Crouzon syndrome-acanthosis nigricans syndrome

Crouzon syndrome with acanthosis nigricans (CAN) is a very rare, clinically heterogeneous form of faciocraniostenosis with Crouzon-like features and premature synostosis of cranial sutures (Crouzon disease, see this term), associated with acanthosis nigricans (AN; see this term).

Summary:
Epidemiology
CAN has an estimated prevalence of 1/1,000,000 newborns. Fewer than 70 cases have been described in the medical literature. A female-to-male sex ratio of 2.4:1 has been reported.
Clinical description
All patients have congenital craniofacial abnormalities consistent with classic Crouzon syndrome including craniosynostosis, midface hypoplasia, shallow orbits with exophthalmos, down-slanting palpebral fissures and hypertelorism, maxillary hypoplasia with convex nose and posteriorly angulated ears. The synostosis usually involves the coronal sutures. Cases of cloverleaf skull have also been reported. Patients also develop velvety hyperpigmented skin (AN) within the first decade of life, found primarily in body folds such as the neck, axillae, eyelids, and the perioral, inguinal and perianal areas. The skin disorder is sometimes widespread and develops early compared to classic AN. Craniovertebral junction and vertebral anomalies such as mild alterations of the interpediculate distances of the distal vertebral column are subtle and inconstant. Choanal atresia or stenosis is often present (41%), and is considered highly suggestive of CAN. Other commonly reported signs include hydrocephalus (43%), oral abnormalities such as cleft palate (see this term), dental malocclusion, cementomas of the jaw (34%), and melanocytic nevi (25%). Kidney involvement has also been reported. Some of these specific features are rare in patients with classic Crouzon syndrome. Intellectual disability, hearing loss and speech delay are uncommon. The severity is the same in affected males and females.
Etiology
CAN is caused by a specific p.Ala391Glu mutation in the fibroblast growth-factor receptor 3 FGFR3 gene (4p16.3), involved in regulation of cell proliferation, differentiation and apoptosis. AN is associated with inadequate stimulation of various fibroblast growth-factor receptors.
Genetic counseling
Most cases are sporadic, associated with paternal aging, although familial cases consistent with autosomal dominant inheritance have been reported.

                            Last update:
                            October 2014

                            - Expert reviewer(s):
                            Dr Corinne COLLET  - Pr Federico DI ROCCO


Crouzon disease is characterized by craniosynostosis and facial hypoplasia.

Summary:
Epidemiology
The estimated prevalence in the general population of Europe is 0.9/100,000 .
Clinical description
Craniosynostosis is variable but many sutures are usually involved. The facial dysmorphology is characterized by ocular hypertelorism, small beaked nose, proptosis, exophthalmos, hypoplastic maxilla and mandibular prognathism. The synostosis is evolutive and is usually either not visible or only slightly visible at birth. It usually manifests by the age of 2 years and becomes progressively more severe. However, precocious and congenital forms have been reported in which hypoplasia of the upper maxilla is pronounced and leads to respiratory difficulties, and the exophthalmia is severe resulting in palpebral malocclusion. Hydrocephaly, descent of the cerebellar tonsils and anomalies in jugular venous drainage are also frequently observed in Crouzon disease and may pose therapeutic problems. Two thirds of patients with Crouzon disease have intracranial hypertension, which may lead to blindness.
Etiology
Crouzon disease is caused by mutations of the fibroblast growth factor receptor FGFR2 (10q25.3-q26) with 80% being located to the immunoglobulin (Ig)-like domain III (IgIII domain) of the extracellular region and an additional 20% of mutations being located in the IgI-IgII domains, transmembrane and tyrosine kinase regions. A distinct form of Crouzon disease associated with acanthosis nigricans has been reported and is caused by a specific mutation (p.Ala391Glu) in the transmembrane domain of another protein from the same family, FGFR3 (Crouzon syndrome - acanthosisnigricans; see this term). Moreover, mutations in ERF (19q13.2) gene encoding the ETS2 repressor, resulting in anosteogenic stimulation, have been associated to a Crouzon-like syndrome.
Genetic counseling
The disease is transmitted in an autosomal dominant manner with variable penetrance.
Management and treatment
Surgical interventions are aimed at preventing cerebral, ophthalmological or respiratory complications and correcting the cranio-facial dysmorphy. The craniofacial surgical approach adopted needs to take into account both the cranial and facial synostosis and should be tailored to each patient.

                            Last update:
                            November 2013

                            - Expert reviewer(s):
                            Dr Eric ARNAUD  - Dr Corinne COLLET  - Pr Federico DI ROCCO


A rare immune complex-mediated vasculitis characterized by the presence of circulating cryoprecipitable immune complexes in the serum, manifesting clinically with the classical triad of purpura, weakness and arthralgia.

Summary:
Epidemiology
It is considered to be a rare disorder, but its true prevalence remains unknown. The disease is more common in Southern Europe than in Northern Europe or Northern America. The prevalence of ''essential'' mixed cryoglobulinemia (MC) has been reported as approximately 1:100,000 (with a female-to-male ratio of 3:1), but this term is now used to refer to only a minority of MC patients without an overt etiological agent.
Clinical description
Two types of MC have been described: type II and type III, based on their immunochemical properties. In type II, the cryoprecipitable immune-complexes are composed of monoclonal Ig M, the autoantibodies , and polyclonal IgGs, the autoantigens ; in type III, the immune-complexes are composed of both oligo-/polyclonal IgMs and polyclonal IgGs. Type I cryoglobulinemia involves monoclonal immunoglobulins of only one isotype and is a distinct disease. MC is characterized by variable organ involvement including skin lesions (orthostatic purpura, ulcers), chronic hepatitis, membranoproliferative glomerulonephritis, peripheral neuropathy, diffuse vasculitis, and, less frequently, interstitial lung involvement and endocrine disorders. Some patients may develop lymphatic and hepatic malignancies, usually as late complications. MC syndrome may be associated with numerous infectious or immunological diseases. When isolated, MC may represent a distinct disease, the so-called ''essential'' MC.
Etiology
The etiopathogenesis of MC is not completely understood. Hepatitis C virus (HCV) infection has been suggested to play a causative role, with the contribution of genetic and/or environmental factors, in the majority of patients. Moreover, MC may be associated with other infectious agents or immunological disorders, such as human immunodeficiency virus (HIV) infection or primary Sjogren syndrome.
Diagnostic methods
Diagnosis is based on clinical and laboratory findings. Circulating mixed cryoglobulins, low levels of complement component 4 and orthostatic skin purpura are the hallmarks of the disease. Leukocytoclastic vasculitis involving medium-sized and, more often, small-sized blood vessels is the typical pathological finding, easily detectable by means of skin biopsy of recent vasculitic lesions.
Differential diagnosis
Differential diagnoses include a wide range of systemic, infectious and neoplastic disorders, mainly autoimmune hepatitis, primary Sjögren syndrome, B-cell lymphomas, and rheumatoid arthritis.
Management and treatment
Treatment should be directed according to the underling etiopathogenesis. The first-line treatment of infection-related MC should with the most appropriate specific anti-infectious therapy (typically antivirals). Patients with an underlying lymphoproliferative or autoimmune disorder should receive appropriate disease-specific therapy. Use of immunomodifiers, immunosuppressors, corticosteroids, and/or plasmapheresis should be tailored to the patient according to the progression and severity of specific clinical manifestations, and may be used alone or in combination/sequence with antivirals. Use of immunomodifiers, immunosuppressor and plasmapheresis may play a major role in HCV-negative MC ('essential' MC syndrome) or in clinically active/relapsed MC that can be observed also after HCV eradication in some patients. Anti-CD20 (rituximab) is increasingly employed as an effective and safe treatment for major MC complications (nephropathy, neuropathy, severe vasculitis, etc.). Long-term monitoring is recommended in all MC patients to assure timely diagnosis and treatment of the life-threatening complications.
Prognosis
Disease persistence and relapse is more likely to be prevented when the clinical history of MC is considered along with early treatment and eradication of HCV. Similarly, timely treatment of more severe manifestations of the MC syndrome can prevent progression of organ damage. The overall prognosis is poorer in patients with renal disease, liver failure, lymphoproliferative disease and malignancies. In addition, MC type II (less frequently MC type III), particularly in patients with long-lasting disease, shows higher predisposition for the development of malignant B-cell lymphoma or other malignancies.

                            Last update:
                            August 2020

                            - Expert reviewer(s):
                            Pr Clodoveo FERRI


A cosmopolitan fungal infection due to Cryptococcus neoformans.

Summary:
Epidemiology
Annual incidence has been estimated at between 1/5,000 and 1/50,000 depending on the geographic region. Immunodeficient patients are the main target.
Clinical description
Primary pulmonary cryptococcosis is usually asymptomatic, but disseminates throughout the organism, particularly to the central nervous system causing subacute meningoencephalitis. Mucocutaneous infection is frequent.
Etiology
C. neoformans is an encapsulated yeast that reproduces by budding. It is abundant in the ground, in fruit, milk, and pigeon droppings. Infection is acquired via the respiratory or digestive route, rarely through the skin, and disseminates in the organism by blood or the lymphatic system. Interhuman transmission does not occur.
Diagnostic methods
Diagnosis is made after detection of encapsulated yeast in cerebrospinal fluid or other affected organs, or in cultures.
Differential diagnosis
Differential diagnoses include the other species of Cryptococcus.
Management and treatment
Amphotericin B and newer antifungal drugs (triazoles) sterilize the lesions. The treatment should be continued for as long as the patient is immunodeficient.
Prognosis
The prognosis is usually good if treatment is well conducted.

                            Last update:
                            October 2008

                            - Expert reviewer(s):
                            Dr Annick DATRY


Cryptogenic late-onset epileptic spasms is a rare epilepsy syndrome characterized by late-onset (after 1 year old) epileptic spasms that ocurr in clusters, associated with tonic seizures, atypical absences and cognitive deterioration. Language difficulties and behavior problems are frequently present. EEG is characterized by a temporal, or temporofrontal, slow wave or spike focus combined with synchronous spike-waves and no hypsarrhythmia or background activity.


Cryptogenic multifocal ulcerous stenosing enteritis

A rare intestinal disease characterized by chronic or relapsing subileus or ileus resulting from multiple unexplained fibrous structures and multiple shallow (i. e. limited to the mucosa or submucosa) ulcerations of the small intestine (mainly the ileum), in the absence of signs of a systemic inflammatory reaction. Patients may present with chronic iron-deficiency anemia due to chronic intestinal blood loss, chronic recurrent abdominal pain, fatigue, edema, or growth retardation. Extraintestinal manifestations such as Sicca syndrome, polyarthralgia, or Raynaud's phenomenon may also be observed.


