Posterior amorphous corneal dystrophy (PACD) is a very rare form of stromal corneal dystrophy (see this term) characterized by irregular amorphous sheet-like opacities in the posterior corneal stroma and in Descemet membrane and mildly impaired vision.

Summary:
Epidemiology
Prevalence of this form of corneal dystrophy is not known. To date cases have been reported primarily in the USA.
Clinical description
Patients usually develop corneal abnormalities in infancy or childhood. The condition is non-progressive or slowly progressive. Visual acuity is usually only minimally affected but in some more severe cases, penetrating keratoplasty (PK) may be warranted. Unlike other corneal dystrophies, non-corneal manifestations have been observed and include abnormalities of the iris (iridocorneal adhesions, corectopia, and pseudopolycoria).
Etiology
The etiology of the condition is not known but it is thought to be genetic. The chromosomal locus of the gene responsible for PACD has not been determined.
Diagnostic methods
Opacities are diffuse gray-white and sheet-like and can involve any layer of the stroma but are most prominent posteriorly. The lesions can be centroperipheral, extending to the limbus, or peripheral, the latter with less pronounced findings and symptoms. There are often transparent stromal breaks in the opacification.
Genetic counseling
An autosomal dominant pattern of inheritance has been reported.
Management and treatment
Since the entire stroma is involved, a penetrating kertopasty is indicated if visual impairment is clinically significant.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Dr Gordon KLINTWORTH


Posterior column ataxia-retinitis pigmentosa syndrome

Posterior column ataxia - retinitis pigmentosa is characterized by the association of progressive sensory ataxia and retinitis pigmentosa.

Summary:
Epidemiology
Around 20 cases have been described in the last 50 years.
Clinical description
Onset of symptoms usually occurs in childhood. The clinical picture is progressive, homogenous and includes severe sensory ataxia, proprioceptive loss (affecting the iliac crest, upper limbs and thorax), generalized areflexia and diffuse pigmentary retinopathy leading to blindness. Scoliosis, camptodactyly, achalasia and/or gastrointestinal motility dysfunction may also be present.
Etiology
The disease is associated with degeneration of the posterior column of the spinal cord. The causative gene, FLVCR1 (1q32.3), has been identified and localized to the AXPC1 locus (1q32-q31).
Genetic counseling
Transmission is autosomal recessive or pseudodominant.
Prognosis
The disease evolves progressively, in some cases leading to a total loss of walking ability and vision after 10 to 30 years of progression.

                            Last update:
                            May 2011


Posterior corneal dystrophies refers to a group of rare genetically determined corneal dystrophies (CDs) characterized by lesions affecting the corneal endothelium and Descemet membrane, and variable effects on vision depending on the type of dystrophy.

Summary:
Epidemiology
Prevalence of this group of corneal dystrophies is unknown.
Clinical description
Age of onset is variable. Five subtypes of posterior CD have been identified and include: Fuchs endothelial CD, Posterior polymorphous CD, Congenital hereditary endothelial dystrophy I and II, and X-linked endothelial CD (see these terms).
Etiology
Posterior corneal dystrophies, like other corneal dystrophies, appear to be genetic disorders. Although the various subtypes have mostly been described in detail, a relationship between some of them has been suggested on the basis of molecular genetic data. There is both phenotypic and allelic heterogeneity. Mutations in the following genes have been found in association with posterior CD: COL8A2 (1p34.2-p32.3), SLC4A11 (20p12), VSX1 (20p11.21), and ZEB1 (10p11.22).
Genetic counseling
Transmission is autosomal dominant or recessive, or X-linked recessive depending on the type.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Dr Gordon KLINTWORTH


A rare neurologic disease characterized by impairment of higher visual processing skills and other posterior cortical functions without any evidence of ocular abnormalities, relatively intact memory and language in the early stages, and atrophy of posterior brain regions.

Summary:
Epidemiology
Posterior Cortical Atrophy (PCA) prevalence is unknown, largely due to the lack of awareness of the syndrome, delayed diagnosis and the variable terminology referring to it (now partially addressed through international consensus criteria).
Clinical description
Early PCA symptoms include visuoperceptual and visuospatial dysfunction, apraxia and alexia. Features of Bálint syndrome (simultanagnosia, optic ataxia and oculomotor apraxia) and Gerstmann syndrome (acalculia, agraphia, finger agnosia and left-right disorientation) are commonly described. The disorder typical onset is between 50-65 years of age. Earliest reported symptoms include difficulties with complex visual behaviors (e.g. driving, reading, and telling the time from an analogue watch). Reading problems include getting lost on the page (visual disorientation), overlapping or miscombined letters (visual crowding) or better reading of small than large print. Odd visual manifestations like abnormally prolonged color after-images and perception of movement of static stimuli are also reported. People with PCA tend to have relatively well preserved memory, insight, and judgment early in the disease course, athough language problems (word finding problems, phonological errors) often emerge early. It should also be noted that PCA is a relatively heterogenous syndrome with some experiencing a very focal visual syndrome, whilst others show a more mixed cognitive picture with prominent visual but also evident episodic memory deficits from early in the disease course. Individuals with PCA often experience anxiety and depression from early on. Extrapyramidal signs, myoclonus, and grasp reflex have also been reported in PCA patients. An international consensus classification framework distinguishes two syndromic description levels. Classification 1 (PCA) defines the core clinical, cognitive, and neuroimaging features and exclusion criteria of the clinico-radiological syndrome. Classification level 2 (PCA-pure, PCA-plus) establishes whether, in addition to the core PCA syndrome, the core features of any other neurodegenerative syndromes are present.
Etiology
A third level of the international classification framework provides disease-level descriptions of the underlying causes of the PCA syndrome, based on available pathophysiological biomarker evidence. This distinguishes between Alzheimer's disease as the most common underlying pathology (PCA-AD), and other causes including Lewy Body disease (PCA-LBD), corticobasal degeneration (PCA-CBD) and prion disease (PCA-prion).
Diagnostic methods
PCA is an under-recognized disorder resulting often in a significant delay in diagnosis. Diagnosis of this clinico-radiological syndrome is based on neurological assessment, specific visual and cognitive testing, and (optional supportive) brain imaging and routine blood tests. MRI characteristically shows bilateral atrophy in the occipital, parietal and posterior temporal lobes, often asymmetric being more pronounced in the right hemisphere. Single photon emission computed tomography (SPECT) or PET show hypometabolism of the posterior cerebral areas as well as in the frontal eye fields in more advanced stages. Conclusive diagnosis of the underlying disease is confirmed on brain autopsy, though CSF and amyloid imaging may help to refine the clinical diagnosis.
Differential diagnosis
Differential diagnosis includes the most commonly associated neuropathology Alzheimer disease, but may also include Lewy body disease, cortico-basal degeneration, and prion diseases such as Creutzfeldt-Jakob disease.
Management and treatment
There is currently no cure for any of the neurodegenerative conditions that most commonly underly the PCA syndrome. Medications like acetylcholinesterase inhibitors, used in the treatment of Alzheimer's disease, are available and might bring relief for some symptoms. Management of PCA is based on visual aids, rehabilitation programs that include psychoeducation, compensatory strategies, and cognitive exercises to cope with visual disabilities. Antidepressant treatments may benefit individuals with PCA who have relatively preserve insight into their decline and often deal with depression, irritability, frustration and a loss of self-confidence. People with PCA and their caregivers are likely to have different needs to people with more typical presentations of Alzheimer's disease, and may benefit from specialized support groups.
Prognosis
Prognosis is poor as PCA is progressive disorder. Life expectancy after PCA diagnosis is thought to be similar (8-12 years) to individuals affected with Alzheimer's disease.

                            Last update:
                            July 2020

                            - Expert reviewer(s):
                            Pr Sebastian CRUTCH


Posterior fusion of lumbosacral vertebrae-blepharoptosis syndrome

A rare syndrome characterized by congenital ptosis and posterior fusion of the lumbosacral vertebrae. It has been described in a mother and her two daughters.


Posterior polymorphous corneal dystrophy

A rare mild subtype of posterior corneal dystrophy characterized by small aggregates of apparent vesicles bordered by a gray haze at the level of Descemet membrane, generally with no effect on vision.

Summary:
Epidemiology
Prevalence of this form of corneal dystrophy is unknown.
Clinical description
Lesions generally develop in early childhood and are mostly bilateral but may be asymmetrical or unilateral in some cases. Most patients are asymptomatic with no corneal edema, but progressive visual impairment due to stromal clouding may rarely occur.
Etiology
PPCD is a genetically heterogenous condition with extremely variable expression. Three genes have been implicated: VSX1 (20p11.21), COL8A2 (1p34.2-p32.3), and ZEB1 (10p11.22), but the evidence implicating VSX1 and COL8A2 is questionable.
Diagnostic methods
Multiple layers of collagen manifesting as focal fusiform or nodular excrescences are found on the posterior surface of Descemet membrane.
Differential diagnosis
PPCD should be distinguished from congenital endothelial dystrophy type 1 (CHED1, see this term), since the two conditions share certain morphological and clinical features.
Genetic counseling
An autosomal dominant pattern of inheritance has been reported.
Management and treatment
Most patients with PPCD do not require therapy, but some may eventually require a penetrating keratoplasty or a procedure for repairing the posterior surface of the cornea, such as a deep lamellar endothelial keratoplasty (DLEK), Descemet stripping endothelial keratoplasty (DSEK), or Descemet stripping automated endothelial keratoplasty (DSAEK).

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Dr Gordon KLINTWORTH


A rare, congenital, fetal lower urinary tract obstruction (LUTO) anomaly characterized by an abnormal congenital obstructing membrane or leaflets that are located within the posterior urethra associated with significant obstruction of the male bladder restricting normal bladder emptying.

