Primary hypertrophic osteoarthropathy (PHO) is a genetically and clinically heterogeneous inherited disorder characterized by digital clubbing and osteoarthropathy, with variable features of pachydermia, delayed closure of the fontanels, and congenital heart disease. There are two types of PHO: pachydermoperiostosis and cranio-osteoarthropathy (see these terms).

Summary:
Epidemiology
Prevalence is unknown. Cranio-osteoarthropathy is the rarest form, with about 30 cases reported to date.
Clinical description
Patients typically present in infancy with clubbing, hyperhidrosis, bone and joint pain and skin thickening. The clinical constellation of PHO includes skin thickening and excessive sweating (pachydermoperiostosis), delayed closure of the cranial sutures (cranio-osteoarthropathy) and congenital heart disease, especially patent arterial duct (see this term).
Etiology
Mutations in the HPGD gene (4q33-q34) encoding 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the main enzyme of prostaglandin degradation, have been identified.
Diagnostic methods
Diagnosis is based on clinical signs and X-ray exam, magnetic resonance imaging (MRI) or radionucleotide bone imaging showing typical bone abnormalities, such as diaphyseal periostosis and acro-osteolysis.
Differential diagnosis
Differential diagnoses include secondary hypertrophic osteoarthropathy, chronic recurrent non-bacterial osteomyelitis, SAPHO and Camurati-Engelman syndromes (see these terms) and chronic bacterial osteomyelitis.
Genetic counseling
PHO is inherited as an autosomal recessive trait; however, heterozygous carriers can have a mild phenotype. Since mutations in the HPGD gene have recently been reported, genetic counseling and prenatal diagnosis might be considered.
Management and treatment
Rheumatological symptoms can be improved by nonsteroidal anti-inflammatory drugs, which have been shown to directly influence the pathogenesis. In addition, corticosteroids or colchicine have been tried. Clinical improvement of the dermatological symptoms is achieved by retinoids. Plastic surgery may be helpful for facial involvement. Finger clubbing surgical reduction has been tried with success.
Prognosis
PHO progresses constantly, leaving patients with chronic debilitating complications, such as clubbing and arthritis.

                            Last update:
                            January 2011

                            - Expert reviewer(s):
                            Pr Hermann GIRSCHICK


Primary hypomagnesemia with hypercalciuria and nephrocalcinosis with severe ocular involvement

Familial primary hypomagnesemia with hypercalciuria and nephrocalcinosis with severe ocular involvement (FHHNCOI) is a form of familial primary hypomagnesemia (FPH, see this term), characterized by excessive magnesium and calcium renal wasting, bilateral nephrocalcinosis, progressive renal failure and severe ocular abnormalities.

Summary:
Epidemiology
To date, approximately 72 cases have been described in the literature.
Clinical description
FHHNCOI has a childhood onset. The initial symptoms may include recurrent urinary tract infections, polyuria and polydipsia. Additional features include nephrocalcinosis, nephrolithiasis, enuresis, abdominal pain, muscular twitches and failure to thrive. The clinical hallmark of this disorder is an ocular abnormality involving severe bilateral myopia with divergent squint, nystagmus, keratoconus, corneal calcifications, cataract, chorioretinitis, pigmentary retinitis, pigmentary maculopathy, macular coloboma, strabismus or visual loss. Renal function generally declines progressively in most patients and patients may reach end stage renal disease in their adolescence or young adulthood. 50% of patients require renal replacement therapy in the second decade of life.
Etiology
FHHNCOI is caused by mutations in CLDN19 (1p34.2) which encodes claudin-19, a protein member of the claudin family which is highly expressed in the tight junctions of the thick ascending limb of Henle's loop, as well as in the retinal epithelium.
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 of the 25% risk of having an affected child.

                            Last update:
                            February 2014

                            - Expert reviewer(s):
                            Dr Rosa VARGAS-POUSSOU


Primary hypomagnesemia with hypercalciuria and nephrocalcinosis without severe ocular involvement

Familial primary hypomagnesemia with hypercalciuria and nephrocalcinosis without severe ocular involvement (FHHN) is a form of familial primary hypomagnesemia (FPH; see this term), characterized by recurrent urinary tract infections, nephrolithiasis, bilateral nephrocalcinosis, renal magnesium (Mg) wasting, hypercalciuria and kidney failure.

Summary:
Epidemiology
To date, more than 110 individuals have been reported in the literature.
Clinical description
FHHN has an onset in childhood and the clinical manifestations are recurrent urinary tract infections, polyuria, polydipsia, enuresis, hematuria, nephrolithiasis and bilateral nephrocalcinosis. Some patients fail to thrive during early childhood and experience seizures, vomiting, abdominal pain, tetany and rarely rickets. Ocular involvement is rare and when observed it is relatively mild (myopia, hypermetropia, astigmatism and strabism). Approximately one third of patients progress to renal failure or end-stage renal disease (ESRD) during adolescence.
Etiology
FHHN is characterized by impaired tubular reabsorption of Mg and calcium (Ca) in the thick ascending limb of Henle's loop due to mutations in CLDN16 (3q27), which encodes claudin-16 (previously known as paracellin 1). A significant residual function is observed in several missense mutations, whereas a complete loss of claudin-16 function appears to be more severe (disease presenting earlier and often progressing to kidney failure at a significantly younger age).
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 of the 25% risk of having an affected child.

                            Last update:
                            February 2014

                            - Expert reviewer(s):
                            Dr Rosa VARGAS-POUSSOU


Primary hypomagnesemia with hypercalciuria and nephrocalcinosis

Familial primary hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a form of familial primary hypomagnesemia (FPH, see this term), characterized by renal magnesium (Mg) and calcium (Ca) wasting, nephrocalcinosis, kidney failure and, in some cases, severe ocular impairment. Two subtypes of FHHNC are described: FHHNC with severe ocular involvement (FHHNCOI) and without severe ocular involvement (FHHN) (see these terms).

Summary:
Epidemiology
To date, approximately 200 cases have been reported in the literature.
Clinical description
The median age of onset ranges from 1 to 8 years. The most common presenting features are recurrent urinary tract infections, nephrolithiasis, nephrocalcinosis, polyuria, polydipsia, enuresis, hematuria and pyuria. Additional manifestations include failure to thrive, seizures, abdominal pain, muscular tetany and, rarely, rickets. Patients develop chronic kidney disease (CKD) that progresses to end-stage renal disease (ESRD). Two subtypes of FHHNC have been described: FHHNCOI and FHHN. Both forms share identical renal manifestations. By contrast, severe ocular involvement (macular coloboma, pigmentary retinitis, nystagmus, or visual loss) has been described in FHHNCOI, while mild nonspecific ocular involvement (myopia, astigmatism, hypermetropia, or strabismus) has been reported in some cases of FHHN.
Etiology
The disease is caused by mutations in the genes CLDN16 (3q28) and CLDN19 (1p34.2), encoding claudin-16 and claudin-19 respectively. Both proteins are expressed in the thick ascending limb of Henle's loop where they interact to form heteromultimers and play a role in the paracellular reabsorption of Mg and Ca. Inactivating mutations in either gene results in urinary loss of Mg and Ca. Ocular involvement occurs in patients with the CLDN19 mutation as claudin-19 is expressed in retinal pigment epithelium.
Diagnostic methods
Diagnosis is based on the triad of hypomagnesemia, hypercalciuria and nephrocalcinosis. Hypocalcemia, hyperuricemia, incomplete distal renal tubular acidosis and hypocitraturia are supportive findings. Parathyroid hormone levels are high before onset of CKD. High fractional urinary excretion of Mg is found while serum level is inappropriately low. Ocular abnormalities are detected by fundoscopy and optical coherence tomography (OCT). Diagnosis is confirmed by genetic screening of CLDN16 and CLDN19.
Differential diagnosis
Differential diagnosis includes Bartter syndrome, autosomal dominant hypocalcemia, Dent disease, hereditary hypophosphatemic rickets with hypercalciuria, distal renal tubular acidosis and other tubular disorders causing early nephrocalcinosis (like primary hyperoxaluria) (see these terms).
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 of the 25% risk of having an affected child.
Management and treatment
Management is mainly supportive and includes administration of Mg supplements in high doses and thiazide diuretics to reduce urinary Ca excretion and the progression of nephrocalcinosis. Indomethacin may be used to increase Ca reabsorption. Therapies aimed at delaying progression of CKD should be provided as well as conventional management strategies for kidney stones. Renal transplantation is the optimal treatment for ESRD. Lens implantation can be proposed to patients suffering from severe ocular abnormalities.
Prognosis
Progression to ESRD is frequent (50% of patients at 20 years). Follow-up data in one of the described cohorts suggested that patients harboring CLDN19 mutations have a higher risk of progression to CKD than patients with CLDN16 mutations.

                            Last update:
                            March 2014

                            - Expert reviewer(s):
                            Dr Rosa VARGAS-POUSSOU


Primary hypomagnesemia with secondary hypocalcemia (PHSH) is a form of familial primary hypomagnesemia (FPH, see this term), characterized by severe hypomagnesemia and secondary hypocalcemia associated with neurological symptoms, including generalized seizures, tetany and muscle spasms. PHSH may be fatal or may result in chronic irreversible neurological complications.

Summary:
Epidemiology
To date, approximately 100 cases have been described in the literature. Both sexes are equally affected.
Clinical description
Disease onset is often in the neonatal period and always before the end of the first year of life. The predominant symptom at initial presentation is generalized and recurrent seizures which are refractory to the conventional convulsive therapy. Additional features that are observed in the newborn period include tetany (that fails to respond to calcium therapy), failure to thrive, restlessness, tremors, muscle spasms, and perioral cyanosis. Cardiac arrhythmia may be observed.
Etiology
Mutations in the gene TRPM6 (9q21.13), encoding the transient receptor potential cation channel subfamily M, member 6, have been found to be responsible for this disease The pathophysiological hallmark of PHSH is the impaired intestinal absorption of magnesium (Mg) accompanied by renal Mg wasting as a result of a reabsorption defect in the distal convoluted tubule. The renal defect is only detected after an intravenous Mg load test. Hypocalcemia seems to be caused by diminished parathyroid hormone (PTH) release as a result of profound hypomagnesemia.
Diagnostic methods
Diagnosis relies on laboratory findings which reveal severely reduced serum Mg levels accompanied by hypocalcemia and barely detectable PTH levels. Urinary calcium (Ca) values are normal. Renal defects may be detected after an intravenous Mg load test. The diagnosis is confirmed by genetic screening of TRPM6. One case of bilateral basal ganglia calcification has been detected by computed tomography brain scan.
Differential diagnosis
Differential diagnosis includes Gitelman and Bartter syndromes, familial primary hypomagnesemia with hypercalciuria and nephrocalcinosis without severe ocular involvement (see these terms), and nutritional rickets.
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 of the 25% risk of having an affected child.
Management and treatment
Management is mainly symptomatic and the standard treatment consists of the exclusive and lifelong administration of Mg. During manifestations, intravenous or intramuscular administrations are preferred, whereas maintenance therapy usually consists of an oral administration of high doses of Mg. However, because of gastrointestinal side effects, some patients require additional parenteral Mg.
Prognosis
Prognosis of PHSH depends on the rapidity of diagnosis. Indeed, delayed diagnosis, or delayed administration of the appropriate treatment may result in convulsions that can be fatal or that may result in chronic, irreversible neurological complications.