A rare form of idiopathic interstitial pneumonia characterized pathologically by organizing pneumonia (OP) that presents with nonspecific flu-like symptoms, as well as cough and dyspnea, and where no etiological agent is found.

Summary:
Epidemiology
Cryptogenic organizing pneumonia (COP) represents 5-10% of interstitial lung diseases. The annual incidence in Iceland has been estimated at 1/90,900.
Clinical description
Mean age of onset is 50-60 years of age and patients present with nonspecific features of mild fever, non-productive cough, malaise, anorexia, weight loss and progressive but mild-to-moderate dyspnea. At auscultation, focal and sparse crackles are often found over the involved areas with clinical features of consolidation in some. There is no sign of finger clubbing. There is often a delay of 3 months or more between the onset of first symptoms and diagnosis. In rapidly progressive cases, dyspnea can be severe. Rare manifestations include chest pain, night sweats, and hemoptysis. Pneumothorax and pneumomediastinum have been reported. COP usually resolves with treatment but relapses occur in up to half of the cases. Though most diagnosed cases are now treated, spontaneous improvement occurring over 3-6 months has also been reported.
Etiology
Etiology is unknown. The stages of COP pathogenesis include the injury phase (permeability edema and fibrin deposits in response to alveolar cell injury), the proliferating phase (formation of fibroinflammatory buds), the mature phase (presence of ''mature'' fibrotic buds in the alveolar space) and the resolution phase (reversibility of lesions).
Diagnostic methods
Diagnosis is based on clinical picture, imaging, histopathology of the lung and the exclusion of all causes of secondary OP. High resolution computed tomographic scan reveals 3 main imaging patterns: multiple patchy alveolar opacities that may migrate (in the majority of cases; typical COP), a solitary focal nodule or mass (focal COP), or diffuse infiltrative opacities (infiltrative or progressive fibrotic COP). Video-assisted thoracoscopy is the method of choice in obtaining lung tissue but transbronchial biopsies, core needle biopsies, and recently transbronchial cryobiopsies are alternate methods. Hallmark histological findings of OP are patchy filling of the lung alveoli and respiratory bronchioles by buds of granulation tissue composed of fibroblasts and myofibroblasts (Masson bodies). Fiberoptic bronchoscopy with bronchoalveolar lavage reveals a mixed inflammatory profile with marked increase in lymphocytes and slight increase in neutrophils and eosinophils. Elevated C-reactive protein serum level and peripheral blood neutrophil count are reported.
Differential diagnosis
The main differential diagnosis is idiopathic chronic eosinophilic pneumonia. Secondary OP must also be excluded by elimination of its possible causes, including primary biliary cirrhosis, ulcerative colitis, Crohn disease, Sweet syndrome, sarcoidosis, Behçet disease, primary pulmonary lymphoma, drugs, inhalation exposure, infections, all connective tissue diseases, especially rheumatoid arthritis and idiopathic inflammatory myopathies, and other specific contexts like solid organ transplantation, bone marrow transplantation, etc.
Management and treatment
Standard therapy for COP is corticosteroids, usually with prednisone doses of 0.75 mg/kg/day for 4 weeks that gradually decreases over a period of 24 weeks. In those with rapidly progressing COP, high-dose intravenous methylprednisolone can be given. Focal COP is often diagnosed by the removal of lesions initially thought to be neoplastic, with further therapy often not needed. Relapses should be treated with a starting dose of 20 mg/day of prednisone then tapered over a period of 12 weeks. Relapses that occur too often or while undergoing corticosteroid therapy should prompt a reappraisal of the diagnosis. Immunosuppressive therapy may rarely be used in severe infiltrative COP.
Prognosis
The prognosis is usually good with most cases resolving after corticosteroid treatment. Morbidity is mostly related to prolonged corticosteroid treatment. However, relapses are seen in 13-58% of patients and can have an effect on quality of life if they are frequent.

                            Last update:
                            October 2022

                            - Expert reviewer(s):
                            Pr Vincent COTTIN | ERN-LUNG*

                                * European Reference Network


Cryptomicrotia-brachydactyly-excess fingertip arch syndrome

A rare genetic, congenital malformation syndrome characterized by the combination bilateral cryptomicrotia, brachytelomesophalangy with short middle and distal phalanges of digits 2 through 5, hypoplastic toenails and excess fingertip arch patterns. There have been no further descriptions in the literature since 1988.


Cryptorchidism-arachnodactyly-intellectual disability syndrome is a rare, multiple congenital anomalies syndrome characterized by psychomotor delay, severe intellectual deficit, severe muscle hypoplasia (with absence of subcutaneous fatty tissue), generalized contractures, craniofacial dysmorphic features (dolichocephaly, esotropia, ears of unequal size, high palate), chest and spinal deformities (i.e. sternum shifted to side, kyphoscoliosis), pulmonary anomalies (unilateral hypoplastic bronchial system), arachnodactyly, and genital abnormalities (cryptorchidism, hypospadias, testicular agenesis). Repeated respiratory tract infections and atelectasis are also associated. There have been no further descriptions in the literature since 1970.


A rare, genetic, neurodevelopmental disorder characterized by global developmental delay, borderline to severe intellectual disability, feeding difficulties, behavioral anomalies, vision anomalies and mild facial dysmorphism. Other associated features may include microcephaly, short stature, urogenital or palatal anomalies (e.g. cleft palate), minor cardiac defects, recurrent infections or hearing loss.

Summary:
Epidemiology
Up to date, 47 individuals worldwide are reported in the literature.
Clinical description
Affected individuals usually present with variable developmental delay or intellectual disability, ranging from learning difficulties with normal intellect to severe cognitive impairment. Developmental delay usually becomes evident in childhood with walking age ranging from 12 months to 3 years and language abilities varying from first words at 12 months to absent speech at 12 years of age. Intrauterine growth retardation during pregnancy or low birth measurements are observed in about one third of the reported cases. Feeding difficulties and failure to thrive are common in infants, sometimes requiring temporary tube feeding. Behavioral anomalies are common and include autistic features, hyperactivity, attention deficit or aggressivity. Further frequent and variable clinical aspects include vision anomalies, sensorineural and/or conductive hearing loss, recurrent infections and minor facial dysmorphism such as a long face with a prominent forehead, long palpebral fissures or a bulbous nasal tip. Microcephaly, cardiac defects and palatal anomalies such as high or cleft palate are present in about 30% of patients. Most of the reported individuals show a body height within the normal range, but short stature and less frequently tall stature has been reported. Febrile seizures or epilepsy occur in few individuals as well as nonspecific MRI and minor skeletal anomalies.
Etiology
The disorder is caused by heterozygous, pathogenic variants (larger deletions, truncating variants or missense variants within the zinc-finger domains) in the CTCF-gene on chromosome 16q22.1, which encodes for an important chromatin organizer.
Diagnostic methods
Diagnosis is confirmed by genetic testing, usually by non-targeted approaches such as multigene panel or exome sequencing.
Differential diagnosis
The differential diagnosis includes 22q11.2 deletion syndrome and a number of other neurodevelopmental disorders associated with feeding difficulties, mild developmental delay and variable anomalies.
Antenatal diagnosis
Prenatal diagnosis is possible when the pathogenic variant has previously been identified in a family member.
Genetic counseling
Transmission is autosomal dominant. Most cases result from a de novo pathogenic variant. Two inherited cases have been reported, where the variant was transmitted from a mildly affected or presumably healthy parent to the affected child, and genetic counseling should be offered in such cases.
Management and treatment
Affected individuals benefit from early developmental support including occupational therapy and special education where needed. Regular evaluation of growth parameters and for vision and hearing anomalies is recommended. If urogenital, cardiac or other anomalies are present or suspected, patients should be referred to the appropriate specialists.
Prognosis
The prognosis is usually good, but depends on severity of the disease and organ involvement. Affected individuals may require life-long support from their caregivers.

                            Last update:
                            December 2020

                            - Expert reviewer(s):
                            Pr Christiane ZWEIER


Curly hair-acral keratoderma-caries syndrome is an extremely rare ectodermal dysplasia syndrome characterized by premature loss of curly, brittle, dry hair, premature loss of teeth due to caries, nail dystrophy with thickening of the finger- and toe-nails, acral keratoderma and hypohidrosis. Additionally, sparse eyebrows and eyelashes, receding frontal hairline and flattened malar region are associated. The severity of features appears to increase with age.


A rare developmental defect during embryogenesis characterized by the triad of anorectal malformations, presacral mass and sacral anomalies.