Summary:
Epidemiology
It is the most common anomaly of LUTO with a prevalence estimated at 1/4,750-6,250 male births. Posterior urethral valves (PUV) occur exclusively in males.
Clinical description
PUV represents a spectrum of severity ranging from a disease fatal in infancy to a disease that is minimal and may not manifest until later in life. In the most severe cases, characterized by antenatal oligohydramnios or anhydramnios, the newborn may presents with severe pulmonary distress and features of Potter sequence including wide-set eyes, flattened nose, receding chin and large, low-set ears deficient in cartilage. In toddlers and older children PUV may present with urinary incontinence, poor growth, urinary tract infections, hypertension, lethargy and ultimately renal failure.
Etiology
The embryology of the urethra is not completely understood, particularly as it pertains to pathologic anomalies. Several different theories have been proposed in the development of PUV. It represents a spectrum of severity based on the timing and severity of obstruction. Congenital obstruction of the urinary tract at a critical time in organogenesis has a profound and lifelong effect on kidney, ureteral and bladder function. The inability of urine to pass out of the body of the fetus results in oligohydramnios which in turn may lead to pulmonary hypoplasia and the features of Potter sequence.
Diagnostic methods
Postnatal diagnosis is suggested on renal ultrasound with findings of dilated, thick-walled bladder and a dilated posterior urethra. Postnatal diagnosis is confirmed with voiding cystotourethrography and cystoscopy.
Differential diagnosis
Differential diagnoses include anterior urethral valves, congenital urethral stricture, urethral atresia and Prune Belly syndrome. The diagnosis is then confirmed by postnatal physical examination and postnatal renal ultrasonography along with voiding cystourethrography.
Antenatal diagnosis
Antenatal diagnosis is based on ultrasound, possibly aided by magnetic resonance imaging studies. PUV is characterized by variably enlarged thick-walled, non-emptying urinary bladder and a dilated posterior urethra. Counseling is dependent upon the ultrasound findings that also suggest possible associated renal dysplasia at the time of prenatal diagnosis.
Genetic counseling
The majority of cases occur sporadically; however, some rare cases observed in siblings indicate autosomal recessive or x-linked recessive inheritance.
Management and treatment
Antenatal treatment involves urinary decompression with a vesico-amniotic shunt. Postnatally, PUV is treated using primary valve ablation or creation of a vesicostomy. Further surgical intervention is dependent on the status of the bladder function as well as renal function. Immediately after birth, infants are placed on antibiotic prophylaxis and a means of draining their bladder is accomplished using suprapubic or transurethral catheter diversion. Pulmonary function is assessed and fluid and electrolyte management performed.
Prognosis
The prognosis of PUV is variable depending on the degree of severity of the LUTO. Patients may be susceptible to urinary incontinence, urinary tract infections and progressive renal damage. Approximately one third of patients born with PUV progress to end stage renal disease and all patients need periodic long-term urologic follow-up care. Without intervention, patients are at risk of renal failure and bladder dysfunction. Fertility may be compromised in patients who are uremic.

                            Last update:
                            September 2020

                            - Expert reviewer(s):
                            Pr Yazan RAWASHDEH | EUROGEN*

                                * European Reference Network


Posterior-predominant lissencephaly-broad flat pons and medulla-midline crossing defects syndrome

A rare genetic syndrome with a central nervous system malformation as a major feature, characterized by cortical malformations including posterior predominant lissencephaly and diffuse pachygyria, as well as midline crossing defects, thin corpus callosum, dysplastic hippocampi, narrowing of the brainstem with small pons and midbrain, widening of the medulla, and small cerebellum. Clinically, patients present global developmental delay, severe intellectual disability with poor or absent speech, axial hypotonia, and early-onset seizures, among others.


Vasculitis, characterized by inflammatory lesions in the wall of vessels, may be due to different viruses.

Summary:
Clinical description
CMV induces vasculitis mainly in immunocompromised patients. Lesions may be cerebral, retinal, colonic, radicular... In less common cases, vasculitis affects immunocompetent patients, thus resembling polyarteritis nodosa (PAN) or cutaneous angiitis. Varicella-Zoster virus (VZV) is responsible for two types of vasculitides which are sometimes associated: · a vasculitis affecting large arteries which usually affects the anterior cerebral circulation and is characterized by an acute focal deficit. Most often it occurs in immunocompetent adults after zoster of trigeminal distribution. · a vasculitis affecting small cerebral vessels occurring in immunocompromised individuals and is responsible for multifocal deficit. VZV vasculitis can appear a few months after rash or even without any rash. HIV is responsible for a protean group of vasculitides. Vessels of all sizes may be affected and histological findings are variable. Nevertheless a particular form consists in a necrotizing vasculitis of the aorta and large arteries (resembling Takayasu's arteritis) with aneurysm formation and risk of rupture. Parvovirus B19 has been incriminated in some cases of PAN, cutaneous and placenta angiitis or pseudo Henoch-Schönlein purpura. Other case reports mention vasculitis related to hepatitis A virus, HTLV1 (Human T-cell Leukemia Virus 1), EBV (Epstein-Barr virus) persistent infection, Hantaan virus.
Etiology
Pathophysiology is partially misunderstood. However, mechanisms including direct injury by the virus or vascular damage resulting from immune reaction are incriminated. For instance, endothelial infection by CMV (cytomegalovirus) seems to play a major role in the occurrence of a vasculitis. Immune complexes, associating an immunoglobulin and a viral antigen, can lead to vasculitis because of the activation of complement and inflammatory cells. Few virus are thought to be responsible for vasculitis even though their triggering role is not always easily confirmed.
Management and treatment
Treatment is based on antiviral agents. Corticotherapy and immunosuppressants are very controversial because of the risk of virus replication. A least, for some authors, adjuvant treatment with immunoglobulins or plasma exchange may be helpful.

                            Last update:
                            September 2003


Postnatal microcephaly-infantile hypotonia-spastic diplegia-dysarthria-intellectual disability syndrome

A rare genetic neurological disorder characterized by postnatal microcephaly, hypotonia during infancy followed in most cases by progressive spasticity mainly affecting the lower limbs, and spastic diplegia or paraplegia, intellectual disability, delayed or absent speech, and dysarthria. Seizures and mildly dysmorphic features have been described in some patients.


Postorgasmic illness syndrome is a rare urogenital disease characterized by the appearance of flu-like symptoms (fever, extreme fatigue, myalgia, itchy burning eyes, nasal congestion/rhinorrhea), as well as mood changes, irritability and concentration, memory and attention difficulties, within a few minutes to a few hours after ejaculation. Symptoms disappear spontaneously 3-7 days after onset.


A rare gynecologic or obstetric disease characterized by an abrupt onset of psychiatric symptoms during the first weeks after childbirth. Clinical features include mood changes, depression, anxiety, delusions, and hallucinations, among others. The disease is associated with a risk of suicide or infanticide, as well as an increased risk for recurrence after the next pregnancy and future non-pregnancy related psychotic episodes.


Postpoliomyelitis syndrome (PPS) is a neurologic disorder characterized by the development of new neuromuscular symptoms such as progressive muscular weakness or abnormal muscle fatigability occurring in survivors of the acute paralytic form of poliomyelitis (see this term), 15-40 years after recovery from the disease, and that is unexplained by other medical causes. Other manifestations that can occur gradually include generalized fatigue, muscle atrophy, muscle and joint pain, intolerance to cold, and difficulties sleeping, swallowing or breathing.


Posttransplant acute limbic encephalitis is a rare, acquired, non-paraneoplastic limbic encephalitis disorder, that develops in the setting of treatment-related immunosuppression, typically after allogeneic hemapoietic stem cell transplantation, characterized by onset of confusion, headache, anterograde amnesia, seizures and/or loss of consciousness 2-6 weeks following transplantation. Bilateral, non-enhancing T2 hyperintensities in limbic structures are observed on magnetic resonance imaging. Mild cerebrospinal fluid pleocytosis and syndrome of inappropriate antidiuretic hormone secretion may also be associated.


Postural orthostatic tachycardia syndrome due to NET deficiency

A rare, genetic, primary orthostatic disorder characterized by dizziness, palpitations, fatigue, blurred vision and tachycardia following postural change from a supine to an upright position, in the absence of hypotension. A syncope with transient cognitive impairment and dyspnea may also occur. The norepinephrine transporter deficiency leads to abnormal uptake and high plasma concentrations of norepinephrine.


A muscular channelopathy presenting with a pure myotonia dramatically aggravated by potassium ingestion, with variable cold sensitivity and no episodic weakness. This group includes three forms: myotonia fluctuans, myotonia permanens, and acetazolamide-responsive myotonia.

Summary:
Epidemiology
These diseases are very rare and their prevalence is unknown.
Clinical description
Myotonia develops during childhood or adolescence and is, by definition, aggravated by potassium ingestion. Cold sensitivity is not systematic but when present, it can be of varying severity. Myotonia is rarely associated with attacks of weakness. Some patients describe a warm-up phenomenon while others report an exacerbation with exercise. Myalgias and cramps are frequent. Intensity and topography of myotonic symptoms may vary. In myotonia fluctuans, episodes of stiffness vary in severity and frequency, and occur during the resting period following exercise. In myotonia permanens, myotonia is continuous and severe and can significantly impair respiration. In acetazolamide-responsive myotonia, stiffness is often painful and myotonia is triggered by fasting and mildly by exercise and cold exposure.
Etiology
PAM is a sodium muscle channelopathy due to missense mutations of the SCN4A gene encoding the alpha subunit of the skeletal muscle voltage-gated sodium channel Nav1.4.
Diagnostic methods
Diagnosis is based on clinical history, physical exam, electromyographic (EMG) and genetic tests. EMG features comprise myotonic discharges and normal responses to the provocative tests (repeated short exercise tests with and without cooling). CPK levels vary depending on myotonia severity.
Differential diagnosis
Differential diagnoses include myotonia congenita (see this term), and cold sensitive myotonias such as paramyotonia congenita and hyperkalemic periodic paralysis with paramyotonia.
Genetic counseling
Transmission is autosomal dominant. Genetic counseling should be offered to affected families informing them of the 50% risk that the child of an affected parent has of inheriting the disease-causing mutation.
Management and treatment
Management of patients consists in medical therapy and avoidance of triggering factors (such as potassium-rich food). Mexiletine or carbamazepine is the treatment of choice except in acetazolamide-responsive myotonia where symptoms dramatically improve with acetazolamide. Physical therapy management with massages and stretching may be useful for pain and retractions. In each condition, close monitoring is necessary during surgery. Depolarizing agents can cause severe ventilation problems due to a paradoxical increase of stiffness in respiratory muscles and must be avoided.
Prognosis
Prognosis is good with stability of symptoms during life but respiratory function may be compromised in severe myotonia permanens.

                            Last update:
                            October 2010

                            - Expert reviewer(s):
                            Dr Savine VICART


A rare partial autosomal monosomy characterized by global developmental delay, intellectual disability, multiple cartilaginous exostoses, and craniofacial anomalies (such as brachycephaly, biparietal foramina, large fontanels, craniosynostosis, ptosis, epicanthic folds, prominent nasal bridge with broad, depressed nasal tip, hypoplastic nares, short philtrum, downturned upper lip, and micrognathia). Additional reported features include behavioral abnormalities, myopia, strabismus, and sensorineural hearing loss, among others.