                            Last update:
                            February 2014

                            - Expert reviewer(s):
                            Dr Rosa VARGAS-POUSSOU


Primary hypomagnesemia-refractory seizures-intellectual disability syndrome

A rare genetic disorder of magnesium transport characterized by infantile onset of generalized seizures and severe hypomagnesemia due to massive renal magnesium wasting. Seizures persist despite magnesium supplementation and are associated with significant global developmental delay and intellectual disability. Brain MRI may show reduced cerebral volume.


Primary immunodeficiency syndrome due to P14/LAMTOR2 deficiency

Primary immunodeficiency syndrome due to p14 deficiency is characterised by short stature, hypopigmentation, coarse facies and frequent bronchopulmonary Streptococcus pneumoniae infections.

Summary:
Epidemiology
To date, it has been described in four members of one family.
Etiology
Linkage analysis led to the identification of a homozygous deletion in the coding region of the ROBLD3 gene, resulting in reduced expression of the endosomal adaptor protein p14.

                            Last update:
                            March 2007


Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency

A rare DNA repair defect other than combined T-cell and B-cell immunodeficiencies characterized by intrauterine and postnatal growth retardation resulting in short stature, microcephaly, glucocorticoid deficiency, natural killer cell deficiency, and recurrent viral infections. Patients may also have increased susceptibility to cancer.


Primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection is a rare primary immunodeficiency due to a defect in innate immunity disorder characterized by selective susceptibility to viral infections, particularly after systemic challenge with live viral vaccines, such as the measles, mumps and rubella (MMR) vaccine. Patients present severe, potentially fatal, manifestations to viral illness, including encephalitis, hepatitis and pneumonitis.


Primary interstitial lung disease specific to childhood due to pulmonary surfactant protein anomalies

A group of interstitial lung diseases (ILD) induced by genetic mutations disrupting surfactant function and gas exchange in the lung. The disorders caused by these mutations affect full-term infants and older children and exhibit considerable overlap in their clinical and histologic presentation.


A rare intestinal disease characterized by dilated intestinal lacteals which cause lymph leakage into the small bowel lumen. Clinical manifestations include edema related to hypoalbuminemia (protein-losing gastro-enteropathy), asthenia, moderate diarrhea, lymphedema, serous effusion and failure to thrive in children.

Summary:
Epidemiology
Prevalence is unknown. Less than 500 cases have been reported worldwide.
Clinical description
Primary intestinal lymphangiectasia (PIL) is generally diagnosed before 3 years of age but may be diagnosed in older patients with very few symptoms. The main symptom is predominantly bilateral lower limb edema related to protein-losing enteropathy associated with hypoalbuminemia. Edema may be moderate (in foot, ankle, calf) to severe with anasarca and can be associated with pericarditis, ascites (chylous or not) or pleural effusion. Fatigue, abdominal pain, weight loss, inability to gain weight, failure to thrive in children, moderate diarrhea, fat-soluble vitamin deficiencies due to malabsorption or iron deficiency with moderate anemia may also be present. In some patients, limb lymphedema is associated with PIL and it is difficult to distinguish from edema. Stemmer's sign is an important element to confirm the diagnosis and also differentiate lymphedema from edema: it is impossible to lift and pinch the skin on the second toe basis because of skin-thickening as the result of fibrosis.
Etiology
The etiology remains unknown. Very rare familial cases of PIL have been reported.
Diagnostic methods
Exsudative enteropathy is confirmed by elevated 24-hour stool alpha-1 antitrypsin clearance. Diagnosis of PIL is confirmed by endoscopic observation of dilated intestinal lacteals with the corresponding histology of intestinal biopsy specimens. Videocapsule endoscopy may be useful to visualize intestinal lymphangiectasia (localization, extent) when endoscopic findings are not conclusive. Characteristic biochemical findings related to lymph leakage into bowel lumen include lymphopenia, hypoalbuminemia, hypogammaglobulinemia, hypocalcemia, and hypocholesterolemia.
Differential diagnosis
The main differential diagnosis includes enteropathy-associated T-cell lymphoma, Whipple disease, Crohn disease, sarcoidosis, tuberculosis (with extrapulmonary involvement), systemic sclerosis, and constrictive pericarditis.
Management and treatment
A strictly low-fat diet associated with medium-chain triglyceride supplementation is the cornerstone of PIL medical management. The absence of fat in the diet prevents chyle engorgement of the intestinal lymphatic vessels thereby preventing their rupture with ensuing lymph loss. Medium-chain triglycerides are absorbed directly into the portal venous circulation and prevent lacteal overloading. Octreotide has been effective in treating some PIL patients. Surgical small-bowel resection is useful in the rare cases with segmental and localized intestinal lymphangiectasia. The need for dietary control appears to be permanent, because clinical and biochemical findings reappear after low-fat diet withdrawal. Albumin infusion is a symptomatic treatment proposed in patients with important serous effusion or uncomfortable lower limb edema. Repeated albumin infusions may be useful in reducing edema but their efficacy is transient. Repeated fat-soluble vitamin supplementation, particularly vitamin D, is required. A prolonged clinical and biological follow-up is recommended.
Prognosis
The prognosis varies. PIL may be asymptomatic or mildly symptomatic in moderate forms of the disease or in patients who follow a low-fat diet. PIL outcome may be poor or even life-threatening when voluminous serous effusion(s) (pleural, pericardial) spontaneously occur, after low-fat diet withdrawal, or in cases with malignant complications. So, several B-cell lymphomas confined to the gastrointestinal tract (stomach, jejunum, mid gut or ileum) or with extra-intestinal localizations have also been reported in PIL patients.

                            Last update:
                            June 2019

                            - Expert reviewer(s):
                            Dr Stéphane VIGNES


A rare biliary tract disease characterized by stone formation within the intrahepatic bile ducts without any known cause, leading to bile stasis and repeated cholangitic episodes. The condition is rare in the Western world but frequent in eastern Asia. Patients usually present before the age of forty with right upper quadrant pain, jaundice, and/or fever. Stones are typically calcium bilirubinate (pigment) stones, and bacteria are present in the bile in almost all cases. Complications are biliary strictures, liver abscess, liver fibrosis, and secondary biliary cirrhosis. Association with cholangiocarcinoma has also been reported.


Primary intraosseous venous malformation is a rare, genetic vascular anomaly characterized by severe blood vessel expansion (most frequently within the craniofacial bones) with painless bone enlargement (usually of mandibule, maxilla and/or orbital, nasal, and frontal bones), typically resulting in facial asymmetry and contour deformation. Midline abnormalities, such as diastasis recti, supraumbilical raphe, and hiatus hernia, are commonly associated. Additional features reported include gingival bleeding, ectopic tooth eruption, exophthalmos, loss of vision, nausea, and vomiting.


Primary laryngeal lymphangioma is a rare, benign, congenital malformation of the lymphatic system characterized by a polypoidal, variable-sized, soft tissue mass located in the larynx. Most lesions manifest by the 2nd year of life and, depending on the size, patients may present with changes in voice, dysphagia, stridor, airway obstruction and/or respiratory distress. Cystic hygroma of the neck is frequently associated.


Primary lateral sclerosis (PLS) is an idiopathic non-familial motor neuron disease characterized by slowly progressive upper motor neuron dysfunction leading to spasticity, mild weakness in voluntary muscle movement, hyperreflexia, and loss of motor speech production.


A heterogeneous group of very rare diseases characterized by a generalized or localized loss of body fat (lipoatrophy).

Summary:
Epidemiology
Prevalence has been estimated at less than 1 case in 100 000.
Clinical description
In some forms, lipoatrophy is associated with selective hypertrophy of other fat deposits. Clinical signs of insulin resistance are often present: acanthosis nigricans, signs of hyperandrogenism. All lipodystrophies are associated with dysmetabolic alterations with insulin resistance, altered glucose tolerance or diabetes, and hypertriglyceridemia leading to a risk of acute pancreatitis. The diabetes leads to chronic complications involving the retina, kidney, nerves and cardiovascular system, and to liver steatosis that could result in cirrhosis.
Etiology
Genetic forms of generalized lipodystrophy (or Berardinelli-Seip syndrome, see this term) result, in most cases, from recessive mutations in one of two genes: either BSCL2 coding seipin or BSCL1 coding AGPAT2, an acyltransferase involved in triglyceride synthesis. The origin of acquired generalized lipodystrophy (Lawrence syndrome, see this term) is unknown but the syndrome is sometimes associated with signs of autoimmunity. Partial lipodystrophies can be familial with dominant transmission. Heterozygous mutations have been identified in the LMNA gene encoding nuclear lamin A/C, or in the PPARG gene encoding the adipogenic transcription factor PPARgamma. Some less typical forms of lipodystrophy, associated with signs of premature aging, have been linked to mutations in the LMNA gene or in the ZMPSTE24 gene encoding the protease responsible for the maturation of prelamin A into lamin A. Acquired partial lipodystrophy (Barraquer-Simons syndrome, see this term) is characterized by cephalothoracic fat loss. Its etiology is unknown but mutations in the LMNB2 gene, encoding the lamina protein lamin B2, may represent susceptibility factors. Highly active antiretroviral treatments for HIV infection are currently the most frequent cause of acquired secondary lipodystrophic syndromes.
Diagnostic methods
The genetic diagnosis is performed in specialized laboratories and, in the most severe forms, antenatal diagnosis may be proposed.
Management and treatment
Treatment of diabetes, dyslipidemia and the resulting complications involves the classical intervention strategies. Insulin-sensitizing drugs are useful. Therapeutic trials with recombinant human leptin in patients with very low leptin levels have reported good results with respect to the metabolic and liver alterations.
Prognosis
The prognosis is linked to the precocity and severity of the diabetic, cardiovascular and liver complications.

                            Last update:
                            April 2007

                            - Expert reviewer(s):
                            Pr Jacqueline CAPEAU


Primary lymphedema is a lymphatic system malformation characterized by swelling of an extremity that can be associated with other lymphatic effusions, due to an underlying developmental anomaly of the lymphatic system (abnormal lymphoangiogenesis). It can be hereditary or not and be congenital or late onset.