Summary:
Epidemiology
Estimated prevalence is 1-9/100,000. Recent data estimates a 1.39:1 female-to-male ratio.
Clinical description
The disease typically presents as a triad of features (all 3 occur in 20% of cases) including anorectal, sacral and presacral anomalies, sometimes accompanied by other pelvic malformations. It may be an emergency at birth or found later with milder symptoms. Around 1/3rd of the patients are asymptomatic and identified through an affected relative or coincidentally on scans. Presacral anomalies may present as a mass and include anterior meningocoele, teratomas (which may also be sacrococcygeal), enteric cysts or a combination of those. Local pressure may cause constipation, incontinence, peripheral or central neurological symptoms. There is a 1-2 % risk of malignant transformation with various tumour types reported. Sacral agenesis occurs as anterior sacral defects. The S1 vertebra is typically intact. It may result in sickle-shaped (scimitar) sacrum or complete sacral agenesis below S2. Bifid or pepperpot sacrum are less frequent. Spinal cord anomalies (tethering, lipoma, cysts) can occur. Tethered cord can cause bowel/ bladder control issues if untreated. Spinal canal defects (e.g. enterothecal fistula) can cause seeding of gut microorganisms resulting in meningitis. Uterine or external genital anomalies occur in 15% of cases. Structural renal tract issues include kidney or bladder anomalies. Asymmetry of the lower limbs has been reported.
Etiology
MNX1 is the only confirmed causal gene to date. All mutational mechanisms have been observed (rearrangements, deletions and SNVs). Cases resulting from 7q36 deletion may be associated with extrapelvic malformations and/or intellectual delay if other genes are involved. Homozygous cases are rare and often lethal early in life. MNX1 is detectable in 57-65% of patients, most frequently in familial cases. The involvement of other genes of interest is ongoing. There is no direct phenotype-genotype correlation. The pathogenic mechanism is still unknown but likely due to MNX1 haploinsufficiency. A disruptive event is speculated to occur during the development of the notochord at Carnegies stage 12 (but has not been observed in humans to date). If the endodermal & ectodermal layers fail to separate, splitting of the notochord and fistula between the gut and the neural tissue may occur.
Diagnostic methods
Diagnosis is based on clinical findings. Plain film X-Ray, CT or MRI are useful. MNX1 gene testing can be offered. No international criteria currently exist.
Differential diagnosis
Differential diagnosis includes caudal regression syndrome, VACTERL association and sacrococcygeal teratoma.
Antenatal diagnosis
Foetal ultrasound can reveal a presacral mass or sacral defects if present. Targeted foetal MRI can be considered. Testing for MNX1 can be considered.
Genetic counseling
Inheritance is autosomal dominant with reduced penetrance and variable expressivity. Genetic counseling and imaging screening can be offered to relatives. If there is an established MNX1 variant, cascade testing can be offered.
Management and treatment
Management depends on presenting features. Surgical correction of anorectal malformations may be necessary. Conservative management (e.g. stool softening agents) and monitoring may be offered for milder cases. Monitoring of presacral mass is advised. Surgical management (coordinated by various surgical specialities) of presacral masses may be necessary. Cancer biomarkers for presacral teratomas are not well established. Sacral agenesis is managed clinically. If there is cord dysfunction, neurosurgery may be required. Caution is advised for spinal procedures, including anaesthesia. Spinal cord tethering may require early surgery to avoid complications. Follow up is important as the cord can retether.
Prognosis
Long term prognosis is good for the majority of patients. Urinary/bowel dysfunction may impact quality of life. Malignant transformation of presacral mass is rare.

                            Last update:
                            April 2023

                            - Expert reviewer(s):
                            Dr John COLEMAN  - Pr Sally Ann LYNCH | ITHACA*

                                * European Reference Network


Curry-Jones syndrome is a form of syndromic craniosynostosis characterized by unilateral coronal craniosynostosis or multiple suture synostosis associated with complete or partial agenesis of the corpus callosum, preaxial polysyndactyly and syndactyly of hands and/or feet, along with anomalies of the skin (characteristic pearly white areas that become scarred and atrophic, abnormal hair growth around the eyes and/or cheeks, and on the limbs), eyes (iris colobomas, microphthalmia,) and intestine (congenital short gut, malrotation, dysmotility, chronic constipation, bleeding and myofibromas). Developmental delay and variable degrees of intellectual disability may also be observed. Multiple intra-abdominal smooth muscle hamartomas, trichoblastoma of the skin, occipital meningoceles and development of desmoplastic medulloblastoma have been reported.


A form of adrenocorticotropic hormone (ACTH)-dependent Cushing syndrome, an endogenous Cushing syndrome (CS), characterized by chronic over-secretion of adrenocorticotropic hormone (ACTH) due to a pituitary corticotroph adenoma.

Summary:
Epidemiology
Cushing disease (CD) is the most common form of endogenous CS. The incidence is estimated to range between 1 out of 588,235 to 833,333 individuals per year, with an estimated incidence of CS (all causes considered) ranging between 1 out of 12,658 to 17,544 individuals per year. The mean age at diagnosis is 40 years and there is a significant female predominance.
Clinical description
The disease manifests with signs of CS (resembling corticosteroid side effects, i.e. faciotruncular fat distribution, hypercatabolic syndrome with thinned skin, proximal muscle weakness, oesteoporosis, metabolic syndrome, ...) as well as skin hyperpigmentation and/or neurological complications in rare cases of corticotropic macro-adenoma.
Etiology
Most corticotroph adenomas arise in a sporadic setting, with somatic activating driver variants in USP8 in around half of cases. Somatic variants in other genes such as USP48 and NR3C1 are less frequent. TP53 and ATXR somatic variants may be associated with more aggressive tumors. Germline mutations are rare.
Diagnostic methods
The first diagnostic step is to confirm CS (i.e. hypercortisolemic state) based on recommended tests. The second step of diagnosis is plasma ACTH detection to distinguish ACTH-dependent CS (values greater than 20 pg/mL) (4.4 pmol/L) from adrenal CS (ACTH values lower than 10 pg/mL) (2.2 pmol/L). When in doubt, a corticotropin-releasing hormone (CRH) test or a high-dose dexamethasone suppression test and adrenal gland computed tomography (CT) are recommended. The third step localizes the site of ACTH over-secretion: pituitary (CD) or non-pituitary (ectopic ACTH secretion; or EAS). Diagnosis of CD is based on dynamic hormonal tests (CRH test, desmopressin test, high-dose dexamethasone suppression test) to analyze the corticotropic response that distinguishes CD (with response often partially regulated: "positive" tests) from EAS (with response generally unregulated: "negative" tests) as well as measures of tumor markers, imaging (pituitary magnetic resonance imaging, thoraco-abdomino-pelvic computed tomography, positron emission tomography/computed tomography with Somatostatin analogue +/- 18-F-DOPA or 18-F-fluorodeoxyglucose), and bilateral inferior petrosal sinus sampling for ACTH assay.
Differential diagnosis
The differential diagnoses of CD are the other forms of Cushing syndrome, nonneoplastic hypercortisolism, generalized glucocorticoid resistance syndrome and lipodystrophy syndromes.
Antenatal diagnosis
Antenatal or preimplantation diagnosis may be proposed in families with identified mutations and severe/incurable diseases.
Genetic counseling
Suspicion of a genetic condition warrants a specialized genetic consultation. In second line, in cases presenting < 18 years or familial forms, genome-wide association studies may be discussed. Genetic counseling may be proposed in families with a known disease-causing mutation.
Management and treatment
Transsphenoidal pituitary surgery by an experienced pituitary surgeon is recommended as the first-line therapy. Removal of the tumor may lead to full recovery but there is a 20-30% persistence risk after surgery and a 15-30% long-term recurrence risk among patients in remission after surgery. After successful pituitary surgery, hydrocortisone replacement is often required for a few months or a few years. In patients who underwent a non-curative surgery, who relapsed or for whom surgery was not possible initially, several options should be considered individually such as second or delayed surgery, medical treatment, bilateral adrenalectomy or pituitary radiotherapy.
Prognosis
Untreated CD can be life-threatening. After remission of CD, sequelae may persist, such as cardiovascular comorbidities, cognitive impairment and psychological disorders.

                            Last update:
                            February 2024

                            - Expert reviewer(s):
                            Dr Laurence GUIGNAT | Endo-ERN*

                                * European Reference Network


A rare adrenal Cushing syndrome characterized by bilateral benign adrenal macronodules (>1 cm) that potentially produce autonomously variable levels of cortisol excess. Although in most cases are ACTH-independent, non-suppressed ACTH levels have been described.

Summary:
Epidemiology
Cushing syndrome due to bilateral macronodular adrenocortical disease (BMAD) is a rare form of endogenous CS, responsible for less than 2% of cases; the actual frequency remains unclear as only some of BMAD patients have an overt CS. Sporadic BMAD predominantly affects women, but the sex ratio is balanced in patients with ARMC5 pathogenic variants while more than 8/10 patients with KDM1A pathogenic variants are women.
Clinical description
Most BMAD cases are identified incidentally during radiological investigation for unrelated conditions. The adrenal glands can be massively enlarged bilaterally with the presence of numerous macronodules; however diffuse adrenal enlargement without nodules has been described. The clinical presentation depends on the extent of excess cortisol, ranging from asymptomatic forms to severe CS. For symptomatic patients, clinical presentation is typically in the fifth decade of life.
Etiology
In isolated BMAD, variants in the ARMC5 gene accounts for more than 80% of the familial forms and about 20-25% of apparently sporadic cases; variants in the KDM1A gene are responsible for BMAD associated with food-dependent CS. A few cases have been reported in association with mosaic variants of GNAS1, a gene which is also responsible for McCune-Albright syndrome (MAS). Genetic mechanisms still remain to be identified in other cases. Rarely, BMAD can be seen in syndromic diseases such as multiple endocrine neoplasia type 1 (MEN1), familial adenomatous polyposis (FAP), or hereditary leiomyomatosis and renal cell cancer (HLRCC).
Diagnostic methods
The first diagnostic step is to confirm CS (i.e. hypercortisolemic state) based on recommended tests. Diagnosis is often difficult because hypercortisolism usually develops slowly over years, may be cyclical and is often associated with subtle CS. Cortisol secretion may be food-dependent with low fasting cortisol concentrations. Hormonal investigations can demonstrate abnormal stimulation of cortisol secretion by various hormones (e.g. GIP, gonadotropin-releasing hormone, aldosterone or androgen secretion). Usually, in BMAD patients with subclinical or overt CS, ACTH is low or sometimes not detectable; however, non-suppressed ACTH levels have also been described. When in doubt, a corticotropin-releasing hormone (CRH) test or a high-dose dexamethasone suppression test and adrenal gland computed tomography (CT) are recommended. The third step is to show bilateral adrenal nodular enlargement on radiological imaging. Diagnosis can be confirmed by histological examination.
Differential diagnosis
Differential diagnoses include other causes of adrenal CS, and ACTH-dependent CS including pituitary (Cushing disease) or extra-pituitary tumors (ectopic ACTH secretion), other causes of bilateral adrenal masses with no CS (bilateral pheochromocytoma, primary aldosteronism, congenital adrenal hyperplasia, bilateral metastasis of solid cancer, etc.).
Antenatal diagnosis
Antenatal or preimplantation diagnosis may be proposed for those with severe and incurable diseases.
Genetic counseling
Genetic consultation to offer genetic analysis should be proposed to all patients with BMAD. In a second step, genome-wide study may be discussed. Genetic counseling may be proposed in families with a known disease-causing mutation.
Management and treatment
A surgical or medical treatment should be considered for patients with overt CS and in cases of ascertained mild autonomous cortisol secretion in the presence of clinical consequences of possibly related to hypercortisolism (i.e. diabetes, hypertension, bone fragility). For patients with no evidence for hypercortisolism at diagnosis, active surveillance should be proposed.
Prognosis
Untreated CS due to BMAD can be life-threatening. Prognosis after treatment is good but quality of life may be affected. In cases of moderate hypercortisolism, long-term morbidity is due to the increased cardiovascular and metabolic risk factors associated with mild CS.