A rare intestinal disease characterized by non-specific inflammation of the ileal reservoir following ileal pouch anal anastomosis surgery. It generally occurs after the restoration of the fecal stream through the pouch and may be classified as acute or chronic, depending on the symptom duration (less or more than 4 weeks). Clinical presentation is variable and unspecific and commonly includes increased stool frequency and fluidity, rectal bleeding, abdominal cramps, bowel urgency, tenesmus, and nocturnal bowel incontinence.


PPARG-related familial partial lipodystrophy

A rare familial partial lipodystrophy characterized by adult onset of distal lipoatrophy with gluteofemoral fat loss, as well as increased fat accumulation in the face and trunk and visceral adiposity. Additional manifestations include diabetes mellitus, atherogenic dyslipidemia, eyelid xanthelasmas, arterial hypertension, cardiovascular disease, hepatic steatosis, acanthosis nigricans on axillae and neck, hirsutism, and muscular hypertrophy of the lower limbs.


PPoma is a type of pancreatic endocrine tumor (see this term) that hypersecretes pancreatic polypeptide (PP) but that does not cause a hypersecretion syndrome (is non-functioning) and instead presents with only non-specific symptoms such as weight loss, abdominal pain, jaundice, diarrhea and/or an abdominal mass, hence leading to a late diagnosis. PPoma can be associated with multiple endocrine neoplasia 1 (MEN-1; see this term).


A rare genetic, neurodevelopmental syndrome characterized by hypothalamic-pituitary dysfunction with severe hypotonia and feeding deficits during the neonatal period followed by an excessive weight gain period with hyperphagia with a risk of severe obesity during childhood and adulthood, learning difficulties, deficits of social skills and behavioral problems or severe psychiatric problems.

Summary:
Epidemiology
Prevalence at birth is estimated at 1/15,000-30,000 worldwide
Clinical description
The severe hypotonia at birth is associated with poor oral and social skills which remain, albeit less clinically evident, throughout life. Characteristic facial features (a narrow forehead, almond-shaped eyes, a thin upper lip and down-turned mouth), as well as very small hands and feet, are frequently observed. After this initial phase, followed by an excessive weight gain without changes in eating, the most striking signs appear: hyperphagia and absence of satiety often leading to severe obesity in affected children as young as three years of age. The situation may deteriorate quickly without strict control of food access. Other associated endocrine abnormalities include short stature due to a growth hormone (GH) deficiency, incomplete pubertal development due to hypogonadism of mixed (central and peripheral) origin, hypothyroidism, premature pubarche and, rarely, corticotropin deficiency. The degree of cognitive dysfunction varies widely but is mild/moderate in most of the individuals. It is associated with learning disabilities, and impaired speech and language development that are aggravated further by psychological and behavioral troubles, impaired social abilities, and control of emotions. Associated comorbidities may include diabetes, sleep-related breathing disorders, gastrointestinal problems, and infections. The Prader-Willi syndrome (PWS) phenotype also occurs in 10% of Fragile X syndrome.
Etiology
The disease is clinically and genetically heterogeneous. Frequently it is caused by either a paternally derived 15q11-q13 deletion, maternal disomy or, very rarely, imprinting defects in the same region.
Diagnostic methods
PWS should be suspected on the presentation of severe neonatal hypotonia, and confirmed by genetic testing which should include methylation analysis, fluorescent in situ hybridization and uniparental disomy testing.
Differential diagnosis
At birth, genetic testing should be used to exclude other causes of hypotonia. If the neonatal phenotype evokes PWS and the genetics are negative, genes for the Prader-Willi-like syndrome (PWS-like) should be searched. In older individuals, the differential diagnosis is of other syndromic obesities such as Bardet-Biedl syndrome, Alström syndrome and, particularly, PWS-like.
Antenatal diagnosis
Diagnosis may be suspected in the last trimester on detection of polyhydramnios, decreased fetal movements and abnormal positions of hand and feet with or without fetal growth restriction. Genetic testing can confirm diagnosis but note that comparative genomic hybridization is not sufficient to exclude PWS.
Genetic counseling
Most cases are sporadic; however, in rare cases dominant transmission may occur with 50% risk where the father carries the imprinting defect.
Management and treatment
Multidisciplinary management should be implemented very early, with particular attention paid to families with psychosocial difficulties. Principally, management is with a strict control of food access and exercise program and, growth hormone (GH) treatment. Associated comorbidities require systematic screening and evaluation. Currently, there are no approved medications to specifically improve the behavioral problems or degree of autonomy obtained. Clinical trials are ongoing for various drugs targeting hyperphagia and behavior.
Prognosis
Obesity is a major factor influencing morbidity and mortality. Early diagnosis, early multidisciplinary care and GH treatment have greatly improved the quality of life of affected children. GH treatment in particular has shown to stabilize body mass index, improve linear growth and adult height and, in children treated before 1 year of age, improve cognitive development. Adolescents benefit from continuing GH treatment. Adults who have received GH as children have lower BMI and less comorbidities. Autonomies can be reached but not complete autonomy.

                            Last update:
                            September 2019

                            - Expert reviewer(s):
                            Dr Gwenaëlle DIENE  - Pr Maithé TAUBER


A rare group of multiple congenital anomalies/dysmorphic syndrome characterized by autism spectrum disorder, developmental delay, intellectual disability, hyperphagia/obesity, and short stature (clinical features overlapping with Prader-Willi syndrome). However, it is a clinically and genetically heterogenous group where patients may completely lack or manifests in minority some classical clinical features of Prader-Willi syndrome such as short stature, hypotonia, hypogonadism, hyperphagia and morbid obesity.


Pre-Descemet corneal dystrophy (PDCD) is a rare form of stromal corneal dystrophy characterized by focal, fine, gray opacities in the deep stroma immediately anterior to the Descemet membrane, with no effect on vision.

Summary:
Epidemiology
The prevalence of this rare entity is unknown.
Clinical description
Onset is usually after 30 years of age but cases have been reported in children as young as 3 years of age. Opacities have a variety of shapes. Large lesions can occur. The rest of the cornea is normal. Various subforms appear to exist but are not clearly defined. Most show progression, while the punctiform and polychromatic pre-Descemet subform is non-progressive.
Etiology
The etiology is unknown; it is unclear whether PDCD is a hereditary or a degenerative disorder.
Genetic counseling
No defnite pattern of inheritance has been identified.
Management and treatment
The deep corneal stroma and Descemet membrane can be stripped. The epithelium and superficial corneal stroma should not be excised.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Dr Gordon KLINTWORTH


Preaxial polydactyly-colobomata-intellectual disability syndrome

A rare multiple congenital anomalies/dysmorphic syndrome characterized by intellectual disability, growth retardation, unilateral preaxial polydactyly, and colobomatous anomalies (including coloboma of the iris, optic nerve head, choroid, and retina). There have been no further descriptions in the literature since 1987.


Precursor B-cell acute lymphoblastic leukemia

A rare acute lymphoblastic leukemia characterized by infiltration of bone marrow and peripheral blood by small to medium-sized blast cells typically positive for the B-cell markers CD19, cCD79a, and cCD22. Predilection sites for extramedullary involvement are the central nervous system, lymph nodes, spleen, liver, and testes. Patients present with evidence of bone marrow failure (i. e. thrombocytopenia, anemia, and/or neutropenia) and variable leukocyte count, as well as lymphadenopathy, hepatomegaly, splenomegaly, bone pain, and arthralgias.


Precursor T-cell acute lymphoblastic leukemia

A rare acute lymphoblastic leukemia characterized by a neoplasm of lymphoblasts committed to the T-cell lineage, involving bone marrow and blood. A value of >25% bone marrow blasts may be used to define leukemia (as opposed to lymphoma) in cases with the presence of a mass lesion in addition to bone marrow involvement. Patients typically present with leukocytosis, and frequently with a large mediastinal or other tissue mass. Lymphadenopathy and hepatosplenomegaly are common.


Predisposition to invasive fungal disease due to CARD9 deficiency

A rare, genetic primary immunodeficiency characterized by increased susceptibility to fungal infections, typically manifesting as recurrent, chronic mucocutaneous candidiasis, systemic candidiasis with meningoencephalitis, and deep dermatophystosis with dermatophytes invading skin, hair, nails, lymph nodes, and brain, resulting in erythematosquamous lesions, nodular subcutaneous or ulcerative infiltrations, severe onychomycosis, and lymphadenopathy.


Predisposition to severe viral infection due to IRF7 deficiency

A rare primary immunodeficiency characterized by a severe, potentially life-threatening course of influenza A infection with acute respiratory distress. Production of type I and III interferons in response to influenza virus is very low, while other immunological abnormalities are absent and no further unusual viral infections occur.


A hypertensive disorder of pregnancy that is characterized by new-onset hypertension with proteinuria presenting after 20 weeks of gestation, and depending on mild or severe forms may initially present with severe headache, visual disturbances, and hyperreflexia.


Premature closure of the arterial duct is a rare arterial duct anomaly, defined as a significant constriction or closure of the fetal arterial duct in the absence of structural heart defects with pathognomonic features of increased right ventricular afterload, tricuspid regurgitation and, consequently, right atrial dilation and right ventricular hypertrophy. The severity of symptoms is related to the degree and rate of ductal constriction and ranges from mild postnatal respiratory distress to development of ventricular failure with fetal hydrops and intrauterine death or severe cardiopulmonary compromise in the postnatal period. It may be associated with a prenatal exposure to cyclooxygenase inhibitors or corticosteroids.


A very rare form of hypophosphatasia characterized by prenatal skeletal manifestations (limb shortening and bowing) that slowly resolve spontaneously and later may develop into the moderate childhood or adult forms of the disease.