Primary lymphoma of the conjunctiva is an extremely rare clonal lymphoid proliferation of the ocular surface, with an indolent course. Clinically it presents with treatment-resistant conjunctivitis, ptosis, excessive tear production or as a painless, salmon-pink, ''fleshy'' patch, with a smooth or multinodular surface, on the bulbar conjunctiva. Histologically it is usually B-cell Non-Hodgkin lymphoma (most often extranodal marginal zone B-cell lymphoma, followed by follicular and diffuse large B-cell lymphoma), with conjunctival T-cell Non-Hodgkin lymphoma being very rare.


Primary mediastinal large B-cell lymphoma

A rare subtype of diffuse large B-cell lymphoma (DLBCL), arising from B cells of thymic origin, predominantly affecting women between the ages of 20-30, and that usually presents with a bulky and rapidly expanding anterior mediastinal mass, often with pleural and pericardial effusions, and that can invade the lungs, superior vena cava, pleura, pericardium, and chest wall, leading to manifestations of cough, dyspnea, and superior vena cava syndrome.


Primary melanoma of the central nervous system is a rare tumor of meninges arising from leptomeningeal melanocytes, typically in the perimedullary or high cervical region, in the absence of melanoma outside the CNS. The tumor is typically a darkly pigmented, solid mass, often containing hemorrhagic or necrotic areas, composed of sheets of pleomorphic cells with prominent nucleoli, with frequent mitotic figures and parenchymal invasion. Intracranial tumor may present with signs of raised intracranial pressure, focal neurological symptoms related to tumor location, seizures or subarachnoid hemorrhage, spinal tumor may present with back pain, muscle weakness, numbness, plegia or urinary incontinence.


A rare glomerular disease characterized by a pattern of glomerular injury on kidney biopsy with characteristic light microscopic changes: mesangial hypercellularity, endocapillary proliferation, and thickening of the glomerular basement membrane (GBM). On the basis of immunofluorescence (IF) the disorder is divided into C3 glomerulopathy (C3G) or immunoglobulin-mediated membranoproliferative glomerulonephritis. Through electron microscopy C3G is further divided into Dense deposit disease, with highly electrondense deposits in the glomerular basement membrane, and C3 glomerulonephritis, with mesangial, intramembranous, subendothelial and subepithelial deposits. Secondary causes (autoimmune, infectious, malignancies) are excluded.


A rare glomerular disease, histologically characterized by thickening of the capillary wall, with immune deposits predominantly containing IgG4 and C3 on the sub-epithelial side, and typically manifesting with nephrotic syndrome.

Summary:
Epidemiology
Globally, the overall incidence of membranous nephropathy (MN) is approximately 1/100,000, of which approximately 80% are Primary membranous nephropathy (PMN). The male to female ratio is 2:1. PMN is rare in children.
Clinical description
Disease onset is typically between 50-60 years of age, presenting with either nephrotic syndrome (edema with confirmed proteinuria, hypoalbuminemia and hyperlipidemia), or nephrotic-range or subnephrotic proteinuria. Renal function is typically normal at presentation. Disease progression is gradual, and occasionally complicated by thrombo-embolic events. Hematuria, hypertension, and reduced glomerular filtration rate can present initially or develop during the disease course. End stage renal disease (ESRD) develops in up to a third of patients 10 years after disease onset.
Etiology
PMN is an auto-immune disease limited to the kidney. Antibodies to the podocytic antigen m-type phospholipase receptor (PLA2R) are detectable in approximately 70% of patients, and antibodies against thrombospondin type-1 domain-containing 7A (THSD7A) in approximately 3% of patients. The pathophysiology of antibody formation is unclear. A genetic predisposition and associations with HLA genes and with polymorphisms in the PLA2R gene have been found.
Diagnostic methods
Typically, diagnosis of PMN is made on kidney biopsy. Diagnostic features include capillary wall thickening, normal cellularity, IgG and C3 along capillary walls on immunofluorescence, and subepithelial deposits on electron microscopy. However, a diagnosis of PMN is strongly suspected on detection of circulating PLA2R antibodies.
Differential diagnosis
Secondary causes of MN should be excluded. These include malignances, infections (Hepatitis B, hepatitis C, syphilis), systemic diseases (SLE, sarcoidosis, IgG4-related kidney disease), drugs (NSAID'S, penicillamine, gold), and paraproteinemia.
Management and treatment
All patients should be managed with optimized conservative therapy, targeting blood pressure, proteinuria, and cholesterol. Use of angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker along with statins is preferred. Patients should also adhere to life-style changes (stop smoking, body weight, dietary sodium and protein restrictions). In patients with severe hypoalbuminemia, prophylactic anticoagulant therapy should be considered. In adults without high risk features, a period of 6 months of conservative therapy is advised before considering additional immunosuppressive therapy. Laboratory parameters (serum creatinine, serum albumin, urine protein to creatinine ratio, anti PLA2R ab levels, urinary LMW proteins) and blood pressure are important parameters to estimate (risk of) progression. In patients with progressive renal insufficiency, or patients with severe nephrotic syndrome and high risk of progression, treatment with immunosuppressive drugs should be started. Current guidelines discuss the use of alkylating agents, calcineurin inhibitors, and rituximab. Prednisone monotherapy is not effective in adults.
Prognosis
Patients with non-nephrotic proteinuria typically have non-progressive disease. In patients with nephrotic syndrome, the natural course of disease is variable ranging from spontaneous remission to ESRD. With current treatment strategies the risk of ESRD has decreased, and only 5-10 % of patients will be non-responsive.

                            Last update:
                            May 2019

                            - Expert reviewer(s):
                            Dr Laura CESCA  - Pr Pierre RONCO | ERKNet* - Dr Marina VIVARELLI | ERKNet* - Pr J.F.M. [Jack] WETZELS | ERKNet*

                                * European Reference Network


Primary microcephaly-epilepsy-permanent neonatal diabetes syndrome is a rare, genetic, neurologic disease characterized by congenital microcephaly, severe, early-onset epileptic encephalopathy (manifesting as intractable, myoclonic and/or tonic-clonic seizures), permanent, neonatal, insulin-dependent diabetes mellitus, and severe global developmental delay. Muscular hypotonia, skeletal abnormalities, feeding difficulties, and dysmorphic facial features (including narrow forehead, anteverted nares, small mouth with deep philtrum, tented upper lip vermilion) are frequently associated. Brain MRI reveals cerebral atrophy with cortical gyral simplification and aplasia/hypoplasia of the corpus callosum.


Primary microcephaly-mild intellectual disability-young-onset diabetes syndrome

A rare, genetic, syndromic intellectual disability disorder characterized by congenital, persistent microcephaly, low birth weight, short stature, childhood-onset seizures, global development delay, mild intellectual disability, and adolescent or young adult-onset diabetes mellitus. Gait ataxia, skeletal abnormalities, dorsocervical fat pad, and infantile cirrhosis may also be associated. Brain morphology is typically normal, although delayed myelination and hypoplastic brainstem have been reported.


A rare myeloproliferative neoplasm characterized by stem-cell derived clonal over proliferation of mature myeloid lineages, such as erythrocytes, leukocytes, and megakaryocytes, with variable degrees of megakaryocyte atypia, associated with reticulin and/or collagen bone marrow fibrosis, osteosclerosis, ineffective erythropoiesis, angiogenesis, extramedullary hematopoiesis, and abnormal cytokine expression.

Summary:
Epidemiology
The annual incidence of primary myelofibrosis (PMF) is approximately 1 case per 100,000 individuals, although an increased prevalence is noted in Ashkenazi Jews.
Clinical description
Age at diagnosis is usually in adulthood, around the sixth decade of life. Clinical manifestations depend on the type of blood cell(s) affected and may include severe anemia, pallor, petechiae, ecchymosis, bleeding, thrombosis, pancytopenia, pruritus, hypermetabolic state, marked hepato/splenomegaly, and/or constitutional symptoms, such as fatigue, fever, and night sweats. Symtomatic portal hypertension and non hepatosplenic extramedullary hematopoiesis may lead to variceal bleeding, ascites, pleural effusion and/or pulmonary hypertension. Leukemic transformation is observed in approximately 20% of patients.
Etiology
Evidence strongly suggests that PMF is attributed to the dysregulation of the JAK2-STAT5 signaling pathway. The mutation JAK2V617F on the JAK2 gene is the most prevalent mutation reported. Additionally, mutations in the MPL gene, which encodes the thrombopoietin receptor, and CALR. Furthermore, the megakaryocyte lineage contributes to the pathogenesis as these cells produce various profibrotic, angiogenic and pro-inflammatory cytokines, which are believed to play a role in bone marrow fibrosis, osteosclerosis and angiogenesis.
Diagnostic methods
The diagnosis is based on the presence of major and minor criteria. It requires meeting all three major criteria, and at least one minor criterion. Major criteria include megakaryocytic proliferation and presence of reticulin and/or collagen fibrosis grades 2 or 3; the absence of other sign of blood and bone marrow cells proliferation and tumour (WHO classification); the mutations test for JAK2, CALR or MPL. Minor criteria include results of blood test for anemia with leukocytosis, increased LDH level and leukoerythroblastosis.
Differential diagnosis
Differential diagnosis of PMF includes other closely related myeloid neoplasms, such as chronic myeloid leukemia, essential thrombocythemia, polycythemia vera, myelodysplastic syndromes, chronic myelomonocytic leukemia, acute panmyelosis with myelofibrosis and acute megakaryoblastic leukemia.
Genetic counseling
The pathology is not inherited although it is linked with important gene mutations which occur at any time in life. Although most cases appear to be sporadic, familial predisposition has been recognized for many years in a subset of cases and epidemiological studies have indicated the presence of common susceptibility alleles.
Management and treatment
Historically, splenectomy and hematopoietic stem cell transplantation (HSCT) have been the treatment for PMF, with the latter being the only treatment modality which prolongs survival or potentially cures PMF. HSCT, however, is associated with important morbidity and high transplant-related death therefore, individual patient risk-benefit assessment is necessary. Drug therapy with JAK inhibitors improves symptoms and splenomegaly but has not been shown to favorably modify disease natural history or prolong survival and therefore risk-benefit should also be carefully evaluated.
Prognosis
Severity and prognosis are variable depending on the affected genes and symptoms. Risk assessment using the International Prognostic Scoring System (IPSS) and the Dynamic IPSS (DIPSS) has proven useful in classifying patients into risk categories at diagnosis and later time points. A more recent score (MIPSS70) is particularly useful for risk stratification for transplantation-age patients.