                            Last update:
                            February 2024

                            - Expert reviewer(s):
                            Pr Jérôme BERTHERAT | Endo-ERN* - Dr Laurence GUIGNAT | Endo-ERN*

                                * European Reference Network


Cushing syndrome due to ectopic ACTH secretion

A form of adrenocorticotropic hormone (ACTH)-dependent Cushing syndrome, an endogenous Cushing syndrome (CS), characterized by the secretion of ACTH by non-pituitary neuroendocrine tumors (NETs) of various locations and various degrees of histological differentiation and aggressiveness.

Summary:
Epidemiology
The annual incidence of Cushing syndrome (CS) due to ectopic ACTH secretion (EAS), is estimated at about 1/1,250,000. The vast majority cases are sporadic and occur in adulthood, with an equal female-to-male ratio.
Clinical description
Clinical features are quite wide ranging. Patients may present like those with CS (truncal and facial obesity and signs of hypercatabolism) and with skin hyperpigmentation, like in Cushing disease (CD), or with skin pigmentation and severe amyotrophy, with or without facial fullness or weight gain. Severe hypokalemia, life-threatening infections, psychiatric disorders, osteoporosis and fractures are seen more frequently in CS due to EAS than in CD. Specific signs depend on the causative tumor, its site and extension, and may include paroxystic hypertension in pheochromocytoma, flush or diarrhea in medullary thyroid carcinoma, and carcinoid syndrome in metastatic carcinoid tumors.
Etiology
The tumors responsible for an EAS have a variety of locations and histological types. The lung is the primary site of 40% of EAS cases (bronchial carcinoid and small cell lung cancer). Other tumors derive mainly from the foregut (larynx, thymus, stomach, duodenum and pancreas). Rarely, pheochromocytomas and medullary thyroid carcinoma secrete ACTH in addition to catecholamines and calcitonin, respectively. Some exceptional inherited cases are described, with ACTH-secreting thymic neuroendocrine tumors (NETs), in the context of multiple endocrine neoplasia type 1 (MEN1), medullary thyroid cancers in MEN2 and pancreatic NETs in the Von Hippel-Lindau syndrome.
Diagnostic methods
The first diagnostic step is to confirm CS (i.e. hypercortisolemic state) based on recommended tests. The second step of diagnosis is plasma ACTH detection to distinguish ACTH-dependent CS (values greater than 20 pg/mL; 4.4 pmol/L) from adrenal CS (ACTH values lower than 10 pg/mL; 2.2 pmol/L). Cortisol and ACTH levels can be very high in EAS. The third step localizes the site of ACTH over-secretion, pituitary (CD) or non-pituitary (EAS). Diagnosis is based on dynamic hormonal tests to analyze the corticotropic response that distinguishes CD (with response often partially regulated: ''positive'' tests) from EAS (with response generally unregulated: ''negative'' tests) as well as measures of tumor markers, imaging (pituitary magnetic resonance imaging, thoraco-abdomino-pelvic computer tomography, positron emission tomography/computed tomography with Somatostatin analogue +/- 18-F-DOPA or 18-F-fluorodeoxyglucose), and bilateral inferior petrosal sinus sampling for ACTH assay. Rare concomitant secretion of corticotropin-releasing hormone (CRH) and ACTH, and exceptional exclusive CRH secretion have been described.
Differential diagnosis
The differential diagnosis of CS due to EAS is CD.
Antenatal diagnosis
Antenatal or preimplantation diagnosis may be proposed for those with severe and incurable diseases (e.g. MEN2, VHL disease, etc.).
Genetic counseling
Suspicion of a genetic disease warrants a specialized genetic consultation. Genetic counseling may be proposed in families with a known disease-causing mutation.
Management and treatment
The ideal treatment is curative surgery of the underlying tumor. Removal of the tumor may lead to full recovery but the condition may recur. If surgery is not curative or possible, a multidisciplinary approach includes chemotherapy, radiotherapy, hormone analogues and/or radionuclide treatment to control tumor growth and associated symptoms. If the tumor is unresectable, or while waiting for the effectiveness of the treatment of the tumor in cases of severe CS, anticortisolic medication and preventive and curative treatment of comorbidities are recommended. Bilateral adrenalectomy can resolve hypercortisolism in cases of non-operable or non-localized secreting tumors or in cases of poor tolerance and inefficacy of medical treatment.
Prognosis
Prognosis depends on tumor histology and staging, and on severity of CS. Untreated CS can be life-threatening.

                            Last update:
                            February 2024

                            - Expert reviewer(s):
                            Dr Laurence GUIGNAT | Endo-ERN*

                                * European Reference Network


Cutaneous collagenous vasculopathy (CCV) is a primary microangiopathy confined to the skin, characterized by multiple and widespread telangiectasias.

Summary:
Epidemiology
It is a rare disorder with less than 20 cases reported in the literature to date.
Clinical description
Most patients present in adulthood with symmetrical telangiectasias appearing on the lower extremities and later progressing to the trunk and upper extremities.
Etiology
The etiology is unknown but CCV is thought to be associated with collagen abnormalities in the skin microvasculature. It can be distinguished from generalized essential telangiectasia (see this term) by characteristic histopathological features that reveal the presence of thickened vascular walls in CCV.

                            Last update:
                            April 2013


Cutaneous larva migrans is a rare parasitic disease characterized by single or multiple, linear or serpiginous, erythematous, slightly elevated cutaneous tracks caused by the larval migration of various nematode species. Tracks are variable in length, generally a few millimeters wide and are frequently located on the feet (although any area of the body is possible). Patients typically present with severe, intractable pruritus, which, in some cases, may cause impaired concentration, loss of sleep, and mood disturbances.


Cutaneous mastocytoma is a form of cutaneous mastocytosis (CM, see this term) generally characterized by the presence of a solitary or multiple hyperpigmented macules, plaques or nodules associated with abnormal accumulation of mast cells in the skin.

Summary:
Epidemiology
Prevalence is unknown but mastocytomas are the second most frequent form of CM in children, accounting for 10-15% of cases.
Clinical description
Patients generally present during infancy, with most presenting in the first three months of life. However, rare cases of onset in adulthood have been reported. Mastocytomas usually appear as oval lesions with red-brown, pink or yellow pigmentation. The diameter varies from around 1-4 cm and the surface may be smooth or have a ''peau d'orange'' appearance. The trunk, face, neck and extremities are the most common sites of involvement. Patients with multiple mastocytomas (up to 5) have been reported with new lesions appearing at different locations up to two months after emergence of the initial lesion. Other skin manifestations may include blistering (most frequent during infancy), pruritus and urticaria. Stroking of the lesions results in Darier's sign and generalized flushing in some cases. Additional systemic symptoms are rarely associated with cutaneous mastocytomas but a few cases with fever, gastrointestinal disturbances (nausea, colic and diarrhea), headaches and asthma-like symptoms have been reported.
Etiology
Mutations in the KIT gene (4q11-q12) have been identified in some patients with CM, however, this mutation is rare in the pediatric population and the etiology and pathogenesis of cutaneous mastocytoma remains to be determined.
Diagnostic methods
Diagnosis is made on the basis of the clinical appearance of the lesions and the presence of Darier's sign. Histopathological examinations confirm the diagnosis by revealing a dense inﬁltrate of mast cells in the upper dermis.
Differential diagnosis
The differential diagnosis generally includes melanocytic nevi, xanthomas and juvenile xanthogranuloma (see this term).
Management and treatment
Treatment is symptomatic and includes oral administration of antihistamines, topical steroids and the use of hydrocolloid dressings to cover the lesions. Trigger factors (such as rubbing of the lesions and use of nonsteroidal anti-inflammatory drugs) should be avoided. Surgical excision provides a definitive cure for patients with alarming symptomatic lesions that do not respond to other forms of treatment and has been recommended as a first-line therapy in some cases.
Prognosis
The prognosis for patients with onset during infancy is good with regression of most lesions during childhood and complete resolution by adolescence. Rare cases of persisting mastocytoma in adulthood have been reported. Spontaneous resolution is less common in patients with adult-onset.

                            Last update:
                            June 2013

                            - Expert reviewer(s):
                            Pr A.P. [Arnold] ORANJE


A rare group of mastocytosis diseases characterized by abnormal accumulation and proliferation of mast cells in the skin and including the three recognised forms: diffuse cutaneous mastocytosis, cutaneous mastocytoma and, the most common form, maculopapular cutaneous mastocytosis. In some cases (most commonly in adults), cutaneous mastocytosis may occur in association with mast cell infiltration of various extracutaneous organs, in which case the disorder is referred to as systemic mastocytosis.


A rare aggressive skin cancer characterized by a rapidly growing nodule with both epithelial and neuroendocrine features, driven in 80% of cases by the oncogenic Merkel cell polyomavirus (MCPyV).

Summary:
Epidemiology
Cutaneous neuroendocrine carcinoma (or Merkel cell carcinoma; MCC) accounts for less than 1% of skin cancers. The annual incidence rates, ranging from 1 out of 1,000,000 to 1 out of 40,000 inhabitants in western countries, has been increasing over the last two decades.
Clinical description
MCC usually occurs in fair-skinned, elderly people. Overall, 10% of MCC patients are immunosuppressed (transplant recipients, HIV, hematological malignancies). The primary tumor is mostly located on sun-exposed areas and appears as an asymptomatic, rapidly growing, red/violaceous cutaneous nodule. One third of patients already have nodal or distant metastasis at time of diagnosis. A complete work up is necessary at baseline (ultrasonography of the regional lymph nodes and a whole-body imaging with a positron emission tomography scan), allowing to classify the disease according to the 4 stages of the American Joint Committee on Cancer (AJCC) system. In less than 10% of cases, MCC is diagnosed in metastatic lymph nodes, with no evidence of skin primary (''occult primary'').
Etiology
In 2008, Feng, Chang and Moore discovered that the genome of the Merkel cell polyomavirus (MCPyV) was integrated in the DNA of 80% of MCC samples. Since then, MCPyV has been found to be an ubiquitary resident of skin flora, acquiring oncogenic properties following the occurrence of very rare events (integration of its DNA into the genome of the host cell and mutations of the viral genome). On the other hand, 20% of MCC are related to UV-induced mutations especially on TP53 and pRB oncogenes. In both subsets, the most likely cell of origin is an epithelial cell of the epidermis.
Diagnostic methods
The diagnosis of MCC requires a biopsy. Histologically, MCCs appear as a proliferation of basophilic cells with scant cytoplasm, a 'salt and pepper' chromatin pattern and high mitotic rate. The tumor is located in the dermis, frequently extending to the subcutaneous tissue, lacking connection with the epidermis. Immunohistochemistry reveals positivity for neuroendocrine (synaptophysin, chromogranin) and epithelial markers, the hallmark being the paranuclear dot-like pattern of cytokeratin 20 expressed by more than 90% of MCC.
Differential diagnosis
Clinical differential diagnosis includes any disease presenting a skin nodule, ranging from benign cysts or lipomas, to skin malignancies such as carcinomas, lymphomas or skin metastases. On histological sections, the main differential diagnoses include basophilic tumors such as small-cell lung carcinoma, carcinoid tumor, malignant lymphoma, and small-cell melanoma, which can be ruled out by appropriate immunohistochemical panels.
Management and treatment
Management should be discussed in tumor multidisciplinary boards based on the disease stage and general health status of the patient. Patients with localized disease should have a wide excision of the primary tumor with a sentinel lymph node biopsy in the regional area. In case of regional disease, a complete lymph node dissection is usually indicated. Adjuvant radiation therapy is usually provided on the site of the primary tumor and can be proposed on the regional lymph node area if involved. In patients with advanced disease, first line treatment consists in immunotherapy with a PD-1/PD-L1 inhibitor. Avelumab is approved in several countries worldwide in this setting, retifanlimab is approved in Europe and the USA, while pembrolizumab is only approved in the USA.
Prognosis
MCC is an aggressive disease with a high propensity to metastasize. Approximately 40% of patients recur within 3 years after initial management, and the overall survival at 5 years is estimated at 60%. The prognosis of patients with advanced disease has improved with the use of immunotherapy.