Summary:
Epidemiology
The prevalence of prenatal benign hypophosphatasia (PB-HPP) is not known. About 50 cases have been reported to date.
Clinical description
PB-HPP may be identified on prenatal ultrasound examination. Patients manifest variable limb shortening and bowing and often have dimples overlaying long bones deformities. Postnatally, skeletal manifestations slowly resolve and patients eventually develop manifestations corresponding to other, non-lethal forms of HPP (either childhood-onset, adult hypophosphatasia or odontohypophosphatasia). Patients display progressive improvement of the skeletal anomalies and mineralization during the third trimester of pregnancy and after birth. Mothers of affected infants generally have biochemical evidence of hypophosphatasia but no clinical manifestations.
Etiology
Mutations in the ALPL gene (1p36.12) are known to cause hypophosphatasia. The specific mechanisms underlying PB-HPP have not been elucidated.
Diagnostic methods
Diagnosis may be suspected pre- or postnatally on radiological and clinical presentation, respectively. However, it is likely that many patients go undiagnosed until later on when they present with another form of HPP (childhood, adult or odonto HPP). Genetic testing confirms the enzyme deficiency.
Differential diagnosis
Antenatally, the main differential diagnoses include osteogenesis imperfect and perinatal lethal HPP. PB-HPP is differentiated from the perinatal lethal form by normal chest and abdominal circumference in utero and a benign post-clinical course.
Antenatal diagnosis
The disorder may be suspected on prenatal ultrasound findings of limb bowing, limb shortening and/or skeletal hypomineralization. Chest and abdominal circumference are typically normal. A family history of hypophosphatasia and/or genetic testing support diagnosis.
Genetic counseling
Autosomal recessive and autosomal dominant patterns of inheritance have been reported, explaining the wide clinical spectrum. AD inheritance appears to be predictive of a benign course. A significant part of PB-HPP cases are dominantly inherited and seem to display a maternal bias of transmission, the fetus being affected only when the mutation is of maternal origin.
Management and treatment
Cesarean section may be indicated where diagnosis is not confirmed. Management is with observation. Enzyme replacement therapy with recombinant alkaline phosphatase may be indicated where skeletal manifestations persist.
Prognosis
The prognosis is generally good.

                            Last update:
                            February 2020

                            - Expert reviewer(s):
                            Dr Severine BACROT  - Dr Etienne MORNET


Prenatal-onset spinal muscular atrophy with congenital bone fractures

A rare genetic motor neuron disease characterized by decreased or absent fetal movements, congenital proximal and distal joint contractures (consistent with arthrogryposis multiplex congenita), and multiple congenital fractures of the long bones. Further manifestations are neonatal respiratory distress, severe muscular hypotonia, areflexia, dysphagia, congenital heart defects, and dysmorphic facial features. Muscle biopsy shows increased fiber-size variation and grouping of larger type I fibers. The disease is usually fatal in infancy due to respiratory failure.


A rare neurologic disease with psychiatric involvement characterized by significantly lower-than-expected body weight due to voluntary reduction of food intake, intense fear of becoming overweight, and a distorted body image, in prepubescent children. Secondary manifestations include growth, developmental, and pubertal delay, decreased bone density, severe metabolic and endocrine dysfunction, cognitive impairment, depression, deterioration of academic or athletic performance, as well as difficulties in familial and peer relations, among others.


Pressure-induced localized lipoatrophy is a rare, acquired, localized lipodystrophy characterized by band-like, horizontal, asymptomatic, lipoatrophic depressions with clinically normal overlying skin usually involving the anterolateral aspect of the thighs. An identifiable history of the repeated mechanical microtrauma due to occupational or postural habits is present.


A rare acquired aplastic anemia characterized by a severe normocytic anemia with normal peripheral leukocyte and platelet counts, reticulocytopenia, high serum ferritin and transferrin saturation levels and isolated, almost complete absence of erythroblasts in the bone marrow with normal granulopoesis and megakaryopoesis. It presents with signs of severe anemia (fatigue, lethargy, pallor, intolerance of physical exercise and exertional dyspnea) in the absence of hemorrhagic symptoms.


A rare disorder that manifest in adults and generally present with a variety of non-specific manifestations (depending on tumor site and infiltration) such as weight loss, exhaustion, hemorrhagic pericardial effusion, heart failure, arrhythmias, and embolisms, or that can also be asymptomatic. In adults 75% of heart tumors are benign, with myxoma being the most common benign tumor (accounting for 50-70% of all primary heart tumors) and rhabdomyosarcoma comprising 75% of malignant heart tumors. Other malignant tumors of the heart include fibrosarcoma and leiomyosarcoma.


Primary anetoderma is a rare skin disease characterized by loss of elastin tissue resulting in localized areas of flaccid skin in the absence of a secondary cause.


A rare, medium or small vessel vasculitis characterized by focal and/or diffuse neurologic symptoms due to a documented arteritic process in the central nervous system, in the absence of other identified underlying cause (infectious, systemic, other neurologic diseases, etc.). It presents with non-specific symptoms of headache, stroke or transient ischemic attacks with cognitive impairment, hemiplegia, weakness, and rarely, with cranial nerve involvement, seizures and ataxia.

Summary:
Epidemiology
The prevalence is unknown, but it is estimated to account for 1% of the systemic vasculitides.
Clinical description
Primary angiitis of the central nervous system (PACNS) usually affects middle-aged adults (mean age 51 years). Clinical presentation is variable, ranging from hyper acute to chronic and insidious, but typically has a progressive clinical evolution. The most common symptom is headache, variable in description but very rarely a thunderclap headache. Other symptoms include cognitive impairment (usually insidious), stroke (typically multiple, occurring over a (long) period and affecting different areas of the vascular bed) and transient ischemic attacks. Rarely, cranial nerve involvement, myelopathy, seizures or ataxia are observed. Associated angiographic abnormalities are common, cerebral MRI is almost invariably abnormal with nonspecific findings (including, rarely, solitary mass lesion), and cerebrospinal fluid (CSF) examination shows aseptic inflammatory abnormalities. Constitutional symptoms such as fever, weight loss and visceral organ involvement are rare and if present, should raise the suspicion of more systemic illnesses.
Etiology
The primary defect is unknown. Pathological inflammation process affecting the small and medium-sized cerebral vessels causes them to become narrowed, occluded and thrombosed, leading to tissue ischemia and necrosis of the territories of the involved vessels.
Diagnostic methods
Diagnosis of PACNS is established in a patient who: (i) has a history of unexplained neurologic deficit after thorough clinical and laboratory evaluation, (ii) has a documented (by cerebral angiography and/or tissue examination) of an arteritic process within the central nervous system, and (iii) no evidence of systemic vasculitis or any other condition to which the angiographic or pathological features could be secondary. Angiography abnormalities encountered in PACNS are characterized by irregular eccentric notched appearance with distal cutoffs and neovascularization, and typically asymmetric involvement. CSF findings resemble those of an aseptic meningitis with modest lymphocytic pleocytosis, normal glucose levels, elevated protein levels and, occasionally, the presence of oligoclonal bands and elevated IgG synthesis.
Differential diagnosis
Differential diagnosis of PACNS is extensive and challenging, and comprises a range of systemic inflammatory conditions, infections, conditions with cerebral angiographic abnormalities (in particular, reversible vasoconstriction syndrome (RCVS) has highly similar clinical presentation; however, the associated headache is predominantly thunderclap by quality), and other neoplastic, genetic or neurological conditions.
Management and treatment
Glucocorticoids combined with immunosuppressive agents, i.e. cyclophosphamide, has been successful in most cases. Accompanying prophylaxis for P. jirovecii and osteoporosis is necessary.
Prognosis
The disease is chronic and relapses are not uncommon.

                            Last update:
                            October 2020

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


A rare intestinal disease characterized by immune-mediated injury of the intestinal mucosa, leading to severe, chronic, intractable diarrhea, malabsorption, and severe weight loss or failure to thrive. Characteristic histologic findings in the small intestine include partial or complete blunting of the villi, deep crypt lymphocytosis, increased crypt apoptosis, and minimal surface intraepithelial lymphocytosis. In addition, the stomach, colon, and esophagus may also be involved. Circulating autoantibodies against enterocytes and/or goblet cells are found in many, but not all, patients. The diagnosis requires exclusion of other causes of villous atrophy.


A rare skeletal developmental defect characterized by congenital upward translocation of the upper cervical spine and clivus into the foramen magnum. It can be asymptomatic or associated with severe neurological dysfunction.


A rare autoimmune cholestatic liver disease characterized by autoimmune mediated damage of small intrahepatic bile ducts leading to cholestasis, fibrosis, and potential cirrhosis.

Summary:
Epidemiology
Primary biliary cholangitis (PBC) incidence rates range from 0.33 to 5.8 per 100,000 inhabitants/year and prevalence rates range from 1.91 to 40.2 per 100,000 inhabitants Women are predominantly affected with a sex ratio of 9:1.
Clinical description
Onset is generally in the 4th to 6th decades of life. Many patients are asymptomatic at diagnosis and are identified incidentally. The initial presenting manifestations include fatigue (80%) and pruritus (20-70%), both of which fluctuate throughout the disease course. Pruritus is prominently on the palms and soles with worsening at night and can have significant impact on quality of life (occupational ability, depression, obsessive-compulsive disorder). Right upper quadrant discomfort is found less commonly. In late stages, xanthomas and xanthelasmas may develop. Osteopenia and osteoporosis with a risk of fractures are also found, along with hyperlipidemia, hypercholesterolemia, and vitamin deficiencies (vitamin A, D and rarely E). Complications related to cirrhosis include portal hypertension (with spider nevi, hyperpigmentation, palmar erythema, ascites, intra-abdominal varices), splenomegaly, muscle wasting, peripheral edema, and hepatocellular carcinoma. Neurological complications include impaired concentration and memory and disturbed sleep. Concomitant autoimmune disorders are common and include Sjögren's syndrome, CREST syndrome, autoimmune thyroid disease, rheumatoid arthritis and Raynaud syndrome, and often correlate with the autonomic dysfunction observed.
Etiology
The liver damage is due to T-cell-mediated destruction of small bile duct epithelial cells causing ductopenia and persistent cholestasis. The exact etiology is currently unknown; however, it is currently believed to involve a combination of environmental factors (e.g. toxins, chemical substances, smoking and infectious agents), genetic predisposition and loss of immune tolerance.
Diagnostic methods
In adult patients with cholestasis (elevated alkaline phosphatase (ALP) and/or gammaglutamyltransferase (GGT)), PBC can be suspected after excluding obstructive jaundice by abdominal ultrasound and systemic diseases. Diagnosis can be made when disease-specific autoantibodies are detected (i.e. antimitochondrial autoantibodies (AMA titer>1:40) and anti-nuclear autoantibodies (ANA) anti-sp100 and anti-gp210). A liver biopsy is recommended when PBC-specific antibodies are absent, autoimmune hepatitis (AIH) or non-alcoholic steatohepatitis (NASH) are suspected, or when other systemic co-morbidities are present and may have a role in the differential diagnosis of cholestasis.
Differential diagnosis
Differential diagnoses include autoimmune hepatitis, primary sclerosing cholangitis, alcoholic and non-alcoholic steatohepatitis and drug-induced hepatotoxicity.
Genetic counseling
Whilst a causal gene has not been identified, first-degree relatives have a higher risk of developing the disease.
Management and treatment
The aim of treatment is to reduce symptoms and slow disease progression. Ursodeoxycholic acid (UDCA) at dosage of 13-15 mg/kg/day is highly effective in improving transplant-free survival, although has limited effect in treating fatigue and pruritus. In patients with inadequate response (25%‐40%), obeticholic acid should be added. Response to UDCA is evaluated, after a period of 6 to 24 months of treatment, based on changes in bilirubin, transaminases and ALP. Patients with advanced disease should be screened for hepatocellular carcinoma, esophageal varices and considered for liver transplant (LT). Cholestyramine is the first line treatment for pruritus; for intolerant or refractory patients rifampin is indicated.
Prognosis
LT-free survival of patients with normal or near-normal liver biochemistry on UDCA is similar to that of the general population, whereas it is significantly reduced in those with abnormal liver biochemistry on treatment. After liver transplant, the recurrence of disease rate may be as high as 18 percent at five years, and up to 30 percent at 10 years. There is no consensus on risk factors for recurrence of the disease. HCC is infrequent in PBC; however, lack of UDCA-response after 12 months of therapy and male sex are associated with increased risk of developing HCC.