                            Last update:
                            May 2019

                            - Expert reviewer(s):
                            Pr Elisa RUMI


Primary non-essential cutis verticis gyrata

A rare genetic dermis disorder characterized by slowly progressive thickening of the scalp, which becomes raised and forms ridges and furrows with symmetrical distribution resembling the cerebral gyri and cannot be flattened by traction or pressure, associated with ophthalmologic (e.g. congenital cataract) and/or neurological abnormalities (e.g. intellectual disability, epilepsy, microcephaly, encephalopathy).


Primary non-gestational choriocarcinoma of ovary is a rare ovarian germ cell malignant tumor (see this term), arising from primordial germ cells, usually presenting with nausea, vomiting, abdominal pain, menstrual irregularities, and characterized by fast growth pattern, metastasis to lung, liver and brain and production of human chorionic gonadotrophin (hCG). It is apparently chemoresistant and has a worse prognosis than gestational choriocarcinoma (see this term) and hence should be distinguished from the latter by DNA polymorphism.


Primary oculocerebral lymphoma is a rare, primary, organ-specific, extranodal non-Hodgkin's lymphoma (typically diffuse large B-cell lymphoma), simultaneously affecting the intraocular compartments (retina, vitreous, optic nerve, uvea and others) and the central nervous system (commonly the cerebellum, spinal cord or pia mater). The presenting symptoms vary depending on the localization of the tumor and may include vitreous floaters or blurred vision, raised intracranial pressure (headache, vomiting, papilledema) and/or focal neurological deficits.


A rare tremor disorder characterized by an isolated high frequency (>12 Hz) tremor that occurs when standing, typically in weight-bearing muscles, causing a feeling of unsteadiness or discomfort, which disappears when not standing.

Summary:
Epidemiology
Prevalence is unknown, however, hundreds of cases have been reported all over the world, with female preponderance (sex ratio: 2:1), and a mean onset around 55-60 years old (range 13-85).
Clinical description
Primary orthostatic tremor (POT) appears on standing and is associated with an intense and disabling sense of unsteadiness, a fear of falling, discomfort, dizziness, shaking, trembling sensations and/or trembling of limbs and trunk. An action tremor (5-10 Hz) may be present in the arms. Symptoms during stance are reduced/abolished by walking, support, sitting, and lying down. Patients often shuffle, wobble, or seek support when standing. Prevalent signs during stance and walking are bent knees, hem sign (trembling of hem of skirt/shirt), and a broad base of support. Tandem gait may be abnormal (with normal heel-to-shin test). The fast tremor may be visible, palpable, and muscle auscultation may reveal a thudding sound (helicopter sign). The 'Orthostatic Tremor Severity and Disability Scale (OT-10)' is an online-available self-report scale which captures OT-related severity and disability based on the presentation of symptoms, such as unsteadiness, discomfort, or shaking when standing, and how they affected the patient's activities of daily living over the course of their past week. The term orthostatic tremor plus is used when OT is accompanied by other neurological symptoms.
Etiology
The pathophysiology of POT is unknown. Strong intermuscular coherence at tremor frequency, also between bilateral head muscles, is thought to be driven by a supraspinal (possibly cerebellar or brainstem) oscillator. The oscillator may also be active in healthy subjects who are made unsteady; POT may represent an exaggerated activity in otherwise physiological pathways involved in postural responses. An alternative hypothesis is that POT is triggered by the weight of the body when standing still, and that the slight imbalance which ensues aggravates the tremor.
Diagnostic methods
Diagnosis is based on clinical examination of symptoms. The diagnostic procedure consists in confirmation of >12 Hz tremor in weight-bearing muscles during stance and absence after sitting (by electromyography) and not placing weight on the feet. There should be no extrapyramidal, cerebellar and/or other signs (except arm tremor), nor abnormal findings at adaptive optics (AO) imaging, electroneurography, or blood tests, which might point to OT-plus, secondary OT, or a comorbidity.
Differential diagnosis
Differential diagnoses include AO slow OT (4-12 Hz), orthostatic myoclonus (irregular bursts), essential tremor, Parkinson's disease, functional neurological disorder, restless legs syndrome, polyneuropathy, neurogenic claudication, and vertigo.
Genetic counseling
A positive family history is rare.
Management and treatment
There is no cure or standard treatment for POT. Effective medication includes benzodiazepines (clonazepam), anti-seizure medication (gabapentin and perampanel), and possibly beta-blockers (propranolol). Treatment response can be poor or wear off, and side-effects can limit daily dosages. Surgical treatment, described in limited numbers of medication refractory patients, includes deep brain stimulation, which showed (variable) improved ability to stand still, possibly diminishing over time, and side-effects. Bilateral spinal cord stimulation improved ability to stand for a majority of patient but had no effect in some. Physical aids (portable/high stool), training muscle strength, conditioning, medical statement and patient brochure/leaflet might be helpful.
Prognosis
POT is often slowly progressive. Severity of symptoms, effect of treatment, and experienced quality of life vary largely between patients.

                            Last update:
                            February 2024

                            - Expert reviewer(s):
                            Dr Anne-Fleur VAN ROOTSELAAR


Cardiac tumours are benign or malignant neoplasms arising primarily in the inner lining, muscle layer, or the surrounding pericardium of the heart. They can be primary or metastatic.

Summary:
Epidemiology
Primary cardiac tumours are rare in paediatric practice with a prevalence of 1.7/1000 to 28/1000 in autopsy series. In contrast, the incidence of cardiac tumours during foetal life has been reported to be approximately 1.4/1000. The incidence of cardiac metastases associated with all types of malignant tumours is estimated to be approximatively 1% (and is 10-20 times higher than primary malignancies of the heart).
Clinical description
The vast majority of primary cardiac tumours in children are benign, whilst approximately 10% are malignant. In contrast, the majority of secondary tumours are malignant. In adults, however, the frequency and type of cardiac tumours in adults differ from those in children with 75% being benign and 25% being malignant. Myxomas are the most common primary tumours in adults constituting 40% of benign tumours. Sarcomas make up 75% of malignant cardiac masses. Rhabdomyoma is the most common cardiac tumour during foetal life and childhood. It accounts for more than 60% of all primary cardiac tumours. The manifestations of a cardiac tumour in foetal life include arrhythmia, congestive heart failure, hydrops, and not infrequently stillbirth. In postnatal life cardiac tumours may lead to cyanosis, murmur, respiratory distress, myocardial dysfunction, valvular insufficiency, arrhythmias, and sudden death.
Diagnostic methods
Echocardiography, Computing Tomography (CT) and Magnetic Resonance Imaging (MRI) of the heart are the main non-invasive diagnostic tools. Cardiac catheterisation is seldom necessary. Tumour biopsy with histological assessment remains the gold standard for confirmation of the diagnosis.
Management and treatment
Surgical resection of primary cardiac tumours should be considered to relieve symptoms and mechanical obstruction to blood flow. Patients with primary cardiac malignancies may benefit from palliative surgery but this approach should not be recommended for patients with metastatic cardiac tumours. Surgery, chemotherapy and radiotherapy may prolong survival.
Prognosis
The outcome of surgical resection in symptomatic, non-myxomatous benign cardiac tumours is favourable. The prognosis for malignant primary cardiac tumours is generally extremely poor.

                            Last update:
                            March 2007

                            - Expert reviewer(s):
                            Dr Joseph DE GIOVANNI  - Dr Jonathan PARSONS  - Dr Orhan UZUN  - Dr Gordon VUJANIC  - Dr Dirk WILSON


Primary peritoneal carcinoma (PPC) is a rare malignant tumor of the peritoneal cavity of extra-ovarian origin, clinically and histologically similar to advanced-stage serous ovarian carcinoma (see this term).

Summary:
Epidemiology
PPC accounts for about 10% of pelvic serous carcinomas.
Clinical description
It is almost exclusively found in women. PPC can occur many years after oophorectomy performed for benign diseases or prophylactic oophorectomy. The tumor appears during adulthood with a mean age at diagnosis of 60 years. Clinical features include abdominal swelling, constipation, gastrointestinal disorders, nausea, vomiting, anorexia and weight loss. The tumor develops in the peritoneum and spreads to the abdomen, pelvis and ovaries.
Etiology
Primary peritoneal carcinoma has an epithelial origin and probably derives from coelomatic embryonal epithelium. The fallopian tubes are suspected as the primary site. Women with breast cancer type 1 (BRCA1) gene mutations present an increased risk of developing a PPC.
Diagnostic methods
Diagnosis is based on elevated cancer markers, with elevated cancer antigen 125 (CA125), and on imaging examinations such as ultrasound and chest-abdominal computed tomography (CAP-CT). Diagnosis is confirmed by biopsies performed during laparotomy or laparoscopy, especially when ovaries are normal or absent.
Differential diagnosis
The main differential diagnosis is epithelial ovarian cancer. PPC and serous ovarian carcinoma are histologically similar, and it is often impossible to determine the organ of origin at late stages when the ovaries, abdominal cavity and fallopian tubes are all involved.
Management and treatment
Management should be multidisciplinary and must be discussed by a panel of physicians in a specialized center. There are currently no validated recommendations on clinical management and no cytotoxic agents have been granted a European Marketing Authorization (MA) in this indication. Combination of cytoreductive surgery (visceral resections and peritonectomy procedures) with hyperthermic intraperitoneal chemotherapy (HIPEC) (off-label use) has been considered in specific patients (i.e. young patients with good general status and low tumor volume) before or after systemic chemotherapy (off-label use) if the disease does not respond to optimal cytoreductive surgery.
Prognosis
Prognosis is poor, similar to or worse than that of ovarian carcinoma.

                            Last update:
                            March 2011

                            - Expert reviewer(s):
                            Pr Olivier GLEHEN


Primary progressive aphasia (PPA) is a neurodegenerative disorder, characterized by a primary dissolution of language, with relative sparing of other mental faculties for at least the first 2 years of illness. PPA is recognized as the language variant in the frontotemporal dementia (FTD; see this term) spectrum of disorders. PPA can be classified into 3 subtypes based on specific speech and language features: semantic dementia (SD), progressive non-fluent aphasia (PNFA) and logopenic progressive aphasia (lv-PPA) (see these terms).


Primary progressive apraxia of speech is a rare neurodegenerative disease characterized by impaired planning or programming of the movements for speech, leading to phonetically and prosodically abnormal speech, in absence, at onset, of any other neurological features (such as aphasia, memory loss, pyramidal signs). Patients usually present articulatory distortions/groping, slow rate, distorted sound substitutions and/or trial and error articulatory movements which begin insiduously and worsen over time.


Primary progressive freezing gait is a rare, heterogeneous, progressively incapacitating neurodegenerative disease characterized by freezing of gait (usually during the first 3 years), later associating postural instability, eventually resulting in a wheelchair-bound state. Other features may include mild bradykinesia, rigidity, postural tremor, hyperreflexia, speech disorder and dementia. The disease is unresponsive to dopaminergic treatments.