                            Last update:
                            February 2024

                            - Expert reviewer(s):
                            Pr Mahtab SAMIMI


Cutaneous photosensitivity-lethal colitis syndrome

A rare inflammatory bowel disease characterized by early cutaneous photosensitivity manifesting by sun-induced facial erythematous and vesicular lesions and severe recurent colitis which lead to untreatable diarrhea. There have been no further descriptions in the literature since 1991.


Cutaneous polyarteritis nodosa (CPAN) is a rare limited form of polyarteritis nodosa (PAN, see this term), characterized by cutaneous vasculitis and mild and transient extracutaneous manifestations such as mild arthralgia, arthritis,myalgia, and rarely peripheral neuropathy.


A rare acquired skin disease characterized by a benign, etiologically variable lymphoproliferative process of the skin mimicking cutaneous lymphoma clinically and/or histologically, while not fulfilling criteria for the diagnosis of a specific disease. Depending on the predominant cell type in the infiltrate, T- and B-cell pseudolymphomas can be distinguished.


A small vessel vasculitis characterized by neutrophilic inflammation predominantly limited to the superficial cutaneous postcapillary venules and without systemic vasculitis or glomerulonephritis. Typical presentation is of unifocal or multifocal palpable purpura on the lower extremities.

Summary:
Epidemiology
The annual incidence of leukocytoclastic vasculitis in the United States is estimated at 1/220,000, of which 45% consist of cutaneous small vessel vasculitis.
Clinical description
The disease onset can occur at any age, and typically presents with non-blanching, palpable purpura and/or petechiae of the lower extremities with unifocal or multifocal distribution. The lesions may coalesce, ulcerate or be surrounded by hemorrhagic bullae. Urticarial lesion can also be observed. Lesions are usually not painful, although they may cause burning and itching. Histological characteristics are non-specific for the disease and include neutrophilic infiltration of the dermal small blood vessel walls, as well as, fibrinoid necrosis and disruption of the vessel wall, leukocytoclasia, endothelial swelling, and erythrocytes extravasation. As the lesion gets older, neutrophils diminish, and lymphocytes become prominent.
Etiology
The disease may be idiopathic (in up to 50% of cases) or secondary to infections, medications, connective tissue diseases, or malignancy. The disease occurs due to the deposition of immune complexes (IC) on the wall of post-capillary venules, which then activates both complement pathways, leading to degranulation of mast cells and neutrophil chemotaxis.
Diagnostic methods
Diagnosis is one of exclusion. In general, skin biopsy samples from lesions between 24-48 hours old, should be examined with light microscopy and direct immunofluorescence. A complete history, review of systems, physical examination, and selected laboratory studies also should be performed to assess for inciting causes or extracutaneous involvement.
Differential diagnosis
The main differential diagnosis is of systemic small vessel vasculitides with cutaneous presentation and includes antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cryoglobulinemic vasculitis, immunoglobulin A vasculitis. Other conditions with similar histopathology include infective endocarditis, macular purpura owing to trauma, skin fragility, pigmented purpuric dermatosis, septic emboli, and livedoid vasculopathy.
Management and treatment
Treatment varies and depends on the chronicity of the disease, the severity of cutaneous involvement, and the presence or absence of both an underlying cause. An isolated episode associated with a known inciting factor may be managed by removal or treatment of the trigger, along with symptomatic measures. First-line systemic treatments for chronic, idiopathic disease include colchicine or dapsone, used singly or in combination. Recurrent, chronic, or severely symptomatic disease that does not respond to the aforementioned therapies may require initiation of an immunosuppressive agent such as azathioprine, mycophenolate mofetil, methotrexate, or rituximab.
Prognosis
The clinical outcome is typically good with 90% resolving in weeks to months of onset, but may be complicated by the occurrence of ulcers (treatment prolongation, infections and scarring). The reported relapse rate is between 8-25%.

                            Last update:
                            October 2020

                            - Expert reviewer(s):
                            Dr Xavier PUECHAL  - Pr Benjamin TERRIER


Cutis gyrata-acanthosis nigricans-craniosynostosis syndrome, also known as Beare-Stevenson syndrome (BSS), is a severe form of syndromic craniosynostosis, characterized by a variable degree of craniosynostosis, with cloverleaf skull reported in over 50% of cases, cutis gyrata, corduroy-like linear striations in the skin, acanthosis nigricans, skin tags, and choanal stenosis or atresia). Additional features include facial features similar to Crouzon disease, ear defects (conductive hearing loss, posteriorly angulated ears, stenotic auditory canals, preauricular furrows, and narrow ear canals), hirsutism, a prominent umbilical stump, and genitorurinary anomalies (anteriorly placed anus, hypoplasic labia, hypospadias). BSS is associated with a poor outcome as patients present an elevated risk for sudden death in their first year of life. Significant developmental delay and intellectual disability are observed in most patients who survive infancy.


Cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies

A rare, genetic, dermis elastic tissue disorder characterized by generalized cutis laxa associated with severe, usually early-onset, pulmonary emphysema, frequent and severe gastrointestinal and genitourinary involvement (i.e. bladder/intestine diverticula and/or tortuosity, gastrointestinal fragility, hydronephrosis), and mild cardiovascular involvement (typically limited to peripheral pulmonary artery stenosis only).


A rare, genetic, developmental defect with connective tissue involvement syndrome characterized by neonatal cutis laxa, marfanoid habitus with arachnodactyly, pulmonary emphysema, cardiac anomalies, and diaphragmatic hernia. Mild contractures of the elbows, hips, and knees, with bilateral hip dislocation may also be associated. There have been no further descriptions in the literature since 1991.


Cutis laxa (CL) is an inherited or acquired connective tissue disorder characterized by wrinkled, redundant and sagging inelastic skin associated with skeletal and developmental anomalies and, in some cases, with severe systemic involvement. Several different forms of inherited CL have been described, differentiated on the basis of the mode of inheritance and differences in the extent of internal organ involvement, associated anomalies and disease severity.

Summary:
Epidemiology
Most cases of CL are inherited, with prevalence at birth being estimated at around 1/1,000,000 and only around 200 families being reported in the literature so far.
Clinical description
Autosomal recessive types of CL (ARCL) appear to be the most common forms with two subtypes being described: ARCL1 and ARCL2 (see these terms). ARCL1 is the most severe form of CL with generalized involvement leading to life-threatening complications (lung atelectesias and emphysema, vascular anomalies, and gastrointestinal and genitourinary tract diverticuli). ARCL2 appears to cover a spectrum of disorders ranging in severity from the wrinkly skin syndrome (see this term) to more severe disease associated with growth and developmental delay, and skeletal anomalies (classic ARCL2, Debré type; see this term). De Barsy syndrome and geroderma osteodysplastica (see these terms) also show significant clinical overlap with ARCL2. Occipital horn syndrome (X-linked cutis laxa (XRCL); see this term) is very similar to ARCL2; however, several patients present a more severe phenotype and systemic involvement. Autosomal dominant CL (ADCL) is generally a mild cutaneous disorder but systemic manifestations (hernias, cardiac valve anomalies, cardiovascular manifestations, gastrointestinal diverticuli and emphysema) have been noted in some cases.
Etiology
Although the underlying etiology remains unknown in many patients with the inherited forms of CL, several genes have been implicated: FBLN5 , EFEMP2 and LTBP4 in ARCL1 (14q32.1, 11q13 and 19q13.1-q13.2) , ATP6V0A2 and PYCR1 in ARCL2 (12q24.3 and 17q25.3), and ELN and FBLN5 in ADCL (7q11.2 and 14q32.1)). Homozygous ELNmutations have also been indentified in four patients with a mild form of ARCL.
Diagnostic methods
Diagnosis is often problematic due to the considerable clinical overlap between the hereditary forms. The diagnostic approach should include a detailed physical examination, family history, skeletal survey, developmental assessment, imaging studies, histological analysis, liver function tests and biochemical analysis, kidney ultrasound, and ophthalmological and cardiac evaluation.
Differential diagnosis
The main differential diagnosis is the Ehlers-Danlos syndromes (see these terms) but similar skin manifestations may also occur in patients with Williams syndrome, pseudoxanthoma elasticum, Hutchinson Gilford syndrome, Barber Say syndrome, Costello syndrome, Cardio-Facio-Cutaneous syndrome and Kabuki syndrome (see these terms). Inherited forms of CL should also be distinguished from acquired CL which is commonly preceded by urticaria, angioedema, local or generalized inflammatory skin disease or drug hypersensitivity reactions.
Antenatal diagnosis
Prenatal diagnosis is feasible by molecular testing for families in which the genetic anomaly has been identified.
Genetic counseling
Correct diagnosis of the hereditary forms is essential for providing adapted genetic counseling to affected families.
Management and treatment
There is no efficient treatment for CL and management is symptomatic. Plastic surgery is not generally indicated for the cutaneous manifestations in inherited forms.
Prognosis
Prognosis is variable, ranging from a usually fatal outcome in childhood in ARCL1 to a normal life expectancy in less severe forms.