                            Last update:
                            July 2020

                            - Expert reviewer(s):
                            Dr Marco CARBONE  - Dr Laura CRISTOFERI  - Dr Alessio GERUSSI  - Pr Pietro INVERNIZZI | RARE-LIVER*

                                * European Reference Network


Primary biliary cholangitis/primary sclerosing cholangitis and autoimmune hepatitis overlap syndrome

A rare hepatic disease characterized by the overlap of primary biliary cholangitis and/or primary sclerosing cholangitis with autoimmune hepatitis, defined by the presence of at least two of the three recognized biochemical, serological, and histological criteria of each disease. The onset of the overlapping diseases can be simultaneous or sequential, with a variable interval of up to several years. Age of onset, gender predisposition, and clinical phenotype vary between each of the diseases, and the clinical presentation ranges from asymptomatic disease or unspecific symptoms such as fatigue, arthralgia, and pruritus, to established cirrhosis and decompensation, or also acute, fulminant hepatitis and liver failure. Association with extrahepatic autoimmune diseases is common.


Primary bone lymphoma is a rare lymphoid hemopathy defined as single or multiple tumors in the bone, not associated with infringement or violation of other extranodal malignant lymph nodes outside the area. It usually presents with bone pain, nerve compression, a palpable mass or fracture, while systemic features (fever, night sweats, fatigue, loss of appetite, weight loss) are not common.


A rare, genetic, hematologic and neurologic disease characterized by chronic, Coombs-negative hemolysis associated with early-onset, relapsing, immune-mediated, inflammatory, axonal or demyelinating, sensory-motor, peripheral polyneuropathy and isolated or recurrent cerebrovascular events (in anterior or posterior circulation).


Primary central nervous system lymphoma (PCNSL) is a rare nervous system tumor, predominantly due to diffuse large B-cell lymphoma, that involves brain, leptomeninges, eyes, or rarely spinal cord, in the absence of systemic diffusion at the time of diagnosis. It is characterized by a solitary tumor that, depending on its location, can lead to a variety of symptoms such as headache, nausea, vomiting (and other signs of raised intracranial pressure), focal neurologic deficits, neuropsychiatric and ocular symptoms, seizures and personality changes.


Primary ciliary dyskinesia-retinitis pigmentosa syndrome

Primary ciliary dyskinesia - retinitis pigmentosa is an X-linked ciliary dysfunction of both respiratory epithelium and photoreceptors of the retina leading to ocular disorders (mild night blindness, constriction of the visual field, and scotopic and photopic ERG responses reduced to 30-60%) associated with primary ciliary dyskinesia (see this term) manifestations (chronic bronchorrhea with bronchoectasis and chronic sinusitis) and sensorineural hearing loss.


A rare, genetically heterogeneous, primarily respiratory disorder characterized by chronic upper and lower respiratory tract disease. Approximately half of the patients have an organ laterality defect (situs inversus totalis or situs ambiguus/heterotaxy).

Summary:
Epidemiology
Primary ciliary dyskinesia (PCD) has an estimated incidence of 1/15,000-1/30,000 live births, but this is probably underestimation. Prevalence is difficult to determine.
Clinical description
Affected patients develop signs of PCD at birth or within the first few months of life. However, owing to the diagnostic challenges, some cases of PCD are not diagnosed until the adulthood. Most full-term neonates have respiratory distress with tachypnea (infant acute respiratory distress syndrome) and usually require supplemental oxygen for days, some for weeks. The usual findings in infants and children are daily rhinitis, and daily year-round wet cough occurring soon after birth, with associated recurrent or chronic bacterial infections of the lower airways. Chronic otitis media is common, sometimes with temporary or permanent hearing loss and impaired speech development. Most patients have recurrent sinus infections. Bronchiectasis develops in an age-dependent manner, and is nearly universal in adults. Pectus excavatum and scoliosis have been reported rarely (5-10%), as well as digital clubbing. Almost all males with PCD are infertile, due to dysmotility of spermatozoa, although a few have normal sperm motility. Reduced fertility or a history of ectopic pregnancies has been reported in affected women. Situs inversus totalis, a mirror-image reversal of all visceral organs, is found in 40-50% of individuals and is known as the Kartagener type. Heterotaxy (discordance of right and left patterns of normally asymmetric structures) is present in at least 12%, and a subset of those have structural congenital heart disease. A very rare association of X-linked PCD with either retinitis pigmentosa or intellectual deficiency has been reported.
Etiology
Pulmonary disease in PCD is related to defects in lung defense mechanisms due to abnormal ciliary structure and function with impaired mucociliary clearance. Mutations in around 46 different genes throughout the genome have been found to be causative. Some of these include DNAH5, CCDC39, DNAI1, CCDC40, DNAH11, ZMYND10, CCDC103, CCDC151 and ARMC4. A third of currently recognized patients do not have mutations in these genes.
Diagnostic methods
Diagnosis is based on the characteristic clinical signs. Methods include molecular genetic testing identifying biallelic pathogenic variants (or hemizygous in males for X-linked genes, or mono-allelic for autosomal dominant trait) in one of the causative genes, as well as transmission electron microscopy identifying specific ciliary ultrastructural defects in biopsy samples. Other supportive tests include measurement of nasal nitric oxide in upper airways (in patients aged of 5 years or more) that tends to be low in PCD, after cystic fibrosis link has been ruled out, high-speed videomicroscopy to assess cilia waveform and beat frequency, immunofluorescent staining to study ciliary structure, and mucociliary clearance analysis to assess impairment.
Differential diagnosis
The main differential diagnoses are cystic fibrosis, immunodeficiency syndromes and gastroesophageal reflux. Additionally, PCD has been noted in patients with Cri du chat syndrome due to the common locus on chromosome 5p. Segmental deletion of chromosome 5p in Cri du chat syndrome usually includes PCD-associated gene DNAH5 and the pathogenic variant in the remaining allele of DNAH5 renders it to PCD.
Antenatal diagnosis
If disease-causing mutations are known in a family, prenatal diagnosis can be performed using molecular analysis.
Genetic counseling
PCD is usually inherited in an autosomal recessive manner. Some cases with autosomal dominant and X-linked trait have been observed. Genetic counseling should be provided to affected families.
Management and treatment
Regular clinical visits to monitor disease status are key. Aggressive treatment is recommended to improve mucus clearance. Antibiotic therapy is required and routine immunization is advised. Sinus disease can be treated with nasal steroids and nasal lavage. Polyps may require surgical treatment. Audiological assessment, hearing aids, and communication assistance should be offered where necessary. Patients with end-stage lung disease are candidates for lung transplantation.
Prognosis
The prognosis depends on timely diagnosis and appropriate treatment. Life expectancy is likely somewhat shortened, although quantitative estimates are not currently available.

                            Last update:
                            November 2019

                            - Expert reviewer(s):
                            Pr Michael KNOWLES  - Pr Maimoona ZARIWALA


A rare temporomandibular joint anomaly characterized by progressive, asymmetrical, non-neoplastic overgrowth of a mandibular condyle. It is unilateral in most cases and leads to progressive facial asymmetry, mandibular deviation, articular dysfunction, and dental malocclusion.


Primary congenital hypothyroidism without thyroid developmental anomaly is a type of primary congenital hypothyroidism (see this term) in which the thyroid gland is anatomically normal.

Summary:
Epidemiology
Thyroid dyshormonogenesis accounts for 10-15% of permanent congenital hypothyroidism (see this term) while TSH receptor mutations cause less than 5%.
Etiology
It may be caused by either resistance to thyroid stimulating hormone (TSH) as a result of TSH receptor mutations or by inborn errors of thyroid hormone synthesis, also known as thyroid dyshormonogenesis (see these terms), and it results in permanent thyroid hormone deficiency that is present from birth.

                            Last update:
                            August 2010

                            - Expert reviewer(s):
                            Dr Stephen LAFRANCHI  - Dr Maynika RASTOGI


Primary congenital hypothyroidism is a type of permanent congenital hypothyroidism (see this term), a permanent thyroid hormone deficiency that is present from birth.

Summary:
Epidemiology
Prevalence is estimated at 1/2,000-1/4,000.
Etiology
Primary congenital hypothyroidism may be due to a developmental anomaly, also known as thyroid dysgenesis where the thyroid gland fails to develop normally, or may occur without a developmental anomaly as a result of an inborn error of thyroid hormone biosynthesis, also known as dyshormonogenesis, or as a result of thyroid-stimulating hormone (TSH) receptor mutations (see these terms). In iodine sufficient countries, 85% of permanent congenital hypothyroidism is due to thyroid dysgenesis. The remaining 10-15% of cases can be attributed to dyshormonogenesis or to defects in peripheral thyroid hormone transport, metabolism or action. Primary congenital hypothyroidism may also be idiopathic (see this term).

                            Last update:
                            August 2010

                            - Expert reviewer(s):
                            Dr Stephen LAFRANCHI  - Dr Maynika RASTOGI


Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma is a rare form of primary cutaneous T-cell lymphoma characterized by rapidly progressing, localized or disseminated nodules, tumors or eczematous skin lesions. It has a particularly aggressive clinical course with a high tendency to spread, in advanced stages, to extracutaneous locations (the central nervous system, lung, testes). Lymph nodes are often spared.


A rare group of skin diseases characterized histologically by the extracellular accumulation of amyloid deposits in the dermis. Rare forms include lichen amyloidosus, X-linked reticulate pigmentary disorder, primary localized cutaneous nodular amyloidosis, and macular amyloidosis.