Primary pulmonary hypoplasia is a rare, isolated, genetic developmental defect during embryogenesis characterized by congenital malformation of pulmonary parenchyma with absence of other anomalies. Neonatally patients present with decreased breath sounds, small lung volume and severe respiratory distress that is not responsive to aggressive treatment (including surfactant instillation/ mechanical respiratory support). It is usually not compatible with life.


A rare neoplastic disease defined as a clonal lymphoid proliferation affecting one or both lungs (parenchyma and/or bronchi) in a patient with no detectable extrapulmonary involvement at diagnosis or during the subsequent 3 months. PPL comprises low grade/indolent B cell PPL forms, the most frequent form represented by the marginal B-cell lymphoma of mucosa associated lymphoid tissue (MALT lymphoma) and other non-MALT low grade lymphomas; and more rarely high-grade B-cell PPL (including diffuse large B cell lymphoma) and lymphomatoid granulomatosis (LYG).

Summary:
Epidemiology
Primary pulmonary lymphoma (PPL) is very rare and represents only 3-4% of extranodal non-Hodgkin lymphoma (NHL, less than 1% of NHL, and only 0.5-1% of primary pulmonary malignancies. MALT lymphoma represents 85-90% of PPL cases and is the most common type of pulmonary lymphoma. The ratio of male to female patients is close to 1:1.
Clinical description
PPL onset generally occurs in the 5th and 6th decades of life, and very occasionally affects those under 30 years of age. The clinical presentations of PPL are variable and depend on the distinct B-cell histological subtype: Low grade B cell PPL including MALT lymphomas have an indolent presentation while high-grade B-cell PPL and LYG may have an aggressive clinical picture. 50% of patients with MALT lymphoma are asymptomatic at presentation. When present, symptoms are not specific and include coughing, mild dyspnea, chest pain, wheezing, and occasionally hemoptysis. Fever and weight loss are present in less than 25% of cases. Patients with high-grade B-cell PPL usually present respiratory manifestations, fever and weight loss while patients with LYG frequently have brain, kidney and otorhinolaryngeal manifestations.
Etiology
PPL are lymphoproliferative disorders that originate frequently from clonal proliferation of the B cell-lineage, most commonly marginal zone B-cells of MALT of the bronchus. MALT lymphomas are thought to be acquired as a result of chronic antigenic stimulation such as smoking, autoimmune disease, or infection while LYG is associated with Epstein-Barr virus (EBV) infection.
Diagnostic methods
Diagnosis of PPL relies on clinical and radiographic findings which are nonspecific and include solitary nodule, multiple ill-defined nodules, consolidated mass with air bronchograms, pleural effusions, atelectasis, and cavities. Histological examination helps diagnose the type of tumor. Immunohistochemical analysis reveals CD19-CD20+ cells.
Differential diagnosis
Radiological appearance may mimic cryptogenic organizing pneumonia, lymphoid interstitial pneumonia (LIP), diffuse lymphoid hyperplasia, follicular bronchitis and bronchioloalveolar carcinoma. LIP may be associated with PPL in case of autoimmune disease.
Management and treatment
The treatment options include watchful observation for indolent types of PPL, surgery in localized tumors, chemotherapy with or without rituximab if the lesions are diffuse or involve both lungs and radiotherapy for patients with a unique, small lesion.
Prognosis
The prognosis for low grade PPL is good with survival equal to that of the general population. However, survival rate for high grade PPL and LYG can be poorer.

                            Last update:
                            November 2019

                            - Expert reviewer(s):
                            Pr Jacques CADRANEL


A group of rare renal tubular diseases characterized by primary defects in bicarbonate reabsorption from urine (proximal renal tubular acidosis) and/or hydrogen excretion into the lumen (distal renal tubular acidosis), resulting in metabolic acidosis with hyperchloremia and a normal plasma anion gap. The glomerular filtration rate is relatively normal.


Primary sclerosing cholangitis (PSC) is a rare, slowly progressive liver disease characterized by inflammation and destruction of the intra- and/or extra-hepatic bile ducts that lead to cholestasis, liver fibrosis, liver cirrhosis and ultimately liver failure.

Summary:
Epidemiology
The prevalence of PSC in Europe ranges from 1/446,000-1/6,170. A male preponderance is observed with a male to female ratio of approximately 2:1.
Clinical description
PSC can occur at any age with a peak incidence around 40 years of age. Symptoms and clinical findings are variable, depending on the stage of the disease. In early stages, unspecific manifestations such as fever, fatigue, pruritus, malaise, abdominal pain, and weight loss are reported, however about 40-50% of patients may be asymptomatic at time of diagnosis. Hepatomegaly, splenomegaly, jaundice, portal hypertension and, in more advanced cases, spider angiomata, ascites and muscle atrophy are observed. The disease course is also highly variable, but in the majority of cases, PSC is slowly progressive, leading to liver cirrhosis, liver failure and the need for liver transplantation over a period of 13-21 years following diagnosis. Several immune-mediated comorbidities are observed in PSC. The most common co-existing condition is inflammatory bowel disease, reported in up to 60-80% of patients of Northern European decent. Other immune-mediated conditions, such as autoimmune hepatitis, thyroid disease, type 1 diabetes mellitus, and celiac disease, are also observed with slightly increased frequencies in PSC patients. A proportion of PSC patients develop malignancies; mainly cholangiocarcinoma, but also increased risk of carcinoma of the large intestine in patients with concomitant IBD. Small-duct PSC is a PSC-variant manifesting with chronic cholestasis, biochemical and histological findings similar to those found in PSC, and a normal cholangiography.
Etiology
The precise etiology of PSC has not yet been established, but it is believed to be multifactorial. Genetic susceptibility factors are known to be involved, and a strong association to genetic variants within the HLA-region on chromosome 6 is observed. The disease is thought to be related to an abnormal immune response to a still unidentified environmental stimulus.
Diagnostic methods
PSC is suspected based on clinical manifestations and altered liver function tests and diagnosis is confirmed through magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP) showing bile duct changes with strictures and dilatations characteristic of the disease.
Differential diagnosis
Differential diagnoses include other hepatic diseases, such as autoimmune hepatitis and primary biliary cholangitis. Exclusion of multiple secondary causes leading to PSC-like bile duct changes, such as IgG4-associated sclerosing cholangitis, mast cell cholangiopathy, infections, biliary calculi or trauma, and other identifiable causes of insults to the biliary tree (leading to the ERCP or MRCP features seen in PSC) is mandatory to establish the diagnosis of PSC.
Management and treatment
Immunosuppressants and chelators are used to treat the symptoms and manage the complications, however, to date there are no medical therapies that cure or alter the disease course of PSC. Replacement therapy of fat-soluble vitamins A, D, E, and K is frequently necessary since patients frequently present deficiency of these vitamins. Liver transplantation is currently the only definitive treatment for patients with advanced disease and the majority of patients require a liver transplantation 13-21 years after diagnosis; either due to disease progression or disease complications, such as treatment-resistant bacterial cholangitis. Endoscopic dilatation, with or without stenting, of biliary strictures may be performed to relieve symptoms of biliary obstruction.
Prognosis
Prognosis after liver transplantation is generally good, however, in a proportion of patients PSC may recur in the transplanted liver, with recurrence rates varying from 10-37%.

                            Last update:
                            March 2017

                            - Expert reviewer(s):
                            Dr Trine FOLSERAAS  - Dr Tom Hemming KARLSEN


A rare systemic autoimmune disease characterized by exocrine gland dysfunction, resulting predominately in keratoconjunctivitis sicca and xerostomia, but also affecting exocrine glands of the skin, as well as respiratory, urogenital, and digestive tract. Extraglandular manifestations include arthritis, interstitial lung disease, renal disease, and peripheral neuropathy. The disease is accompanied by a substantially increased risk to develop B-cell non-Hodgkin lymphoma, especially MALT (mucosa-associated lymphoid tissue) lymphoma.


A rare central nervous system malformation characterized by a fluid-filled longitudinally oriented cavity (syrinx) within the spinal cord, which may or may not communicate with the central canal, does not have an ependymal lining, and is either idiopathic or seen as a familial malformation. Clinical manifestations in symptomatic patients include neuropathic pain, as well as sensory and motor disturbances. Typical presentations may be cape-like loss of pain and temperature sensation along the torso and arms, or disproportionately greater motor impairment in upper compared to lower extremities.


Primary tethered cord syndrome is a genetic, non-syndromic congenital malformation of the neurenteric canal, spinal cord and column characterized by progressive neurologic deterioration (pain, sensorimotor deficits, abnormal gait, decreased tone or abnormal reflexes), musculoskeletal changes (foot deformities and asymmetry, muscle atrophy, limb weakness and numbness, gait disturbances, scoliosis) and/or genitourinary manifestations (bladder and bowel dysfunction). Midline cutaneous stigmata in the lumbosacral region, such as turfs of hair, skin appendages, dimples, subcutaneous lipomas, skin discoloration or hemangiomas, are frequently associated.


Primary triglyceride deposit cardiomyovasculopathy

A rare inborn error of metabolism characterized by massive accumulation of triglycerides in the myocardium and coronary arteries, while plasma triglyceride levels are normal. Patients present in adulthood with signs and symptoms of coronary artery disease and severe heart failure. Concomitant skeletal myopathy is common. Vacuole formation in polymorphonuclear leukocytes is typically observed.


Primary unilateral adrenal hyperplasia (PUAH) is a surgically-correctable form of primary (hyper) aldosteronism (PA; see this term) characterized by renin suppression, unilateral aldosterone hypersecretion, and moderate to severe hypertension secondary to hyperplasia of the adrenal gland.

Summary:
Epidemiology
The prevalence of primary unilateral adrenal hyperplasia is unknown.
Clinical description
PUAH may be associated with hypokalemia, which, when present, may be symptomatic with muscular weakness, cramps, paresthesia or palpitations with or without atrial fibrillation.
Etiology
The etiology of PUAH is not known.
Diagnostic methods
Diagnostic methods include peripheral aldosterone and renin determinations, adrenal venous sampling which makes it possible to differentiate unilateral from bilateral aldosterone hypersecretion, and CT scan showing normal adrenals or unilateral adrenal hyperplasia.
Management and treatment
Unilateral adrenalectomy abolishes aldosterone hypersecretion and hypokalemia in most patients with PUAH.
Prognosis
Blood pressure is significantly improved in the majority of the patients, but hypertension is cured in only 50% of cases.