                            Last update:
                            July 2010

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


Cutis marmorata telangiectatica congenita (CMTC) is a congenital localized or generalized vascular anomaly characterized by a persistent cutis marmorata pattern with a marbled bluish to deep purple appearance, spider nevus-like telangiectasia, phlebectasia and, occasionally, ulceration and atrophy of the affected skin.

Summary:
Epidemiology
About 300 cases have been reported so far. Both genders seem equally affected.
Clinical description
In 90% of cases, the skin anomalies are observed at birth or shortly after birth, and may become more accentuated in the first few weeks. CMTC manifests with a localized or generalized reticulated, frequently asymmetrical, blue-violet colored vascular network in the skin. Skin changes may range from fine diffuse capillary anomalies without atrophy to atrophic or ulcerated larger purple reticulated bands. The cutaneous lesions most commonly occur on the legs, less commonly on the arms and trunk, and rarely involve the face and scalp. More than 50% of the CMTC patients present with associated cutaneous and/or extracutaneous anomalies (referred to as the macrocephaly-CMTC syndrome; see this term), most frequently body asymmetry (hypotrophy or hypertrophy of an involved extremity) and vascular lesions (capillary malformations). Other associated anomalies include neurological abnormalities (psychomotor retardation, seizures, and hypotonia), ocular anomalies (retinal detachment and congenital glaucoma; see this term), syndactyly, and macrocephaly. CMTC can also be associated with Adams-Oliver syndrome (see this term).
Etiology
The etiology remains unknown.
Diagnostic methods
Diagnosis is clinical. If the head is affected, ocular and neurological examination should be performed. Possible associated anomalies should be excluded by a careful clinical examination. Histopathologic findings are often nonspecific or show dilated capillaries and veins in the dermis.
Differential diagnosis
Differential diagnoses include Klippel-Trénaunay syndrome, Sturge-Weber syndrome, Bockenheimer syndrome, some port-wine stain capillary malformations, and macrocephaly-CMTC (see these terms). Persistence of skin changes with local warming distinguishes CMTC from physiological cutis marmorata.
Genetic counseling
CMTC occurs sporadically but a genetic basis has been proposed for some affected families.
Management and treatment
Treatment is usually not required. Laser therapy has been tried in several patients with persistent CMTC and variable outcomes have been reported.
Prognosis
Prognosis is generally good, with a tendency for clinical improvement during infancy or even complete resolution.

                            Last update:
                            September 2009

                            - Expert reviewer(s):
                            Pr Giovanna ZAMBRUNO


A rare intoxication characterized by onset of toxic manifestations within seconds to hours - depending on the route, duration, dosage, and source of exposure - after inhalation of volatile cyanides (especially from fire smoke), ingestion of cyanide (including use of certain medications) or contact with the skin or mucous membranes. In severe cases following inhalation, signs of hyperventilation appear within seconds or minutes and are followed by loss of consciousness with convulsions and ultimately cardiovascular collapse and/or respiratory arrest. Other clinical signs include dizziness, weakness, palpitations, and anxiety, followed by dyspnea, pulmonary edema, confusion, ataxia, and paralysis.


A rare parkinsonian syndrome due to intoxication which develops in individuals surviving an acute cyanide intoxication episode or due to chronic exposure to small cyanide doses. It presents several weeks after acute exposure with progressive typical clinical features of parkinsonism including bradykinesia, rigidity, dystonia, hypomimia, hypokinetic dysarthria, postural instability and retropulsion but no resting or postural tremor. Brain MRI reveals bilateral lesions in the pallidum, posterior putamen, substantia nigra, subthalamic nucleus, temporal and occipital cortex, and cerebellum.


A rare primary immunodeficiency characterized by regular oscillations in blood neutrophil counts from normal or subnormal levels to severe neutropenia, usually with a cycle length of about 21 days. Symptoms during the neutropenic phase include fever, mouth ulcers, but also pneumonia, and peritonitis, among others. Mode of inheritance is autosomal dominant.


Cyclosporosis is a parasitic disease caused by Cyclospora cayetanensis, a recently discovered coccidia that was initially described in Peru and then in most intertropical zones. Infection occurs through ingestion of contaminated food or water and leads to abdominal pain, anorexia and diarrhoea, which may resolve spontaneously in immunocompetent individuals but may persist in a chronic form in immunocompromised subjects, leading to a decline in their general state of health.

Summary:
Epidemiology
The prevalence is unknown.
Diagnostic methods
The diagnosis is made by parasitological examination of the stools.
Management and treatment
Treatment revolves around administration of cotrimoxazole.

                            Last update:
                            December 2006

                            - Expert reviewer(s):
                            Dr Luc PARIS


Cylindrical spirals myopathy is a rare form of congenital myopathy characterized by global muscle weakness, hypotonia, myotonia and cramps in the presence of cylindrical, spiral-shaped inclusions (located in the central and/or subsacrolemmal areas of muscle fibers) in skeletal muscle biopsy. Abnormal gait, scoliosis, epileptic encephalopathy and psychomotor delay may be associated.


A rare multiple congenital anomalies/dysmorphic syndrome characterized by a specific facial appearance (consisting of a thickened, ridged, triangular skin fold extending from the glabella to the anterior fontanel, bilateral elevation of the medial portion of the eyebrows, hypertelorism, low-set ears, posteriorly rotated ears, and widow's peak), variable skeletal deformities, and neuromuscular and sensory defects, which can be incapacitating in some individuals. Reported features include limb muscle wasting, congenital kyphoscoliosis, hip dislocation, congenital talipes equinovarus, arthrogryposis, joint stiffness/ankyloses, ptosis, and cataracts. Intelligence is normal. There have been no further reports since 1992.


A benign epithelial ovarian tumor characterized by a usually unilateral, cystic, unilocular or multilocular lesion with a thin wall or septa and no intracystic solid portion on imaging. It often presents with abdominal pain or an asymptomatic abdominal mass and can be associated with ovarian torsion or malignant transformation.


A rare inborn error of metabolism characterized by abnormal accumulation of plasma cystathionine and subsequent increased urinary excretion due to cystathionine gamma-lyase deficiency. The condition is considered benign without pathological relevance. Mode of inheritance is autosomal recessive.


A rare parasitic disease characterized by slowly enlarging cysts of the liver, lungs and other organs which often go unnoticed for years. They are caused principally by the larval form (also called metacestode) of Echinococcus granulosus sensu lato tapeworm. The adult form of this tapeworm parasitizes the intestine of dogs. Cystic echinococcosis (formerly hydatidosis) generally affects large domestic herbivores and humans are dead-end hosts, infected through contact with herding dogs or through ingestion of food contaminated with canine excrement.

Summary:
Epidemiology
The reported annual incidence of human infection in Europe is around 0.15 per 100 000 population. The disease is much more common worldwide, with overall prevalence ranging from 2.1 per 100 000 in China to 1.7% (with a 95% confidence interval between 1.1-2.6) in African countries.
Clinical description
After ingestion, the larvae develop very slowly, forming cysts that are not diagnosed until 5 to 20 years after contamination. The liver (60% of cases), lungs (20% of cases) and other organs (kidneys, spleen, brain, etc.) are the principle sites of cyst formation. When symptoms exist, they are unspecific and depend on the affected organs. They include abdominal pain, malaise, nausea, vomiting, weight loss. Chronic cough, chest pain and shortness of breath can occur in cases of pulmonary cyst. The disease is often asymptomatic but can become fatal if left untreated for years.
Etiology
It is caused by the larval form (called metacestode) of the tapeworm Echinococcus granulosus.
Diagnostic methods
Diagnosis is mainly based on imaging (abdomen, thorax, etc.) and serologic testing. Cyst type (i.e development stage) should be determined using ultrasound and/or MRI: active (CE1, CE2), transitional (CE3a, CE3b) or inactive (CE4, CE5).
Differential diagnosis
The differential diagnosis includes solitary simple liver cyst, polycystic liver disease and neoplastic liver cyst (cystadenoma and cystadenocarcinoma).
Management and treatment
A stage-specific approach is recommended, based on cyst stage, size, location, presence/absence of complications as well as available medical expertise and equipment. Treatment may involve radical surgery or percutaneous treatments associated with short term antiparasitic treatment with benzimidazoles (BMZ), benzimidazoles alone or watch-and-wait approach (follow-up without treatment, for inactive cysts).
Prognosis
The main risk is fissure or rupture of the cyst, associated with allergic/anaphylactic reaction and dissemination of the parasite. Recurrence after surgical or radiological procedure could also occur. Attributable mortality is low (1-2%) and mainly linked to disseminated and/or atypical forms (in the bone or brain).

                            Last update:
                            August 2023

                            - Expert reviewer(s):
                            Pr Frédéric GRENOUILLET


Cystic fibrosis-gastritis-megaloblastic anemia syndrome

A rare genetic disease characterized by cystic fibrosis, gastritis associated with Helicobacter pylori, folate deficiency megaloblastic anemia, and intellectual disability. There have been no further descriptions in the literature since 1991.


A rare, genetic pulmonary disorder characterized by sweat, thick mucus secretions causing multisystem disease, chronic infections of the lungs, bulky diarrhea and short stature.