Primary cutaneous anaplastic large cell lymphoma (C-ALCL) is a rare T-cell non-Hodgkin lymphoma that affects the skin and generally shows no extracutaneous involvement at presentation. It belongs to the spectrum of primary cutaneous CD30+ lymphoproliferative disorders along with lymphomatoid papulosis (see this term) with which it shares overlapping clinical and histopathologic features.

Summary:
Epidemiology
The prevalence of primary C-ALCL is unknown but it accounts for approximately 9% of cutaneous lymphomas. The male/female ratio is of 3:2.
Clinical description
Primary C-ALCL generally occurs in adults and rarely in children and adolescents. Large solitary or multiple slow-growing erythematous skin plaques, nodules or tumors develop, in either a localized or multifocal distribution. These lesions may ulcerate and/or itch. In 10% of cases, primary C-ALCL extends beyond the skin to lymph nodes and manifests as a painless swelling, especially in the neck, armpit or groin. It can also extend to extranodal sites. General symptoms, usually present in cases with extracutaneous involvement, include loss of appetite, weight loss, fatigue, and night sweats (B symptoms).
Etiology
Etiology is unknown.
Diagnostic methods
Diagnosis is based on physical examination and medical history, and is confirmed by histopathological and immunohistochemical evaluation of skin biopsies showing cell infiltrates of anaplastic cytology (atypical large cells with abundant cytoplasm, prominent nucleoli, and horseshoe-like or reniform nuclei), within the dermis or subcutis, with constant membrane expression of the CD30 T-cell antigen in the majority (>75%) of neoplastic cells, a variable loss of pan-T antigens (CD2, CD3, CD5), and a lack of expression of epithelial membrane antigen (EMA) and CD15. Additional tests include blood analysis and imagery (PET-scan, CT-scan, MRI) that are used to differentiate the cutaneous from the systemic form.
Differential diagnosis
Differential diagnosis includes lymphomatoid papulosis, metastatic melanoma, squamous cell carcinoma, diffuse large B cell lymphoma and Hodgkin lymphoma (see these terms).
Management and treatment
If lesions are solitary or localized to a single area, excision and/or radiation therapy is performed. If lesions are disseminated in multiple sites on the body, chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or CHOP-like regimens constitutes the first-line treatment. Chemotherapy can be combined with autologous stem cell transplantation. Recently, anti-CD30 monoclonal antibody therapy (e.g. brentuximab vedotin) has emerged as a promising alternative therapeutic option.
Prognosis
The prognosis is generally good, with a five-year survival rate of 90%. In 25% of cases, spontaneous regression is observed. Relapses, generally without any extracutaneous dissemination, may sometimes occur (approximately in 30% of cases).

                            Last update:
                            March 2014

                            - Expert reviewer(s):
                            Pr Martine BAGOT


Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma

A rare, primary cutaneous T-cell lymphoma characterized by solitary cutaneous nodule or only regional disease, typically occurring on the head and neck, and involving entire dermis. Sometimes, subcutis and adnexal structures are involved, as well. The infiltrate is nodular or diffuse, composed of small to medium sized pleomorphic lymphocytes and showing mild to moderate cytologic atypia. Neoplastic T-cells are mixed with B-cells, histiocytes, plasma cells and eosinophils.


Primary cutaneous diffuse large B-cell lymphoma, leg type

A rare, aggressive, primary cutaneous B-cell lymphoma characterized by rapidly progressive, red to bluish, often ulcerating, nodular tumors predominantly involving the lower legs. Histology shows sheets of centroblasts and immunoblasts that spare the epidermis, but infiltrate the dermis and subcutaneous tissues, and often disseminate extracutaneously. The neoplastic cells typically express CD20, CD79a, Bcl-2, MUM-1, and FOXP1, but are negative for CD10.


Primary cutaneous follicle center lymphoma

A rare, indolent primary cutaneous B-cell lymphoma characterized by a solitary or grouped erythematous plaques or tumors, preferentially located on the head, neck or trunk region, and composed of centroblasts and centrocytes arranged in a follicular, diffuse, or mixed growth pattern. The lesions are smooth and typically do not ulcerate. The neoplastic cells express pan B cell markers and Bcl-6, and typically lack Bcl-2.


Primary cutaneous gamma/delta-positive T-cell lymphoma is a rare, usually aggressive, subtype of cutaneous T-cell lymphoma characterized by infiltration of the epidermis, dermis or subcutaneous tissue by a clonal population of mature, gamma/delta positive cytotoxic T-cells. Typically it presents with ulcerating plaques, tumors, or subcutaneous nodules on the skin of the extremities, however, frequent involvement of mucosal and extranodal sites (such as the nasal cavity, gastrointestinal tract or lungs) is also observed. Cases associated with panniculitis may present with hemophagocytic syndrome (abrupt onset of fever, rash, cytopenia, hepatosplenomegaly and neurological compromise). Infiltration of lymph nodes, spleen and bone marrow is uncommon and resistance to multilineage chemotherapy is reported.


Cutaneous lymphoma is a heterogeneous entity with respect to its clinical and pathological features, evolutive profile, prognosis, molecular aetiology and response to therapy. These specifications have been taken into account in recent classifications, which have placed particular importance on the prognostic implications of these different entities.

Summary:
Clinical description
Cutaneous T-cell lymphomas can be subdivided into forms with a good prognosis (Mycosis fungoides and CD30+ cutaneous T-cell lymphoma), forms with a poor prognosis (Sezary syndrome and peripheral T-cell lymphoma) and forms with a variable prognosis (pleomorphic small/medium-sized T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, cutaneous T/NK cell lymphomas (referred to as nasal-type lesions), epidermotropic CD8+ T-cell lymphomas and the TCRgamma-delta phenotype). The group of cutaneous B-cell lymphomas includes marginal zone B-cell lymphomas and primary cutaneous follicular lymphomas (both of which have a good prognosis), cutaneous large B-cell lymphomas of the leg (with a variable prognosis), and blastic NK lymphomas (associated with a poor prognosis).
Management and treatment
While treatment is effective and the prognosis is favourable for low grade forms, recent therapeutic innovations relying on the use of biological tools are likely to improve the prognosis for the most severe forms, such as those already existing in the form of anti-CD20 monoclonal antibodies (rituximab) for disseminated cutaneous B-cell lymphomas, and anti-CD52 monoclonal antibody (alemtuzumab) for refractory forms of cutaneous T-cell lymphoma. Deciphering the key molecular mechanisms underlying these malignancies should create new therapeutic perspectives in the close future.

                            Last update:
                            April 2007

                            - Expert reviewer(s):
                            Pr Hervé BACHELEZ


Primary cutaneous marginal zone B-cell lymphoma

A rare, indolent primary cutaneous B-cell lymphoma characterized by multifocal, red to violaceous papules, plaques or nodules localized predominantly on the trunk and extremities. Histologically, these are dermis infiltrates consisting of small, marginal zone B cells, lymphoplasmacytic cells, and plasma cells. Marginal zone B cells express CD20, CD79a and Bcl-2, and are negative for CD5, CD10 and Bcl-6. Plasma cells are typically located at the periphery, and express CD138, CD79a, and monotypic light chains.


Primary cutaneous peripheral T-cell lymphoma not otherwise specified

An extremely rare, primary cutaneous T-cell lymphoma disorder characterized by solitary, or multifocal and diffuse, cutaneous lesions, ranging from tumor-like patches, plaques, papules, nodules, and/or erythroderma, located on any area of the body, which rapidly progress and may become ulcerated and/or infected. Systemic involvement may be associated.


A rare acquired skin disease characterized by benign proliferation of mature plasma cells with a typical triad of cutaneous lesions, polyclonal hypergammaglobulinemia, and superficial lymphadenopathy, without an apparent underlying cause. The skin lesions consist of multiple round-to-oval, red-to-dark-brown macules, papules, and plaques most commonly found on the trunk, but also the face, neck, and axillae.


A progressive cutaneous disorder predominantly affecting males, characterized by hypertrophy and thickening of the skin of the scalp, forming convoluted furrows with deep, tender, and cerebriform cutaneous folds. Hair is usually normal in the furrows and sparse on the folds. It can be isolated or associated with other abnormalities, such as intellectual deficit, epilepsy, cataract, blindness, and deafness.


A rare intestinal disease characterized by congenital partial or complete lack of the collagen mesh network in the intestinal wall, resulting in hypoperistalsis or aperistalsis. The enteric nervous system is normal or near-normal in the affected areas, although hypo- and dysganglionosis may be found in some proximal segments of the colon and/or small bowel. Patients present with chronic intractable slow transit constipation.


A rare primary torsion dystonia characterized by focal or segmental dystonia with onset either in the cranial-cervical region or in the upper limbs. Age of onset varies between 5 years and adulthood, with a mean age of onset of 16 years. Clinical manifestations are generally mild and slowly progressive.


Primary dystonia, DYT17 type is a rare, genetic, isolated dystonia initially presenting as torticollis, and later progressing to segmental or generalized dystonia. Dysphonia and dysarthria also occur later in the disease course.


A rare isolated dystonia characterized by segmental dystonia that predominantly affects the distal limbs and leads to abnormal posture. This disease has a progressive clinical course and may develop into generalized dystonia but remains mild overall.


Primary dystonia, DYT21 type is a subtype of mixed dystonia with a late-onset form of pure torsion dystonia.


A rare genetic dystonia characterized by focal or segmental isolated dystonia involving the face, neck, upper limbs (commonly writing dystonia), larynx, or trunk, with an onset from childhood to early adulthood. Dystonia may be tremulous, giving rise to head or hand tremor. Mode of inheritance is autosomal recessive.


DYT4 type primary dystonia is characterized by predominantly laryngeal dystonia (manifesting as whispering dysphonia) and cervical dystonia (manifesting as torticollis).

Summary:
Epidemiology
So far, the disease has been reported in one large Australian family.
Clinical description
The age of onset varies from 13 to 37 years. Some patients develop generalized dystonia and psychiatric symptoms.
Etiology
The locus for DYT4 remains unknown.
Genetic counseling
The disease is transmitted in an autosomal dominant manner.

                            Last update:
                            April 2009


A rare genetic movement disorder characterized by dystonia affecting at first an upper limb, less frequently beginning in the head and neck region, before slowly spreading to other locations. The clinical spectrum, like age of onset, is variable with focal, segmental, or generalized distribution, but cranial involvement with speech difficulties and cervical involvement are typical, whereas lower limbs are often spared. With progression of the disease, many patients suffer from generalized dystonia while mostly remaining ambulatory.