                            Last update:
                            July 2011

                            - Expert reviewer(s):
                            Pr Laurence AMAR  - Pr Pierre-François PLOUIN  - Dr Olivier STEICHEN


Primitive neuroectodermal tumor of the cervix uteri is a rare cancer of cervix uteri derived from neural crest cells, histologically composed of small, round neoplatic cells with variable degree of neural, glial and ependymal differentiation. Macroscopically, the tumor is often a large, soft, poorly circumscribed mass with infiltrative borders and necrotic areas. It presents with dysfuntional vaginal bleeding or discharge, lower abdominal pain and uterine enlargement.


Primitive neuroectodermal tumor of the corpus uteri is a rare cancer of corpus uteri derived from neural crest cells, characterized by small, round neoplastic cells with variable degree of neural, glial and ependymal differentiation. Macroscopically, the tumor is often a large, poorly circumscribed polypoid mass with necrotic areas and hemorrhage. It usually presents with lower abdominal or pelvic pain, irregular vaginal bleeding or discharge, pelvic mass and uterine enlargement.


Portal vein thrombosis (PVT) is associated with acute (recent) or chronic (long-standing) thrombosis of the portal system.

Summary:
Epidemiology
Prevalence of the primary form (PVT not associated with cirrhosis or a tumour) is estimated at between 1 and 9/100,000. PVT may occur at any age.
Clinical description
Acute thrombosis may be asymptomatic or may manifest as abdominal pain, fever and intestinal ischemia (ileus, rectal bleeding, and ascites). In some cases, intestinal necrosis (manifesting as peritonitis and multivisceral failure) may occur if treatment is delayed. Chronic PVT is associated with cavernous transformation resulting in portal hypertension. PVT may be discovered fortuitously as a result of investigations for hypersplenism or intestinal varices. Haemorrhage due to rupture of these varices is a major complication. Portal cholangiopathy (due to biliary compression resulting from cavernous transformation) leads to calculus or cholestasis in rare cases.
Etiology
The most frequent causes of PVT are advanced cirrhosis and malignant tumours in adults, and neonatal omphalitis or cannulation of the umbilical vein in children. In the absence of a tumour or advanced cirrhosis, PVT may be caused by localised intra-abdominal inflammation or be associated with a general prothrombotic state caused by a myeloproliferative syndrome (25% of cases), G20210A mutations in the factor II (prothrombin) gene (10% of cases), antiphospholipid syndrome, or by deficiencies of antithrombin, protein C, protein S or factor V Leiden. PVT is generally caused by an association of these causes.
Diagnostic methods
Diagnosis of acute PVT or cavernous transformation can be easily established through non-invasive imaging techniques: Doppler ultrasound and tomodensitometry. MRI is a useful tool for diagnosing portal cholangiopathy. It is essential to search for the local or generalised cause of PVT.
Differential diagnosis
Differential diagnosis should include all other causes of abdominal pain (with or without fever) for acute PVT and all other causes of portal hypertension without hepatic insufficiency for chronic PVT.
Genetic counseling
Although some causes of PVT are hereditary, PVT is not an inherited disease. Genetic counselling should be proposed for patients with a hereditary predisposition for thrombosis.
Management and treatment
Treatment of acute PVT includes administration of anticoagulants (for 3 to 6 months) and treatment of the underlying causative factor(s). Permeability is restored after treatment in 10-40% of cases. Exploratory laparotomy and intestinal resection may be necessary if intestinal necrosis is present. In chronic PVT, the portal hypertension is treated according to the same protocols as those established for cirrhosis. If management of the portal hypertension is satisfactory, long-term anticoagulant therapy is recommended for patients in a permanent prothrombotic state or in case of extension to the superior mesenteric vein.
Prognosis
For patients receiving early diagnosis and appropriate treatment, the prognosis is good but varies depending on the associated conditions and age at onset.

                            Last update:
                            April 2008

                            - Expert reviewer(s):
                            Pr Dominique VALLA


PRKAR1B-related neurodegenerative dementia with intermediate filaments

A rare, genetic neurodegenerative disease characterized by dementia and mild parkinsonism with poor levodopa response. Presenting clinical manifestations are memory problems, short attention span, disorientation, language impairment, rigidity, bradykinesia, postural instability and behavioral changes, including apathy, anxiety and delusions.


Proboscis lateralis (PL) is a rare congenital facial abnormality characterized by failed development of the external nose on one side that is replaced by a tubular structure composed of skin and soft tissue usually attached at the inner canthus of the eye and therefore often associated with maldevelopment of the nasal cavity or paranasal sinuses of the affected side. PL is also associated with other craniofacial abnormalities such as orbital anomalies, cleft lip/palate, frontal encephalocele and holoprosencephaly (see these terms).


Progeria-short stature-pigmented nevi syndrome

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by intrauterine growth retardation and short stature, microcephaly, premature aging, bird-like facies with lack of facial subcutaneous fat, multiple pigmented nevi, sensorineural hearing loss, and variable intellectual disability. Immunodeficiency and development of tumors have also been described.


Progeroid and marfanoid aspect-lipodystrophy syndrome

A rare systemic disease characterized by a neonatal progeroid appearance (not associated with other manifestations of premature aging) associated with facial dysmorphism (e.g. macrocephaly or arrested hydrocephaly, proptosis, downslanting palpebral fissures, retrognathia), generalized, extreme, congenital lack of subcutaneous fat tissue (except in the breast and iliac region) and incomplete signs of Marfan syndrome (mainly severe myopia, joint hyperextensibility and arachnodactyly). Metabolic disturbances are not associated.


Progeroid features-hepatocellular carcinoma predisposition syndrome

A rare inherited cancer-predisposing syndrome characterized by early-onset hepatocellular carcinoma, genomic instability, and progeroid features, such as short stature, low body weight, muscular atrophy, lipodystrophy, bilateral cataracts, and premature hair graying. Dysmorphic craniofacial features include triangular face, small, deep-set eyes, and micrognathia. Kyphoscoliosis, sloping shoulders, mild pectus excavatum, bilateral contractures of the elbows and fingers, bilateral clinodactyly, and pes planus have also been reported.


Progeroid syndrome, Petty type is a rare premature aging syndrome characterized by pre-and postnatal growth retardation, a congenital premature-aged appearance with distinctive craniofacial dysmorphism (wide calvaria with large open anterior fontanel and wide metopic suture, broad forehead, small face, micrognathia), markedly diminished subcutaneous fat, cutis laxa and wrinkled skin, without delay in psychomotor development. Scant, brittle hair, hypoplastic nails and delayed, abnormal dentition, as well as hypoplastic distal phalanges, umbilical hernia and eye abnormalities (myopia/hyperopia, strabismus), are also commonly associated.


Progressive autosomal recessive ataxia-deafness syndrome

A rare genetic disease characterized by severe progressive sensorineural hearing loss and progressive cerebellar signs including gait ataxia, action tremor, dysmetria, dysdiadochokinesis, dysarthria, and nystagmus. Absence of deep tendon reflexes has also been reported. Age of onset is between infancy and adolescence. Brain imaging may show variable cerebellar atrophy in some patients.


Progressive bifocal chorioretinal atrophy (PBCRA) is an early-onset chorioretinal dystrophy characterized by large atrophic macular and nasal retinal lesions, nystagmus, myopia, poor vision, and slow disease progression.

Summary:
Epidemiology
It has been described in two large families.
Etiology
Transmission is autosomal dominant and the causative gene has been mapped to a region on chromosome 6q, close to the macular dystrophy retinal 1 (MCDR1) locus.

                            Last update:
                            September 2006


A rare leukoencephalopathy characterized by acute episodes of neurological deficit (ataxia, dysarthria, seizures) with irritability and opisthotonus followed by either steady deterioration or alternating periods of rapid progression and prolonged periods of stability.

Summary:
Epidemiology
So far around 20 patients have been reported in the literature.
Clinical description
Onset occurs in infancy or early childhood.
Etiology
The etiology remains unknown.
Diagnostic methods
MRI imaging reveals irregular asymmetric patches of leukoencephalopathy with cavities, vascular permeability and cystic degeneration affecting principally the corpus callosum, cerebral and cerebellar white matter, and spinal cord.
Genetic counseling
The mode of transmission is autosomal recessive.

                            Last update:
                            September 2008


A rare genetic neurological disorder characterized by postnatal onset of severe global developmental delay, profound mental retardation, progressive microcephaly, progressive spasticity evolving into spastic quadriplegia with joint contractures, generalized seizures, and irritability. Severe choreoathetosis and dysmorphic features are absent. Brain imaging shows progressive cerebellar atrophy followed by cerebral atrophy affecting both white and grey matter, but no pontine involvement.


A rare retinal dystrophy characterized by photophobia, progressive loss of visual acuity, nystagmus, visual field abnormalities, abnormal color vision, and psychophysical and electrophysiological evidence of abnormal cone function. Progressive cone dystrophy usually presents in childhood or early adult life, and patients tend to develop rod photoreceptor dysfunction in later life.


Progressive deafness with stapes fixation

Stapes fixation (stapedovestibular ankylosis) is a hearing loss condition that appears as a consequence of annular ligament destruction followed by excessive connective tissue production during the healing process. This condition is mainly observed in otosclerosis, but is also found in chronic otitis media with tympanosclerosis, and other rare bone diseases such as Paget's disease and osteogenesis imperfecta (Lobstein disease).

Summary:
Epidemiology
The prevalence of symptomatic otosclerosis is estimated as 0.1 to 0.5% of the population in the United-States and Western Europe, thus this is not a rare disease. The prevalence of otosclerosis appears to be lower in the Chinese, Japanese, and Latin American populations, and is much lower in the Black population. Tympanosclerosis occurs in 9 to 38% of chronic otitis media cases. The prevalence of Paget's disease associated with temporal bone involvement is estimated as 0.2 to 1% of Caucasian adults. The prevalence of osteogenesis imperfecta is 1/20 000 births. Hearing loss is observed in 26 to 60% of these patients.
Etiology
The etiology of otosclerosis is still unknown. Otosclerosis appears to be a multifactorial disease. Autosomal dominant and a low penetrance (40%) transmission is observed in familial cases. The role of infection with the measles virus as a triggering factor is currently being investigated. Osteogenesis imperfecta is principally related to the mutation of the collagen 1A1 (COL1A1) and 1A2 (COL1A2) genes. The etiology of Paget's disease is still unclear. Tympanosclerosis is a sequela of middle ear chronic inflammation.
Diagnostic methods
Otoscopy is normal in otosclerosis, Paget's disease, and osteogenesis imperfecta. It reveals middle ear lesions in tympanosclerosis. Audiometry shows a conductive or mixed hearing loss with abolished stapedial reflexes. Computerised tomography (CT) scanning is crucial for the diagnosis of stapes fixation. It detects the bone lesions of otosclerosis as a hypodense regions mainly localized to the anteriorpart of the oval window. In osteogenesis imperfecta and Paget's disease, lesions involve the whole temporal bone and the skull, and result in thickening of the ossicles. In tympanosclerosis, calcified plaques are typically diffuse in the middle ear cleft and involve the oval window.
Differential diagnosis
Differential diagnosis should include minor ossicular malformations presenting with a normal otoscopy, a conductive hearing loss, and abolished stapedial reflexes. In case of otosclerosis, an audiometry with stapedial reflex assessment should be recommended for the parents, siblings, and children (above 20 years of age) of the patient. In all the above etiologies, the progression of the hearing loss is generally slow.
Management and treatment
The hearing loss due to stapes fixation is rarely profound and should always resolve early during follow-up. The conductive component of the hearing loss can be restored by surgery or hearing aids. The associated sensorineural component is managed by hearing aids or cochlear implants, depending on its severity. Sodium fluoride has been reported to slow the progression of otosclerosis lesions, and the consequent sensorineural hearing loss.