Summary:
Epidemiology
Cystic fibrosis (CF) is the most common genetic disorder among Caucasians. In Europe, the average prevalence at birth is 1/5,000; the average prevalence in the general population is 1/9,000. There is wide variation in both rates depending on geographic location.
Clinical description
CF is chronic and usually progressive. Symptoms often start at birth and involve the lungs and gastrointestinal tract. A common presentation might include thick secretions and chronic infections in the lung, bulky diarrhea and short stature. Abnormal airway secretions, inflammation and infections lead to bronchiectasis and early death. CF-related diabetes (CFRD) occurs at high frequency, rising to nearly 50% of patients surviving to age 50. Male sterility is common. Individuals with mild phenotypes may have mild or absent respiratory symptoms in childhood, but some may have infertility or may develop bronchiectasis or pancreatitis later in life. These individuals are typically diagnosed by newborn screening, but may be diagnosed later in life.
Etiology
Abnormal chloride channel function causes high salt content sweat and highly viscous mucus secretions. CF is a monogenic autosomal recessive disease caused by CFTR mutations. Among thousands of mutations, less than 300 cause disease when present in a homozygous or compound heterozygous state. About 70% of patients are homozygous for the delta F508 allele; 30 other mutations account for 20% of cases. Genotype and phenotype correlate poorly, but mutations associated with pancreatic insufficiency lead to more severe phenotypes. Mutations permitting residual CFTR function (e.g. R117H) are associated with the milder phenotype. Many factors influence phenotype.
Diagnostic methods
Diagnosis requires a typical clinical syndrome and either laboratory confirmed CFTR protein dysfunction or presence of two disease-causing mutations of CFTR on heteroalleles. Sweat testing confirms protein dysfunction. Newborn screening may presumptively diagnose CF before symptoms.
Differential diagnosis
Any cause of bronchiectasis may mimic CF including primary ciliary dyskinesia, immunodeficiency, autoimmune disease, untreated pneumonia, esophageal reflux, or anatomic limitation to airway clearance such as in scoliosis. Some unusual or rare conditions falsely elevate sweat chloride suggesting CF. Genetic testing helps in these cases.
Antenatal diagnosis
In at risk pregnancies, mutation analysis of chorionic villus samples after gestation week eight is possible for diagnosis.
Genetic counseling
The pattern of inheritance is autosomal recessive. Genetic counseling should be offered to at risk couples carrying CF mutations (identified by birth of a child with CF, neonatal screening detection of carrier status or family history), informing them that the risk of having an affected child at each pregnancy is 25%.
Management and treatment
Treatment is transitioning from addressing symptoms to correcting biochemical defects. The oldest therapies include bronchial drainage and broad spectrum antibiotics for increasingly resistant pathogens. Pancreatic enzyme replacement with vitamin and calorie supplements improve digestion and nutrition. Insulin replacement for CFRD addresses lack of insulin release not seen in other types of diabetes. New CFTR modulators partly restore chloride channel function in about 90% of patients. However, they do not treat absent, truncated or severely malformed proteins.
Prognosis
Lung disease is the main driver of morbidity and mortality. However, non-specific treatments improved the expectation of life at birth to more than 35 years, and with the advent of CFTR modulator therapy life expectancy has increased to nearly 50 years. Prognosis for newborns with CF may soon approach that of general populations. However, aging CF patients may be more vulnerable to disease associated with aging than the general population.

                            Last update:
                            October 2020

                            - Expert reviewer(s):
                            Dr Theodore LIOU


Cystic hamartoma of lung and kidney is a rare developmental malformation reported in 3 patients characterized by the presence of benign hamartomatous cysts in kidney and lung, clinically presenting as abdominal mass. Others associated features include hyperplastic nephromegaly, medullary dysplasia and mesoblastic nephroma. There have been no further descriptions in the literature since 1987.


Cystic leukoencephalopathy without megalencephaly is characterised by non-progressive leukoencephalopathy, bilateral cysts in the anterior part of the temporal lobe, cerebral white matter anomalies and severe psychomotor impairment. Less than 50 patients have been described in the literature so far. Inheritance is most likely autosomal recessive.


Cysticercosis is a parasitic infectious disease characterized by cyst formation in the target tissue of Taenia solium (tapeworm) parasite larvae ingested via the feces of a human with a tapeworm (human-to-human fecal-oral transmission) leading to variable clinical manifestations in muscle, the brain, spinal cord, and eyes. Infection of muscle tissue is generally asymptomatic. Cyst development in the brain and spinal cord is known as neurocysticercosis (NCC) and may cause seizures and headache. NCC can follow a serious course and may be life-threatening. Severe cases of cysticercosis are treated with albendazole and anti-inflammatory drugs.


A rare lysosomal disease characterized by an accumulation of cystine inside the lysosomes, causing damage in different organs and tissues, particularly in the kidneys and eyes. Three clinical forms have been described: nephropathic infantile, nephropathic juvenile and ocular.

Summary:
Epidemiology
The prevalence at birth is estimated at around 1/100,000- 1/200,000.
Clinical description
In the infantile form (the most common), the first clinical signs appear between 3 and 6 months of age, with a polyuria-polydipsia syndrome and marked growth delay secondary to a generalized proximal tubular dysfunction with severe fluid-electrolyte balance alterations (renal Fanconi syndrome). Hypophosphatemic rickets causing bone deformities are also observed. Ocular involvement caused by cystine deposits in the cornea is responsible for photophobia which usually appears after 3 years of age. Cystine deposits in various organs progressively lead to hypothyroidism, insulin-dependent diabetes, hepatosplenomegaly with portal hypertension in some patients, and muscle and cerebral involvement. In the absence of specific treatment, the disease progresses to end stage renal failure before the age of 10. The first symptoms of juvenile cystinosis (< 5% of patients), typically appear around 6-8 years of age with a milder form of proximal tubulopathy and/or proteinuria in nephrotic syndrome. Progression to renal failure occurs later than in the infantile form. Finally, the ocular form is observed in adults who are generally asymptomatic and may suffer only from photophobia.
Etiology
Cystinosis is due to a defect in cystine transport out of lysosomes. The causative gene, CTNS (17p13), encodes cystinosin, a lysosomal membrane protein. Mutations in this gene have been detected for all 3 forms of the disease, with a 57-kb deletion detected in 60%-70% of alleles in patients from Northern Europe. Severe truncating mutations cause a more severe disease (infantile form) while mutations allowing the protein residual function cause milder phenotypes (juvenile or ocular).
Diagnostic methods
The diagnosis is based on blood and urine analysis showing features of renal Fanconi syndrome (metabolic acidosis, hypokalemia, hypophosphatemia, hyperaminoaciduria, glycosuria, low molecular weight proteinuria), detection of cystine crystals in the cornea and determination of elevated cystine levels in leucocytes. It is confirmed by CTNS gene analysis.
Differential diagnosis
Differential diagnosis includes other diseases causing renal Fanconi syndrome (Lowe syndrome, Dent disease, galactosemia, fructose intolerance, thyrosinemia, mitochondrial nephropathies, Wilson disease, Fanconi-Bickel syndrome, lysinuric protein intolerance, idiopathic Fanconi syndromes, secondary Fanconi syndrome due to drug toxicity or substance abuse, recovery of acute tubulus necrosis), diseases causing phosphaturia and rickets, and proteinuria of unknown etiology.
Antenatal diagnosis
A prenatal, genetic diagnosis is possible in families with a previously affected child.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling is recommended for affected families. The risk of disease transmission is 25% where both parents are unaffected carriers; disease severity depends on the mutation.
Management and treatment
Treatment consists of administering electrolytes, alkali, phosphate and vitamin D supplements; indomethacin, which improves the general status and growth; and cysteamine. Cysteamine lowers the cystine content in the lysosomes, thereby slowing or even stopping the progression to renal failure and the development of extra-renal manifestations. The side effects of cysteamine include gastrointestinal symptoms, bad breath, sweat odor and allergic reactions. A delayed-released formulation has been developed and approved in the USA and Europe, which allows patients to receive cysteamine twice a day, thus improving compliance and quality of life. Topical cysteamine eye drops (0.5%) are also needed as systemic cysteamine has no effect on cystine corneal deposits.
Prognosis
Life expectancy has significantly improved with therapy. Cysteamine delays the need for renal replacement therapy. The disease does not recur in the graft after renal transplantation but continues to progress in other organs and may cause complications (swallowing dysfunction, neurologic complications, lung disease) that may worsen the prognosis.

                            Last update:
                            February 2020

                            - Expert reviewer(s):
                            Pr Elena LEVTCHENKO | ERKNet*

                                * European Reference Network


A rare disorder of renal tubular amino acid transport characterized by recurrent formation of kidney cystine stones.

Summary:
Epidemiology
Prevalence of cystinuria has high ethnogeographic variation, ranging from 1:2,500 in the Libyan Jewish population to 1:100,000 in Sweden. The mean global value is estimated at 1:7,000.
Clinical description
Cystinuria develops in patients of any age but renal colic due to cystine stone appears generally in the first two decades of life, with a median age of onset of 15 years. Male patients tend to present with more aggressive disease, and occurrence of renal stones before the age of 3 is more frequent in males. Urolithiasis is bilateral in more than 75% of cases and recurrence rate is over 60%, with a higher rate in male patients. Renal insufficiency is uncommon.
Etiology
Cystinuria is due to mutations in SLC3A1 (2p21) and SLC7A9 (19q13.11). Both genes are expressed in the renal proximal tubules and the intestinal tract and code for subunits of trans-epithelial transporters for the dibasic amino acids cystine, ornithine, lysine and arginine. The transporter deficiency leads to accumulation of cystine in the urine and subsequent precipitation of cystine crystals or even stone formation. Classification of patients now relies on genetic criteria: type A and type B cystinuria are respectively associated with mutations in the genes SLC3A1 and SLC7A9. Heterozygotes with mutation in one SLC3A1 allele are unaffected, while those who carry mutation in a single SLC7A9 allele show moderately increased urine output of cystine and dibasic amino acids and have a higher risk of developing renal stones when compared to the general population.
Diagnostic methods
Diagnosis relies on physical examination, detection of cystine stones and assay of excreted cystine in urine, which in children and young infants may be normalized for urine creatinine. Analysis reveals urinary cystine excretion over 300 - 400 mg/day. Renal ultrasound imaging is the method of choice for stone detection and follow-up. Molecular genetics may confirm diagnosis.
Differential diagnosis
Differential diagnosis includes three syndromes in which cystinuria is present: 2p21 deletion syndrome, hypotonia-cystinuria syndrome (HCS) and atypical HCS.
Antenatal diagnosis
Detection of a hyperechoic colon at routine ultrasound scan before 36 weeks of gestation may suggest a possible diagnosis of cystinuria with a high positive predictive value (89%). In any case, confirmation of the diagnosis should be made after delivery.
Genetic counseling
Type A cystinuria has an autosomal recessive mode of inheritance, whereas dominant transmission with incomplete penetrance is typically observed in type B cystinuria.
Management and treatment
Treatment requires several approaches to prevent stone formation or growth: high hydration to reduce urinary cystine osmolality, urinary alkalinization to increase cystine solubility (mainly with potassium citrate), and pharmacological cystine-binding medications (alpha-mercaptopropionylglycine, or tiopronin, and D-Penicillamine) to lower free cystine levels in the urine. Measuring the free fraction of cystine in the urine enables titration of the treatment with cystine binding drugs. Side effects of D-Penicillamine and tiopronin, in particular proteinuria, are not uncommon and require routine monitoring with dipsticks and frequently lead to discontinuation of the treatment; they also require zinc, copper and/or vitamin B6 supplementation. Low protein diet in adults or even adolescents is not very effective. When a cystine stone is still small (under 12 mm), extracorporeal shock wave lithotripsy is feasible, but with low efficiency due to the consistency of cystine stones. Over this size, laser stone fragmentation or even percutaneous nephrolithotomy is necessary.
Prognosis
Prognosis is good but low patient compliance and recurrence of stone formation and subsequent interventions can very rarely induce renal insufficiency.