Primary effusion lymphoma (PEL) is a large B-cell lymphoma located in the body cavities, characterized by pleural, peritoneal, and pericardial fluid lymphomatous effusions and that is always associated with human herpes virus-8 (HHV-8).

Summary:
Epidemiology
The prevalence is unknown but it accounts for less than 1% of non-AIDS related lymphomas and approximately 3% of AIDS-related lymphomas.
Clinical description
PEL is most frequently found in young men that are positive for HIV or have pre-existing AIDS. Very rare non-HIV related cases have been reported but these patients are almost all elderly or immunodeficient due to another cause. Peritoneal, pleural, and pericardial fluid lymphomatous effusions are observed with, in the majority of cases, no mass-like extranodal extension of lymphoma. Symptoms of PEL depend on the body cavity affected and are caused by the accumulation of the malignant effusion. Pleural or pericardial disease has dyspnea as a symptom while abdominal distension is experienced in peritoneal disease. PEL is usually extremely aggressive and dissemination of lymphoma to distant sites, opportunistic infections and HIV-related complications are often fatal. In the rare HIV-negative cases the outcome may be better.
Etiology
The precise etiology is unknown. PEL is always associated with HHV-8, also known as Kaposi sarcoma-associated herpes (KSHV) and is most frequently found in immunodeficient patients, especially those with advanced AIDS. An infection with Epstein-Barr virus (EBV) is also present in the majority of PEL cases. The gene products of these viral genomes are thought to inhibit cell apoptosis and promote uncontrolled cell division and subsequent neoplastic transformation.
Diagnostic methods
Body cavity fluid is analyzed cytologically and by flow cytometry for the presence of clonal large neoplastic cells (with immunoblastic, anaplastic or plasmablastic appearances) with prominent nucleoli, round to irregular nuclei and occasionally vacuolated cytoplasm. To be given a diagnosis with PEL an infection with HHV-8 must be present. A latency-associated nuclear antigen-1 (LANA-1) assay detects any evidence of HHV-8 in tissue samples. Complete blood counts and positron emission tomography/computed tomography (PET/CT) scans should also be performed to determine the extent of the disease.
Differential diagnosis
Differential diagnoses include diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, which can present with lymphomatous effusion, anaplastic large cell lymphoma (ALCL; see these terms) and pyothorax-associated lymphoma (PAL).
Management and treatment
PEL is usually refractory to conventional chemotherapy and treatment guidelines are not well defined. Highly active antiretroviral therapy (HAART) should be administered concurrently with chemotherapy in all HIV positive PEL patients. The chemotherapy regimen cyclophosamide, doxorubicin, vincristine and prednisone (CHOP) is most commonly used. Research into molecular targeting therapy for the treatment of PEL is ongoing. There is a single case report of a durable remission for more than 18 months with the use of sobuzoxane.
Prognosis
PEL has a very poor prognosis with an average life expectancy of 3-4 months after diagnosis. Rare patients with HIV-negative PEL have durable progression free survival after chemotherapy.

                            Last update:
                            October 2012

                            - Expert reviewer(s):
                            Dr Ephraim HOCHBERG


Primary erythermalgia is characterized by intermittent attacks of red, warm, painful burning extremities. It spontaneously arises during early childhood and adolescence in the absence of any detectable underlying disorder.

Summary:
Epidemiology
It may occur sporadically or as an inherited disease, but less than 30 kindreds with familial primary erythermalgia have been reported in the literature so far.
Clinical description
Clinically, it is characterized by episodes of symmetrical red congestion, vasodilatation, and burning pain in both the feet and lower legs provoked by exercise, long standing and exposure to warmth that usually compels patients not to wear socks or closed shoes even in winter and to search for relief by immersion of feet in ice-cold water.
Etiology
The gene for autosomal dominant erythermalgia, SCN9a, is located on chromosome 2q. SCN9a is a 26 exon gene encoding the voltage-gated sodium channel alpha subunit Nav1.7. This channel is found mainly in dorsal root ganglia and sympathetic ganglia neurons. All mutations detected so far are missense and lead to a gain of function by lowering the activation threshold of Nav1.7, resulting in hyperexcitability of pain signaling neurons.
Diagnostic methods
The molecular diagnosis relies on sequencing of all coding exons of SCN9a. All mutations so far detected are private mutations (i.e. all families have their own unique mutations). Clinical diagnostic criteria are: attacks of local red congestion and vasodilation with increased local skin temperature and burning pain; a bilateral and symmetric distribution of symptoms; onset and aggravation of symptoms in response to distress, exercise and heat; relief provided by cold, rest and elevation of the affected extremities; the absence of a primary or associated disease; the condition being refractory to treatment.
Differential diagnosis
Differential diagnosis includes erythromelalgia and secondary erythermalgia. In erythromelalgia, the burning pain and red congestion are usually unilateral or asymmetrically distributed with preferential involvement of one or more toes, the forefoot soles or fingertips. The platelet count is always elevated > 400 x 10 9/L, and aspirin relieves symptoms. Secondary erythermalgia is acquired, mostly develops at a later age and is invariably linked with the use of drugs or underlying disease (vasculitis, neuropathy). In contrast to erythromelalgia, the platelet count in both secondary and inherited primary erythermalgia is normal.
Genetic counseling
In familial cases, the disorder is inherited as an autosomal dominant trait. Genetic counselling should be adapted according to the family history of the patient and affected parents should be informed of the 50% risk of reoccurrence.
Management and treatment
Analgesic therapy for the neuropathic pain is problematic. However, voltage-gated sodium channels are potential targets for local anesthetics (lidocaine), systemic antiarrhythmics (mexiletine) and antiepileptic drugs such as phenytoin. In several patients, oral mexiletine (600 mg daily) rapidly improved symptoms suggesting that blocking the voltage-gated sodium channels is a valid therapeutic option.
Prognosis
Prognosis depends on the severity of the disease. In severe cases the burning pain leads to an urgent need to cool the affected extremities. As a consequence, the affected skin from the limb (mostly the feet) can macerate resulting in skin fissures, skin infections and, possibly life-threatening sepsis. Amputation may be required in case of repeated infections. The very severe burning pain can lead to profound psychological consequences and depression.

                            Last update:
                            January 2007

                            - Expert reviewer(s):
                            Pr J.P.H. [Joost] DRENTH


Primary essential cutis verticis gyrata is a rare, progressive dermis disorder characterized by thickening of the scalp resulting in redundancy of the skin which gives rise to folds and grooves that give the scalp a cerebriform appearance. Folds cannot be corrected by pressure or traction and typically are symmetric and extend anteroposteriorly from vertex to occiput and/or transversely in occipital region. Additional features may include mild subungual hyperkeratosis and distal onycholysis of the nail plates of the great toes. It is not associated with neurological and ophthalmological changes, nor with secondary causes.


A rare genetic odontologic disease characterized by failure of eruption of non-ankylosed permanent teeth without evidence of obvious mechanical obstruction. Posterior teeth are preferentially affected (typically with involvement of all teeth distal to the most mesial non-erupted tooth), resulting in a posterior open bite. Non-ankylosed teeth tend to become ankylosed, and orthodontic treatment of affected teeth is generally unsuccessful.


Primary familial polycythemia is an inherited hematological disorder resulting from mutations in the erythropoietin (EPO) receptor and is characterized by an elevated absolute red blood cell mass caused by uncontrolled red blood cell production in the presence of low EPO levels.

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
The hematological disorder is present at birth but the clinical symptoms, if they develop, can be discovered at any time during childhood or adulthood. Clinical features can include headache, dizziness, epistaxis and exertional dyspnea. Thrombotic events have been observed. The hematological features include the presence of isolated erythrocytosis without evolution into leukemia or other myeloproliferative disorders, absence of splenomegaly, normal white blood cell and platelet counts, and low plasma EPO levels.
Etiology
Primary familial polycythemia is caused by mutations in the EPO receptor (EPOR) gene (19p13.3-p13.2) resulting in hypersensitivity to EPO. The mutations result in a receptor that is ''switched on'' to stimulate red blood cell production by erythroid progenitor cells but that has no ''switch off'' mechanism.
Diagnostic methods
Diagnosis is based on evidence in kindreds of isolated erythrocytosis without splenomegaly, low serum EPO levels, normal hemoglobin oxygen affinity and bone marrow erythroid progenitors that exhibit EPO hypersensitivity.
Differential diagnosis
Differential diagnoses include polycythemia vera (see this term), although there is no propensity to leukemic transformation or development of other myeloproliferative neoplasms in primary familial polycythemia, and secondary polycythemia (see these term). Polycythemia vera can be excluded on the basis of the absence of mutations in the JAK2 gene (9p24), and secondary polycythemia should be suspected if EPO levels are normal to high.
Genetic counseling
Transmission is usually autosomal dominant although sporadic cases have been reported. At least 14 different mutations have been described in single families.
Management and treatment
Patients with polycythemia should be individually assessed. Reducing the hematocrit (Hct) by phlebotomy reduces the blood viscosity and may be of benefit. Clinical symptoms are effectively relieved by phlebotomy. However, the increased risk of cardiovascular morbidity is not ameliorated by maintaining a normal Hct. If venesection is judged appropriate, the sparse evidence suggests it can reduce the Hct when it is over 54%. In patients with an increased risk of thrombosis, previous thrombosis, peripheral vascular disease, diabetes or hypertension, venesection should be considered at Hct less than 54%. In those with no specific contraindication, low-dose aspirin is relatively safe and may be of benefit to patients with erythrocytosis.
Prognosis
Primary familial polycythemia does not necessarily carry an adverse prognosis in early life and most patients have a benign clinical course, but it is associated with an increased risk of thrombosis and vascular mortality in later life.

                            Last update:
                            July 2010

                            - Expert reviewer(s):
                            Pr Jean BRIERE


A rare generalized, genetic disorder of proximal tubular transport characterized by excessive urine output with loss of low molecular weight solutes (amino acids, glucose, low-molecular weight proteins, organic acids, carnitine, calcium, phosphate, potassium, bicarbonate) and water, and which can be life threatening.