                            Last update:
                            September 2006

                            - Expert reviewer(s):
                            Dr Alexis BOZORG GRAYELI


Progressive encephalomyelitis with rigidity and myoclonus

A rare stiff person syndrome spectrum disorder characterized by limb and truncal rigidity, stimulus-sensitive spasms, myoclonus, hyperekplexia, autonomic disturbance, and brainstem involvement or other neurological defects. The condition is progressive and potentially life-threatening, especially due to respiratory failure. It may be associated with the presence of glycine receptor or glutamic acid decarboxylase antibodies, as well as thymomas or lymphomas.


Progressive encephalopathy with leukodystrophy due to DECR deficiency is a rare mitochondrial disease, which presents with neonatal hypotonia, central nervous system abnormalities (ventriculomegaly, corpus callosum hypoplasia, cerebellar atrophy), acquired microcephaly, failure to thrive, developmental delay and intermittent lactic acidosis provoked by catabolic stress (e.g. infection). Hyperlysinemia and elevated C10:2 carnitine can be detected in plasma. Later on, epilepsy, cerebellar ataxia, renal tubular acidosis, severe encephalopathy, dystonia, spastic quadriplegia and other complications may develop.


Progressive epilepsy-intellectual disability syndrome, Finnish type

Progressive epilepsy-intellectual deficit, Finnish type (also known as Northern epilepsy) is a subtype of neuronal ceroid lipofuscinosis (NCL; see this term) characterized by seizures, progressive decline of intellectual capacities and variable loss of vision.

Summary:
Epidemiology
Prevalence is unknown but the disorder is principally reported in Northern Finland.
Clinical description
The disorder is characterized by generalized tonic-clonic seizures with onset at 5 to 10 years of age and subsequent slowly progressive mental deterioration. The seizures increase in frequency until puberty after which the epileptic activity starts to decline. The intellectual deficit is severe, develops 2-5 years after the onset of seizures and progresses continuously through adulthood. Visual problems are not a prominent feature of this disorder; if present they may be mild and go unrecognized.
Etiology
Progressive epilepsy-intellectual deficit, Finnish type is caused by mutations in the CLN8 gene (8p23.3) encoding a putative transmembrane protein of unknown function.
Diagnostic methods
Diagnosis is based on the clinical picture, family history and electron microscopy studies of tissue specimens showing intracellular accumulation of storage material. The diagnosis can be confirmed by molecular analysis.
Differential diagnosis
The differential diagnosis should include other causes of dementia and seizures starting at school age, including atypical forms of other NCL disorders (typically juvenile NCL (see this term) caused by mutations in PPT1 (CLN1 disease), TPP1 (CLN2 disease), or CTSD (CLN10 disease)), as well as mitochondrial disorders and chronic types of encephalitis (see these terms).
Antenatal diagnosis
Prenatal diagnosis is feasible for families in which the disease-causing mutation has already been identified and genetic counseling should be provided.
Genetic counseling
Progressive epilepsy-intellectual deficit, Finnish type is transmitted in an autosomal recessive manner
Management and treatment
Treatment is supportive only with palliative care including administration of anticonvulsants, as well as educational, psychological, and psychiatric management.
Prognosis
Although patients suffer from slow cognitive decline, life expectancy is less severely reduced than in other forms of NCL with juvenile onset and patients may reach 50 or 60 years of age.

                            Last update:
                            February 2010

                            - Expert reviewer(s):
                            Pr Alfried KOHLSCHÜTTER


Progressive essential tremor-speech impairment-facial dysmorphism-intellectual disability-abnormal behavior syndrome

A rare genetic syndromic intellectual disability characterized by global developmental delay, moderate to severe intellectual disability, motor and language impairment, behavioral abnormalities (with mood instability, aggression, and self-mutilation), and progressive hand tremor. Facial dysmorphism includes narrow palpebral fissures, large ears, long philtrum, and prominent chin.


Progressive external ophthalmoplegia-myopathy-emaciation syndrome is a rare mitochondrial oxidative phosphorylation disorder due to nuclear DNA anomalies characterized by progressive external ophthalmoplegia without diplopia, cerebellar atrophy, proximal skeletal muscle weakness with generalized muscle wasting, profound emaciation, respiratory failure, spinal deformity and facial muscle weakness (manifesting with ptosis, dysphonia, dysphagia and nasal speech). Intellectual disability, gastrointestinal symptoms (e.g. nausea, abdominal fullness, and loss of appetite), dilated cardiomyopathy and renal colic have also been reported.


Progressive familial intrahepatic cholestasis type 1

PFIC1, a type of progressive familial intrahepathic cholestasis (PFIC, see this term), is an infantile hereditary disorder in bile formation that is hepatocellular in origin and associated with extrahepatic features.

Summary:
Epidemiology
Estimated prevalence at birth of PFIC types 1-3 varies between 1/50,000 and 1/100,000 births. PFIC1 is the less frequent type of PFIC.
Clinical description
Its onset occurs mostly during infancy. Clinical signs of cholestasis (discolored stools, dark urine) usually appear in the first months of life with recurrent or permanent jaundice associated with hepatomegaly and severe pruritus. Patients usually develop fibrosis and end-stage liver disease before adulthood. Extrahepatic features have been reported including persistent short stature, watery diarrhea, pancreatitis and sensorineural deafness.
Etiology
PFIC1 is due to mutations in the ATP8B1 gene (18q21-22) encoding the FIC1 protein expressed at the canalicular membrane of hepatocytes as well as in other epithelia. In hepatocytes, abnormal protein might indirectly disrupt biliary bile acid secretion, explaining the low biliary bile acid concentration found in PFIC1 patients. Extrahepatic features of the disease are probably related to the extrahepatic expression of FIC1.
Diagnostic methods
PFIC1 should be suspected in children with a clinical history of cholestasis of unknown origin after exclusion of the other main causes of cholestasis presenting with normal serum gamma-GT activity and high serum bile acid concentration. Usually, serum alpha-fetoprotein level is normal and alanine aminotransferase values are below five times the upper limit of normal. Liver ultrasonography is usually normal but may reveal a huge gallbladder. Liver histology reveals canalicular cholestasis and the absence of true ductular proliferation with only periportal biliary metaplasia of hepatocytes. When performed, cholangiography shows a normal biliary tree and allows bile collection. Biliary lipid analysis reveals mildly decreased biliary bile salt concentration. Genotyping confirms the diagnosis.
Differential diagnosis
In the scope of cholestasis with normal gamma-GT, differential diagnosis includes mainly primary bile acid synthesis defects and PFIC2 (see these terms).
Antenatal diagnosis
Prenatal diagnosis can be proposed if a mutation has been identified in each parent.
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Ursodeoxycholic acid therapy (UDCA) should be initiated in all patients to prevent liver damage but is not fully effective. Rifampicin is helpful to control pruritus. Nasobiliary drainage may help to select potential responders to biliary diversion. However, because of severe cholestasis, half of patients are ultimately candidates for liver transplantation (LT). Diarrhea often worsens after LT and might be favorably managed by bile adsorptive resin treatment. LT does not prevent extrahepatic progression of the disease, and does not lead to catch-up growth. Furthermore, severe steatohepatitis of the liver graft has been reported. Specialized follow-up is mandatory lifelong. FIC1 defect predisposes to development of intrahepatic cholestasis of pregnancy (see this term).

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Christiane BAUSSAN  - Pr Emmanuel GONZALES  - Pr Emmanuel JACQUEMIN  - Dr Anne SPRAUL


Progressive familial intrahepatic cholestasis type 2 (PFIC2), a type of progressive familial intrahepatic cholestasis (PFIC, see this term), is a severe, neonatal, hereditary disorder in bile formation that is hepatocellular in origin and not associated with extrahepatic features. Initially, PFIC2 was reported under the name Byler syndrome.

Summary:
Epidemiology
Estimated prevalence at birth of PFIC types 1-3 varies between 1/50,000 and 1/100,000. PFIC2 represents half of PFIC cases.
Clinical description
Onset occurs in the neonatal period. Clinical signs of cholestasis (discolored stools, dark urine) usually appear in the first months of life with recurrent or permanent jaundice associated with hepatomegaly and severe pruritus. Early appearance of liver failure and/or progression to hepatocellular carcinoma within the first years of life may complicate the course of PFIC2. Patients usually develop fibrosis and end-stage liver disease before adulthood.
Etiology
PFIC2 is due to mutations in the ABCB11 gene (2q24) encoding the bile salt export pump (BSEP) protein resulting in impaired biliary bile acid secretion which leads to decreased bile flow and bile salt accumulation in hepatocytes with ongoing severe hepatocellular damage. BSEP is only expressed in hepatocytes, and extrahepatic features are not present in PFIC2.
Diagnostic methods
PFIC2 should be suspected in children with a clinical history of cholestasis of unknown origin after exclusion of the other main causes of cholestasis presenting with normal serum gamma-GT activity and high serum bile acid concentration. Usually, serum alpha-fetoprotein level is elevated and alanine aminotransferase values are over five times the upper limit of normal. Liver ultrasonography is usually normal but may reveal a huge gallbladder and sometimes biliary stones. Liver histology reveals canalicular cholestasis, the absence of true ductular proliferation with only periportal biliary metaplasia of hepatocytes, pronounced lobular and portal fibrosis and inflammation, hepatocellular necrosis and giant cell transformation. BSEP immunostaining is helpful for diagnosis. When performed, cholangiography shows a normal biliary tree and allows bile collection. Biliary lipid analysis reveals dramatically decreased biliary bile salt concentration. Genotyping confirms the diagnosis.
Differential diagnosis
In the scope of cholestasis with normal gamma-GT, differential diagnosis includes mainly primary bile acid synthesis defects and PFIC1 (see these terms).
Antenatal diagnosis
Prenatal diagnosis can be proposed if a mutation has been identified in each parent.
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Ursodeoxycholic acid therapy (UDCA) should be initiated in all patients to prevent liver damage but is not fully effective. Rifampicin is helpful to control pruritus. Nasobiliary drainage may help to select potential responders to biliary diversion. However, because of severe cholestasis, liver failure or hepatocellular carcinoma, half of patients are ultimately candidates for liver transplantation (LT). Close monitoring of hepatocellular carcinoma should be offered from the first year of life. Due to hepatocellular carcinoma and rapid liver failure, the course in patients with PFIC2 appears to be more severe than in patients with PFIC1.
Prognosis
Early treatment with UDCA or biliary diversion may prevent significant morbidity and mortality from end-stage liver disease. Furthermore, patients may develop biliary stones, drug-induced cholestasis, and/or intrahepatic cholestasis of pregnancy (see this term) further in the disease course. Specialized follow-up is mandatory and lifelong.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Christiane BAUSSAN  - Pr Emmanuel GONZALES  - Pr Emmanuel JACQUEMIN  - Dr Anne SPRAUL


Progressive familial intrahepatic cholestasis type 3 (PFIC3), a type of progressive familial intrahepatic cholestasis (PFIC, see this term), is a late-onset hereditary disorder in bile formation that is hepatocellular in origin. Onset may occur from infancy to young adulthood.