                            Last update:
                            September 2019

                            - Expert reviewer(s):
                            Dr Luca DELLO STROLOGO | ERKNet*

                                * European Reference Network


Cystoid macular dystrophy is an autosomal dominantly inherited cystoid macular edema manifesting with macular atrophy, strabismus and, sometimes, pericentral retinitis pigmentosa (see this term). It is associated with a poor visual prognosis.


Cytophagic histiocytic panniculitis (CHP) is a very rare form of panniculitis manifesting as recurrent multiple subcutaneous nodules (which may progressively become ecchymotic and ulcerated), and histologically characterized by lobular panniculitis with lymphocytic and histiocytic infiltration in the subcutaneous adipose tissue.

Summary:
Epidemiology
The exact prevalence is unknown, but less than 100 cases have been reported (mostly middle-aged and elderly patients).
Clinical description
The histiocytic infiltration often involves lymph nodes, bone marrow and other tissues of the reticuloendothelial system. Severe fever, malaise, pancytopenia, hepatosplenomegaly, and mucosal ulcers are common systemic symptoms.
Etiology
The etiology remains unclear. In more than 50% of cases, the disease occurs in immunocompromised patients (those with immunodeficiency, autoimmune disease or hematological disease) and is triggered by an infection (mainly with a virus from the herpes-virus family).
Diagnostic methods
Diagnosis relies on the histological features of fat infiltration.
Differential diagnosis
Differential diagnosis includes malignant histiocytosis and virus-associated hemophagocytic syndrome, as well as systemic Weber-Christian panniculitis (see these terms). A search for subcutaneous T-cell lymphoma is mandatory.
Management and treatment
Management involves symptomatic treatment and systemic chemotherapy. Combinations of cytotoxic and immunosuppressive drugs have been reported to be efficient. Chemotherapy followed by stem cell rescue should be considered in severe cases.
Prognosis
Although remissions have been reported, the disease tends to follow a chronic course often complicated by terminal hemorrhagic diathesis and organ system failure.

                            Last update:
                            June 2007

                            - Expert reviewer(s):
                            Pr Giovanna ZAMBRUNO


Cytosolic phospholipase-A2 alpha deficiency associated bleeding disorder

A rare genetic hematologic and intestinal disease characterized by childhood onset of bleeding tendency with epistaxis, gum bleeding, gastrointestinal bleeding, hematuria, and menorrhagia due to impaired platelet aggregation and secretion, as well as recurrent gastrointestinal ulcera. Mildly reduced levels of coagulation factor XI have been reported in addition.


Czeizel-Losonci syndrome (CLS) is an exceedingly rare, severe, congenital genetic malformation disorder characterized by split hand/split foot, hydronephrosis, and spina bifida. Spinal and skeletal manifestations were thoracolumbar scoliosis, spinabifida (spina bifida occulta or spina bifida cystic), Bochdalek diaphragmatic hernia, and radial defects.There have been no further descriptions in the literature since 1987.


A rare inborn error of metabolism characterized by severe neonatal epileptic encephalopathy, episodes of apnea and respiratory distress, severe global developmental delay or absent psychomotor development, severe muscular hypotonia or absent voluntary movements, feeding difficulties and failure to thrive, absence of visual contact, abnormal brain morphology (including cerebral atrophy, ventriculomegaly and hypoplasia or dysplasia of the corpus callosum), mild dysmorphic features (frontal bossing, hypertelorism, downslanting palpebral fissures, flat nasal bridge), elevated CSF and plasma lactate and urinary Krebs cycle metabolites.


D-2-hydroxyglutaric aciduria (D-2-HGA) is a rare clinically variable neurological form of 2-hydroxyglutaric aciduria (see this term) characterized biochemically by elevated D-2-hydroxyglutaric acid (D-2-HG) in the urine, plasma and cerebrospinal fluid.

Summary:
Epidemiology
Exact prevalence and incidence of this disorder are not known but about 80 cases have been reported to date. No geographical predominance has been found for this disorder.
Clinical description
D-2-hydroxyglutaric aciduria has extremely variable clinical manifestations. Severe cases are characterized by neonatal or early infantile-onset epileptic encephalopathy. Marked hypotonia, cerebral visual failure, developmental delay, seizures, involuntary movements, and cardiomyopathy are common in these cases. Facial dysmorphic features have been reported frequently and include a flat face with a broad nasal bridge, and external ear anomalies. In mild cases, the clinical picture is more variable. Developmental delay and hypotonia are the most common findings. No correlation between D-2-HG levels and clinical symptoms has been found. Some patients with elevated D-2-HG levels are asymptomatic. In general, D-2-hydroxygluratic aciduria caused by heterozygous IDH2 mutations, has a more severe clinical course than D-2-hydroxygluratic aciduria caused by mutations in the D2HGDH gene.
Etiology
Mutations in the D2HGDH gene (2p25.3) encoding mitochondrial D-2-hydroxyglutarate dehydrogenase have been identified in approximately 50% of patients with this disorder. Others were found to harbor a pathogenic heterozygous mutation in the IDH2 gene (15q21-qter) encoding mitochondrial isocitrate dehydrogenase.
Diagnostic methods
Diagnosis is established on the basis of excess D-2-hydroxyglutaric acid in the urine and MRI findings: subependymal cysts, delayed cerebral maturation, and periventricular white-matter abnormalities in severe cases.
Differential diagnosis
Urinary organic acid screening does not allow differentiation between L-2-hydroxygluratic acid and D-2-hydroxyglutaric acid. Therefore, this differentiation has to be performed subsequently by a specialized laboratory.
Antenatal diagnosis
Prenatal diagnosis can be performed by mutational analysis and detection of increased levels of D-2-hydroxyglutaric acid in amniotic fluid.
Genetic counseling
D-2-HGA caused by mutations in the D2HGDH gene follows an autosomal recessive pattern of inheritance. Genetic counseling is complicated due to the extremely wide clinical picture and poor understanding of the genetic etiology and underlying mechanisms. In contrast, D-2-HGA caused by a de novo heterozygous mutation in the IDH2 gene, is an autosomal dominant trait, with the exception for one reported family.
Management and treatment
There is no specific treatment for D-2-hydroxyglutaric aciduria. Management mainly involves control of seizures when they are present.
Prognosis
The prognosis is entirely dependent on the severity of the clinical picture and course of the disease.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Pr G.S. [Gajja] SALOMONS  - Dr E.A. [Eduard] STRUYS


A rare inborn error of metabolism characterized by abnormal urinary excretion of D-glyceric acid due to D-glycerate kinase deficiency. Reported manifestations are highly variable and include a severe encephalopathic picture, chronic metabolic acidosis, developmental delay, intellectual disability, microcephaly, seizures, behavioral abnormalities, as well as only mild speech delay and apparently normal development.


A rare multiple congenital anomalies/dysmorphic syndrome characterized by the association of congenital hypoparathyroidism, nephropathy, congenital lymphedema, mitral valve prolapse and brachytelephalangy. Additional features include mild facial dysmorphism, hyperthricoses, and nail abnormalities. There have been no further descriptions in the literature since 1993.


Dandy-Walker malformation-postaxial polydactyly syndrome

A syndromic disorder with, as a major feature, the association between Dandy-Walker malformation and postaxial polydactyly. The Dandy-Walker malformation has a variable expression and is characterized by a posterior fossa cyst communicating with the fourth ventricle, the partial or complete absence of the cerebellar vermis, and facultative hydrocephalus. Postaxial polydactyly includes tetramelic postaxial polydactyly of hands and feet with possible enlargement of the fifth metacarpal and metatarsal bones, as well as bifid fifth metacarpals.


A rare X-linked genetic condition due to deficiency of the lysosomal-associated membrane protein 2 (LAMP2) characterized by severe cardiomyopathy and variable degrees of muscle weakness, frequently associated with intellectual deficits (in males).

Summary:
Epidemiology
More than 100 families have been described in the literature so far.
Clinical description
The disease classically manifests in males at a median age of 13-14 years. The clinical picture may be severe in both sexes, but onset generally occurs later in females and disease progression tends to be slower in females.
Etiology
The disease is caused by mutations in the LAMP2 gene, localised to Xq24. The LAMP2 protein is an essential component of the lysosomal membrane and appears to play a role in autophagosome-lysosome fusion and the cellular process of autophagy. Originally the condition was classified as a 'glycogen storage disease' reflecting elevated glycogen visible on histological analysis; however, as the condition is not due to a specific defect in glycogen storage, the name Danon disease is currently preferred.
Diagnostic methods
The main diagnostic method is molecular genetic testing for identification of loss-of-function variants in LAMP2. Histological and/or electron microscopy findings of cytoplasmic vacuoles and increased cellular glycogen levels can be suggestive of the diagnosis. Exclusion of Pompe disease should be done if LAMP2 molecular testing is non-conclusive. Staining of LAMP-2 protein revealing reduced or absence in males heart, muscle, lymphocytes, may also be performed for diagnosis, but is not widely available clinically. Identification of a LAMP2 pathogenic variant in a proband allows cascade testing of other at-risk relatives.
Differential diagnosis
The differential diagnosis should include X-linked myopathy with excessive autophagia (XMEA) and glycogen storage disease type 2.
Antenatal diagnosis
Antenatal diagnosis of at-risk pregnancies can be done if a known LAMP2 pathogenic variant has been detected in a parent (typically detected in the mother as males with this disease have reduce reproductive fitness).
Genetic counseling
Genetic counseling is recommended for the X-linked inheritance pattern seen in the disease.
Management and treatment
There is no specific treatment for this disease. Symptomatic treatment is required for the cardiac manifestations and patients may require a heart transplant.
Prognosis
Patients are at risk of sudden death due to arrhythmia and/or heart failure during early adulthood. Death or transplant occurs at median ages in males and females of 19-21 years and 34-38 years, respectively.

                            Last update:
                            January 2024

                            - Expert reviewer(s):
                            Dr Eric ADLER  - Dr Matthew TAYLOR