Summary:
Epidemiology
The prevalence of the condition is not known.
Clinical description
Onset is typically between infancy and childhood with symptoms related to tubular loss of nutrients, water and electrolytes. Typical clinical features include failure to thrive and rickets, normoglycemic glycosuria and polyuria with bicarbonaturia leading to hyperchloremic metabolic acidosis. Nephrocalcinosis and kidney stones are less common.
Etiology
The genetic etiology has been identified in a handful of families, and includes mutations in either GATM (15q21.1), involved in mitochondrial function, EHHADH (3q27.2), due to a specific mutation (c.7G>A) that introduces a mitochondrial targeting motif, or SLC34A1 (5q35.3) which encodes the proximal tubular sodium-phosphate transporter, NaPi-IIa. However, the disease may be due to unidentified mutations. Of note, the gene SLC34A1 is also associated with two other diseases: autosomal recessive infantile hypercalcemia and dominant hypophosphatemia with nephrolithiasis or osteoporosis.
Diagnostic methods
Diagnosis is based on clinical presentation as well as plasma electrolytes levels and evaluation of urinary solute excretion (aminoaciduria, proteinuria, phosphaturia, calciuria, uricosuria, glycosuria).
Differential diagnosis
Before the diagnosis of primary Fanconi renotubular syndrome is made all causes of secondary Fanconi syndrome must be ruled out, including both inherited (cystinosis, tyrosinemia type I, fructosemia, Wilson's disease, galactosemia, glycogen storage disease, Dent disease, Oculocerebrorenal syndrome of Lowe, arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome, mitochondrial cytopathies) and acquired disorders (drug or heavy metal poisoning, malignancies).
Genetic counseling
The majority of reported cases are sporadic and may be associated with de novo mutations. However, hereditary forms have been reported. The pattern of inheritance is autosomal dominant for EHHADH and GATM, and autosomal recessive for SLC34A1. The risk of transmission to offspring is 50% for autosomal dominant disease and, where both parents are heterozygous for the pathogenic mutation, 25% in autosomal recessive disease.
Management and treatment
Treatment is symptomatic. Kidney transplantation is curative.
Prognosis
With adequate fluid, electrolyte and nutrient supplementation, adequate physical and neurocognitive development is usually possible. Mutations in GATM are associated with progressive chronic kidney disease, whereas this has not been observed with EHHADH-associated disease.

                            Last update:
                            January 2020

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

                                * European Reference Network


Primary hepatic neuroendocrine carcinoma (PHNEC) is a rare hepatic tumor that may manifest with abdominal pain or fullness, as well as diarrhea or weight loss. More than 10% of cases are asymptomatic and in rare cases a carcinoid syndrome may be observed.

Summary:
Epidemiology
PHNEC has been estimated to have an incidence of approximately 1/500,000, accounting for <1% of all malignancies. PHNEC is slightly more frequent in females.
Clinical description
The age of onset is variable. In the early stages of PHNEC, patients may exhibit nonspecific symptoms, including upper abdominal pain and distension or fullness, while some may suffer from carcinoid syndrome (paroxysmal flushing, episodes of asthma-like wheezing, right-side heart failure and diarrhea). Progression of PHNEC is accompanied by the symptoms caused by tumor compression to adjacent organs, dyspepsia, weight loss and fatigue. More than 10% of cases are asymptomatic. PHNEC is not associated with cirrhosis or other forms of preexisting liver disease.
Etiology
The etiology of PHNEC is still unknown but it is thought to arise from Kulchitsky cells originating in the neural crest. It is also hypothesized that chronic inflammation in the biliary system may initiate intestinal metaplasia, which predisposes to the development of neuroendocrine tumors. Another possibility is that they originate from ectopic pancreatic or adrenal tissues within the liver.
Diagnostic methods
Diagnosis relies on laboratory findings showing negative serum alpha-fetoprotein levels and negative results for other conventional tumor markers (carcinoembryonic antigen, CA125 and CA19‑9) in addition to non-contrasted computed tomography (CT) scans showing low-density masses, with some having a cystic component. Dynamic contrast CT reveals enhanced masses in the early phase and low density masses in the late phase. On magnetic resonance imaging (MRI), PHNEC usually presents with low intensity on T1-weighted images and high intensity on T2-weighted images, and appears as a large dominant hypervascular mass accompanied by satellite nodules, with rapid washout and capsular enhancement on dynamic MRI and restricted diffusion on diffusion-weighted imaging. An octreoscan is recommended as it may detect small metastatic masses. Histologically, PHNEC appears as a hemorrhagic, non-capsulated mass, with central, irregular fibrosis and hyaline degeneration. The diagnosis may be confirmed by immunohistochemistry where the cells present a strong positivity for neurosecretory markers such as chromogranin, synaptophysin, neuron specific enolase, and S-100 protein.
Differential diagnosis
Differential diagnosis includes hepatic adenoma, hepatocellular carcinoma, cholangiocarcinoma, congenital liver hemangioma (see these terms), focal nodular hyperplasia, primary hepatic angiosarcoma, secondary hepatic neuroendocrine carcinoma, or hepatic metastases from any other primary cancer site.
Management and treatment
Surgery is often the only curative option and provides the most favorable outcome. For ill-defined lesions, a palliative cytoreductive surgery in combination with transcatheter arterial embolization (TACE) and subsequent administration of lanreotide (a long acting somatostatin analogue) may be effective. Targeted radiation therapy, given as either SIRT (selective internal radiation therapy) or PRRT (peptide receptor radiation therapy) is of theoretical benefit.
Prognosis
Early detection and treatment are key in achieving a good prognosis. The prognosis depends on the pathological type, degree of differentiation, and size and boundary of the tumor as well as the presence of metastasis and the physical status of the patient.

                            Last update:
                            October 2014

                            - Expert reviewer(s):
                            Pr Graeme POSTON


Primary hyperaldosteronism-seizures-neurological abnormalities syndrome

A rare, genetic, neurologic disease characterized by primary hyperaldosteronism presenting with early-onset, severe hypertension, hypokalemia and neurological manifestations (including seizures, severe hypotonia, spasticity, cerebral palsy and profound developmental delay/intellectual disability).


A rare hypereosinophilic syndrome characterized by hypereosinophilia produced by clonal eosinophils derived from neoplastic stem cells in the absence of any secondary cause of eosinophilia and persisting for at least six months. The condition is associated with signs of organ infiltration, dysfunction, and damage. Clinical manifestations are highly variable, depending on the organ systems involved, and include dermatologic, pulmonary, cardiac, gastrointestinal, and cerebral manifestations, among others.


Primary hypergonadotropic hypogonadism-partial alopecia syndrome

A rare endocrine disorder characterized by primary hypogonadism and partial alopecia. Females present with Mûllerian hypoplasia, absent or streak ovaries, hypoplastic internal genitalia, primary amenorrhea, and sparse or absent axillary and pubic hair. Some patients also presented sparse eyebrows, microcephaly, flat occiput, dorsal kyphosis or mild intellectual disability. The only described male presents with germinal cell aplasia. Affected individual all present partical scalp alopecia.


A disorder of glyoxylate metabolism characterized by an excess of oxalate resulting in kidney stones, nephrocalcinosis and ultimately renal failure and systemic oxalosis. There are 3 types of PH, types 1-3, all caused by liver-specific enzyme defects.

Summary:
Epidemiology
Primary Hyperoxalurias (PH) prevalence ranges from 1-3/1 000 000 and the estimated incidence is between 1-2/10 000 000 per year with no differences between sexes. There are higher rates reported in isolated populations, especially in the Middle East and North Africa. A significant proportion of patients are diagnosed at adulthood which implies an important underdetection of patients. PH1 accounts for 85% of patients, PH2 8-10% and PH3 5-7%.
Clinical description
Hyperoxaluria may lead to kidney stones, nephrocalcinosis and ultimately renal failure and systemic oxalosis. Symptoms can appear at any age and may vary from infantile failure to thrive and cortical nephrocalcinosis with renal failure to hematuria, medullary nephrocalcinosis or sporadic stone disease, even within one family. PH1 is the most severe form; overall, more than 70% of PH1 patients develop end-stage kidney disease over time; this may even occur in patients with sporadic stone disease. Storage of oxalate occurs in severe renal failure and may affect bone, eyes, heart, arteries and peripheral nerves (systemic oxalosis). PH2 has a more benign course; no infantile oxalosis has been described and end-stage kidney disease occurs at relatively late age in about 20% of patients. PH3 is most benign with so far only a few reports of renal impairment and no end-stage kidney disease.
Etiology
PH type 1 is caused by mutations of the AGXT gene causing dysfunction of the liver-specific peroxisomal enzyme alanine glyoxylate aminotransferase (AGT). Over 50 different mutations have been found, leading to either absence or dysfunction of AGT. Two common Western mutations (G170A, Phe152Ile) lead to a mitochondrial mistargeting of AGT. Type 2 is caused by mutations of GHRPR gene causing dysfunction of the cytosolic enzyme glyoxylate/hydroxypyruvate reductase, type 3 by mutations in HOGA1 causing dysfunction of the mitochondrial enzyme 4-hydroxy-2- oxoglutarate aldolase.
Diagnostic methods
Diagnosis methods consist of an analysis of urine collection for 24h (at least 2 consecutive assessments) on oxalate, creatinine, glycolate (PH1), citrate (decreased in PH1), L-glycerate (PH2) and HOGA (PH3). Mutation analysis on AGTX gene can be done in case of hyperoxaluria. If negative or in case of high l-glycerate or HOGA mutation analysis on GRHPR or HOGA1 genes are realized. Assessment for systemic oxalosis in case of high plasma-oxalate and /or eGFR<40: fundoscopy, US heart, bone assessment.
Differential diagnosis
Differential diagnosis includes hypercalciuria, hypocitraturia, cystinuria.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
If eGFR>30 ml/min/1.73m2: the patient needs first high fluid intake (>3 liter/day/m2 body surface). Then pyridoxine challenge in PH1 starting dose 5 mg/kg/day, increase to max 20; reduction urine oxalate >30% = positive response (about 30% of patients in Europe). In third potassium-citrate 0,5 mmol/kg/day. If eGFR<30 ml/min/1.73m2 it is consider to direct combined liver-kidney transplantation, sequential liver-kidney transplantation in case of severe systemic oxalosis or kidney transplantation in B6 responsive PH1 patients. Dietary oxalate restriction is probably of limited use.
Prognosis
Severe infantile oxalosis has a poor prognosis quoad vitam. The prognosis for other PH1 B6 unresponsive patients is poor with respect to renal function (> 80% renal failure over time), better for B6 responsive patients, if timely diagnosed and treated. End-stage kidney disease has been found in 20% of PH2 patients, so far not in PH3.

                            Last update:
                            January 2020

                            - Expert reviewer(s):
                            Pr J.W. [Jaap] GROOTHOFF | ERKNet* - Pr Bernd HOPPE

                                * European Reference Network