Summary:
Epidemiology
Estimated prevalence at birth of PFIC types 1-3 varies between 1/50,000 and 1/100,000. PFIC3 represents one third of PFIC cases.
Clinical description
Clinical signs of cholestasis (discolored stools, dark urine) appear within the first year of life in about one third of patients, or later with recurrent episodes of jaundice and mild pruritus. PFIC3 evolves into secondary biliary cirrhosis. Gastrointestinal bleeding due to portal hypertension might be the presenting symptom in adolescents or young adults.
Etiology
PFIC3 is due to mutations in the ABCB4 gene (7q21), encoding the multi-drug resistant 3 protein (MDR3), resulting in impaired biliary phospholipid (PL) secretion. Detergent effects of hydrophobic bile salts are not countered by biliary PLs and lead to cholangitis. Low biliary PL levels are insufficient to maintain solubility of cholesterol and promote bile lithogenicity.
Diagnostic methods
PFIC3 should be suspected in children, adolescents, or young adults with a clinical history of cholestasis of unknown origin after exclusion of the other main causes of cholestasis. Patients present with high serum gamma-GT activity, normal cholesterol levels and moderately elevated bile acid concentrations. Liver ultrasonography is usually normal but may reveal a huge gallbladder and sometimes biliary stones. Liver histology reveals portal fibrosis and true ductular proliferation with mixed inflammatory infiltrate and, at a later stage, signs of biliary cirrhosis. MDR3 immunostaining is helpful for diagnosis. Cholangiography shows a normal biliary tree making it possible to rule out sclerosing cholangitis. Bile collection allows biliary lipid analysis showing decreased biliary phospholipid levels. Genotyping confirms the diagnosis.
Differential diagnosis
Differential diagnosis includes biliary tract diseases and causes of intrahepatic cholestasis and of cirrhosis with elevated gamma-GT.
Antenatal diagnosis
Prenatal diagnosis can be proposed if a mutation has been identified in each parent.
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Ursodeoxycholic acid therapy (UDCA) should be initiated in all patients to prevent liver damage. Beneficial effects of UDCA are usually observed in patients who harbored at least one missense mutation. In half of the patients, UDCA therapy fails and liver transplantation is required due to liver failure. In patients responding to UDCA, PFIC3 may be complicated by cirrhosis, portal hypertension and hepatocellular carcinoma. Furthermore, patients are at high risk of biliary stones, drug-induced cholestasis, and/or intrahepatic cholestasis of pregnancy (see this term) further in the disease course, especially if UDCA therapy is stopped. Specialized follow-up is mandatory and lifelong.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Christiane BAUSSAN  - Pr Emmanuel GONZALES  - Pr Emmanuel JACQUEMIN  - Dr Anne SPRAUL


Progressive familial intrahepatic cholestasis (PFIC) refers to a heterogeneous group of autosomal recessive disorders of childhood that disrupt bile formation and present with cholestasis of hepatocellular origin.

Summary:
Epidemiology
The exact prevalence remains unknown, but the estimated prevalence at birth varies between 1/50,000 and 1/100,000.
Clinical description
Three types of PFIC have been identified and are related to mutations in hepatocellular transport system genes involved in bile formation. PFIC1 and PFIC2 (see these terms) usually appear in the first months of life, whereas onset of PFIC3 (see this term) may also occur later in infancy, in childhood or even during young adulthood. Main clinical manifestations include cholestasis, pruritus and jaundice. Serum gamma-glutamyltransferase (GGT) activity is normal in PFIC1 and PFIC2 patients, but is elevated in PFIC3 patients. Additional manifestations may include short stature, sensorineural deafness, watery diarrhea, pancreatitis, elevated sweat electrolyte concentration and liver steatosis.
Etiology
Both PFIC1 and PFIC2 are caused by impaired bile salt secretion due respectively to defects in ATP8B1 encoding the FIC1 protein, and in ABCB11 encoding the bile salt export pump protein (BSEP). Defects in ABCB4, encoding the multi-drug resistant 3 protein (MDR3), impair biliary phospholipid secretion resulting in PFIC3.
Diagnostic methods
Diagnosis is based on clinical manifestations, liver ultrasonography, cholangiography and liver histology, as well as on specific tests for excluding other causes of childhood cholestasis. MDR3 and BSEP liver immunostaining, and analysis of biliary lipid composition should help to select PFIC candidates in whom genotyping could be proposed to confirm the diagnosis.
Differential diagnosis
Differential diagnoses include diseases that present with progressive cholestatic liver disease of childhood.
Antenatal diagnosis
Antenatal diagnosis can be proposed for affected families in which a mutation has been identified.
Management and treatment
Ursodeoxycholic acid (UDCA) therapy should be initiated in all patients to prevent liver damage. In some PFIC1 or PFIC2 patients, biliary diversion can also relieve pruritus and slow disease progression. However, most PFIC patients are ultimately candidates for liver transplantation. Monitoring of hepatocellular carcinoma, especially in PFIC2 patients, should be offered from the first year of life. Hepatocyte transplantation, gene therapy or specific targeted pharmacotherapy may represent alternative treatments in the future.
Prognosis
PFIC patients usually develop fibrosis and end-stage liver disease before adulthood.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Christiane BAUSSAN  - Pr Emmanuel GONZALES  - Pr Emmanuel JACQUEMIN  - Dr Anne SPRAUL


Progressive hemifacial atrophy (PHA) is a rare acquired disorder, characterized by unilateral slowly progressive atrophy of the skin and soft tissues of half of the face leading to a sunken appearance. Muscles, cartilage and the underlying bony structures may also be involved.

Summary:
Epidemiology
The prevalence is estimated to be at least 1/700,000 individuals, women being slightly more affected than men.
Clinical description
PHA usually presents during the first 20 years of life, characterized by slowly progressive unilateral atrophy of various tissues (skin, connective tissue, fat, muscle and rarely, underlying bony structures) in the territory of the 5th cranial nerve. PHA may start with alopecia, hair hypopigmentation, and atrophy may be preceded by cutaneous induration and hypo- or hyperpigmentation. PHA may extend to the upper lip and/or one side of the tongue and the masticatory muscles, resulting in deviation of the nose/mouth toward the affected side, unusual twisted or raised appearance of the upper lip, micrognathia, difficulty opening/closing the jaws and chewing/smiling/speaking, trismus, abnormal exposition of certain teeth, late eruption and/or atrophic roots and malocclusion. Rarely both sides of the face and the skin on the arms/trunk/leg or the entire body may be involved. Seizures and headaches are the most common neurologic symptoms. Ophthalmologic anomalies (enophthalmos, globe retraction, ptosis, iris heterochromia, uveitis, retinal vasculitis, glaucoma and eyelid atrophy) may result in visual impairment or blindness. Ear involvement (ipsilateral misshaping of the ear, abnormal small appearance and protrusion from the head) may also be observed. Anxiety and depression are common. A significant overlap between clinical and histological features of PHA and localized scleroderma ''en coup de sabre'' is reported.
Etiology
The exact etiology of PHA is unknown. Due to the presence of autoimmune diseases in several cases (e.g., systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease and ankylosing spondylitis), autoimmunity may be a cause of PHA, along with facial or head trauma, meningoencephalitis, abnormal development or hyperactivity of the sympathetic nervous system, neuro-vasculitis, angiogenesis anomalies, and slow viral infections.
Diagnostic methods
PHA diagnosis is based on clinical and histopathology features. The skin biopsy reveals homogenized dermal sclerosis, fat atrophy, decrease in adnexal structures, and perivascular plasma cells and lymphocytes. Computerized tomography (CT) and magnetic resonance imaging (MRI) may display infarction, hemorrhage and white matter hyper-density. Ultrasounds, ocular/dental imaging and photographs allow the monitoring of disease activity and progression.
Differential diagnosis
Differential diagnosis includes localized scleroderma, Rasmussen syndrome, hemifacial microsomia, Goldenhar syndrome, idiopathic facial palsy, Berardinelli-Seip congenital lipodystrophy and partial acquired lipodystrophy. Patients with face injuries (e.g. burns), fat necrosis and congenital deformities (e.g. wry neck) should also be considered.
Genetic counseling
PHA is sporadic in most cases, but rare familial cases have been reported. The effective transmission of the disease has not yet been reported. Genetic counseling is not recommended at this time.
Management and treatment
PHA management is symptomatic, requiring a multidisciplinary approach (pediatricians or internists, plastic surgeons, dentists, ophthalmologists, dermatologists, neurologists). Surgical management (fat/silicone injections, flap/pedicle grafts or bone implants) is usually not advised until the progression of PHA is stabilized. Patients with cerebral involvement may be considered for immunosuppressive therapy.
Prognosis
In some cases, the atrophy stops before the entire face is affected, with rare recurrence and no disability other than the cosmetic effects in the mild cases. Occasionally, PHA course may be accelerated, secondary to stress, surgery and pregnancy or shortly after childbirth.

                            Last update:
                            July 2015

                            - Expert reviewer(s):
                            Dr Nirav PATEL  - Dr Stanislav TOLKACHJOV  - Dr Megha TOLLEFSON


Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome is a rare, genetic, neuro-ophthalmological syndrome characterized by post-natal, progressive microcephaly and early-onset seizures, associated with delayed global development, bilateral cortical visual impairment and moderate to severe intellectual disability. Additional manifestations include short stature, generalized hypotonia and pulmonary complications, such as recurrent respiratory infections and bronchiectasis. Auditory and metabolic screenings are normal.