, eclabium, and flattened ears, that later develops into a severe scaling erythroderma. Harlequin ichthyosis is the most severe disorder of this group.

Summary:
Epidemiology
The incidence is estimated to be less than 1/300,000 births.
Clinical description
Affected infants born encased in a collodion membrane (taut, shiny, translucent membrane appearing as an extra skin layer) with armorlike white-grayish scales, distributed throughout the body, and divided into irregular and quadrangular plates by deep fissures, with severe restriction of movements. Facial features are distorted due to extreme ectropion, conjunctival edema, eclabium and broadened nose. Infants also present with contractures, synechiae of auricles and/or toes with a possible risk of autoamputation. The risk of death is high during the neonatal period, babies being susceptible to severe temperature dysregulation, feeding difficulties, infections and respiratory problems. When they survive, the collodion membrane sheds after a few weeks and transforms into severe erythroderma with severe scaling and persistent ectropion. Other clinical features are often associated such as palmoplantar keratoderma, failure to thrive, short stature, malformed ears and digits, nail deformities and alopecia.
Etiology
HI is due to recessive mutations in the ABCA12 gene encoding the ATP-binding cassette (ABC) transporter, involved in lipid transport from lamellar granules to the apical surface of granular layer keratinocytes. Homozygous mutations in this gene cause protein function loss and affect important nucleotide-binding fold domains and transmembrane domains resulting in impaired lipid barrier function.
Diagnostic methods
Diagnosis is based on clinical examination. Biopsy is not useful but reveals massive compact orthohyperkeratosis. Skin ultrastructure shows vesicular lamellar bodies ghosts and a paucity of secreted lamellar granules in the stratum corneum. Molecular analysis reveals homozygous ABCA12 mutations.
Differential diagnosis
HI may be confused with less severe forms of ichthyosis. Later in life, the differential diagnosis includes other disorders from the autosomal recessive congenital ichthyosis (ARCI) group, restrictive dermopathy, infantile systemic hyalinosis, and Neu-Laxova syndrome.
Antenatal diagnosis
Prenatal diagnosis is mandatory and consists in DNA analysis of amniocentesis and chorion villus sampling materials, rather than fetal skin biopsies. Ultrasonography shows diffuse scaling, digital contractures, flattened rudimentary external ear, nasal hypoplasia, everted eyelids, typical fish mouth, open fetal mouth, and macroglossia.
Genetic counseling
The disease is transmitted as an autosomal recessive trait. Genetic counseling should be offered to the affected families informing them of the 25% risk of recurrence in each pregnancy.
Management and treatment
In the neonatal period, management requires a multidisciplinary approach (dermatologists, neonatologists, ophthalmologists, surgeons, dieticians, and psychologists for family support). Gastrostomy may be necessary. Emollients and oral retinoids (1-2mg/kg/day) are recommended. It is important to keep invasive procedures to a minimum in order to avoid skin infections. Management of survivors is similar for all severe ARCIs and includes the use of emollients, keratolytics, and retinoids.
Prognosis
HI is associated with substantial (50%) morbidity and mortality soon after birth and throughout childhood due to sepsis and/or respiratory failure (75% of cases). Survivors can have a normal life expectancy but may develop severe skin disease with eye complications related to persistent ectropion, delayed developmental and motor milestones, and social difficulties. Current medical treatments achieved a significant improvement in quality and expectancy of life, however the severity of the disease might still affect life duration. The prognosis of the disease with actual treatments is still under evaluation.

                            Last update:
                            December 2022

                            - Expert reviewer(s):
                            Dr Michela BRENA | ERN-Skin* - Dr Sophie GUEZ | ERN-Skin*

                                * European Reference Network


Harlequin syndrome (HSD) is an autonomic disorder occurring at any age and characterized by unilateral flushing and sweating, involving the face and sometimes arm and chest, in condition of thermal, exercise or emotional stress without sympathetic ocular manifestations. However, tonic pupils, parasympathetic oculomotor lesion and pre- or postganglionic sudomotor sympathetic deficit can rarely occur.


A rare multiple congenital anomalies/dysmorphic syndrome characterized by the association of intellectual deficit, facial dysmorphism (a highly arched palate, pointed chin, and small mouth, hypotelorism, a long nose and large protruding ears), arachnodactyly, hypogenitalism (undescended testes and hypospadias) and failure to thrive.


A rare metabolic disorder belonging to the neutral aminoacidurias, mainly characterized by skin photosensitivity, ocular and neuropsychiatric features, due to abnormal renal and gastrointestinal transport of neutral amino acids (tryptophan, alanine, asparagine, glutamine, histidine, isoleucine, leucine, phenylalanine, serine, threonine, tyrosine and valine).

Summary:
Epidemiology
The estimated prevalence is approximately 1 in 30,000.
Clinical description
Most subjects who fulfil the biochemical diagnostic criteria (mostly detected by newborn screening programs) remain asymptomatic. In the few symptomatic subjects, clinical symptoms usually appear in childhood (3-9 years of age), but sometimes manifest as early as 10 days after birth, or as late as early adulthood. Symptomatic subjects usually present with skin photosensitivity (pellagra-like skin eruption), neurological symptoms (intermittent cerebellar ataxia, spasticity, delayed motor development, trembling, headaches, and hypotonia), and psychiatric symptoms (anxiety, emotional instability, delusions, and hallucinations). Ocular manifestations may occur (double vision, nystagmus, photophobia, and strabismus). Intellectual deficit and short stature have been described in a few patients. Exacerbations are seen most frequently in the spring or early summer after sunlight exposure. Symptoms may also be triggered by fever, drugs, and emotional or physical stress. They progress over several days and last for 1-4 weeks before spontaneous remission occurs.
Etiology
Hartnup disease is caused by mutations in SLC6A19 gene (5p15.33), encoding the sodium-dependent and chloride-independent neutral amino acid transporter B(0)AT1, expressed predominately in proximal renal tubules and intestinal epithelium.
Diagnostic methods
Neutral hyperaminoaciduria (determined by urine chromatography) is the diagnostic hallmark. Diagnostic confirmation relies upon the mutation analysis of the SLCA19 gene (broad allelic heterogeneity).
Differential diagnosis
Pellagra is the main differential diagnosis. Blue diaper syndrome, ataxia-telangiectasia, hydroa vacciniforme, pityriasis alba, and xeroderma pigmentosum should be excluded.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Symptomatic subjects benefit from a high-protein diet, sunlight protection, and avoidance of photosensitizing drugs. Treatment includes nicotinamide supplements (40 to 200 mg per day). Some patients may respond to a tryptophan-rich diet. Patients with severe central nervous system involvement require neurologic and psychiatric treatment.
Prognosis
The presentation of the disorder is commonly benign. Hartnup disease probably does not adversely affect pregnancy and would be harmless to the fetus.

                            Last update:
                            July 2019

                            - Expert reviewer(s):
                            Pr Udo WENDEL