A rare genetic neurological disorder characterized by infantile onset of progressive leukoencephalopathy, microcephaly, severe global developmental delay, and spasticity resulting in quadriparesis and posture deformation. Additional features include an abnormally exaggerated startle reflex, seizures, dystonia, and hypomimia or amimia, as well as progressive chest deformities and contractures of large and hyperextensibility of small joints, among others. Thin corpus callosum is a prominent feature in brain imaging, in addition to white matter abnormalities consistent with leukoencephalopathy.


A rare obstetric disease characterized by inadequate blood flow to the placenta during pregnancy, resulting in a decrease in trans-placental transfer of oxygen and nutrients to the fetus, potentially leading to fetal growth retardation, distress, or death. Maternal risk factors include preeclampsia, gestational diabetes, and smoking, among others.


A rare gestational trophoblastic neoplasm characterized histologically by invasion of myometrium by intermediate trophoblastic cells without chorionic villi and containing human placental lactogen hormone (hPL). Tissue necrosis is usually absent and hemorrhage is mild. The tumor develops from the placental implantation site and always occurs following pregnancy, voluntary termination of pregnancy (VTP) or miscarriage. Indicative signs are irregular metrorrhagia some time after spontaneous miscarriage or VTP, presence of metastasis or unexplained metrorrhagia in the weeks and months following normal childbirth or ectopic pregnancy.


Plague is a severe bacterial infection caused by the Gram-negative bacterium Yersinia pestis.

Summary:
Epidemiology
It is extremely rare in Europe but still spreads in Africa and, to a lesser degree, in Asia and Latin America.
Clinical description
There are two clinical forms of the disease: bubonic plague, characterized by painfully inflamed lymph nodes called "buboes'', an elevated temperature and an altered clinical state; and pulmonary plague which manifests itself as thoracic pain, a cough with bloody expectoration, an elevated temperature, an altered clinical state and consciousness disorders.
Etiology
Plague is transmitted from animals to humans by fleas. Rodents are the reservoir for the disease. Plague is also transmitted between humans via the respiratory route.
Diagnostic methods
Diagnosis is based on isolation of the bacterium in the bubo, blood or expectoration, or from serology.
Management and treatment
Many classes of antibiotics are effective against Yersinia pestis (aminoglycosides, tetracyclines, cotrimoxazole, rifampicin, fluoroquinolones etc.).
Prognosis
Without treatment, the course of the disease is rapidly fatal.

                            Last update:
                            November 2009

                            - Expert reviewer(s):
                            Dr F RACHILLAS


A rare plasma cell neoplasm characterized by peripheral plasmacytosis, usually with extensive and diffuse infiltration of the bone marrow, and monoclonal paraproteinemia. Neoplastic plasma cells may also be found in extramedullary sites, such as the liver or spleen, among others. Most cases present as primary plasma cell leukemia without previous diagnosis of myeloma. The condition can also represent leukemic transformation of plasma cell myeloma (secondary plasma cell leukemia). Clinical manifestations include lymphadenopathy, organomegaly, renal failure, bone marrow failure, and peripheral neuropathies. High serum levels of lactate dehydrogenase and beta2-microglobulin, as well as hypercalcemia (potentially leading to hypercalcemic crisis) are typically observed.


A rare aggressive B-cell non-Hodgkin lymphoma characterized by neoplastic cells resembling B immunoblasts or plasmablasts with a CD20-negative plasmacytic phenotype. The tumor may occur in the oral cavity, the gastrointestinal tract, or other, predominantly extranodal, sites and is typically associated with immunodeficiency or -suppression. The tumor cells are EBV-positive in most cases. Patients often present with disseminated bone involvement. Paraproteinemia may also be detected. Prognosis is generally poor.


Plasmacytoma is a localized mass of neoplastic monoclonal plasma cells that represents approximately 5% of all plasma cell neoplasms. There are two separate entities: primary plasmacytoma of the bone and extramedullary plasmacytoma of the soft tissues. Of the extramedullary plasmacytomas, 80% occur in the head and neck, usually in the upper respiratory tract. The median age at diagnosis is 50 years and the male to female ratio is 3:1. Long-term survival is possible following local radiotherapy, particularly for soft tissue presentations.


Platyspondylic lethal skeletal dysplasia (PLSD), Torrance type (PLSD-T) is a skeletal dysplasia characterised by severe limb shortening (short and broad long bones), platyspondyly with wafer-like vertebral bodies, short ribs with anterior cupping, severe hypoplasia of the lower ilia and radial bowing. Histological findings include slightly enlarged chondrocytes and hypercellularity. The prevalence is unknown. The disorder is transmitted as an autosomal dominant trait and is caused by mutations in the C-propeptide domain of the COL2A1 gene. Although PLSD-T is generally lethal, survival to adulthood has been reported in two families.


PLCG2-associated antibody deficiency and immune dysregulation

A rare, hereditary, immune deficiency with skin involvement characterized by early-onset cold urticaria after generalized exposure to cold air or evaporative cooling and not after contact with cold objects. Additional immunologic abnormalities are often present - antibody deficiency, recurrent infections, autoimmune disease and symptomatic allergic disease.


PLEC-related intermediate epidermolysis bullosa simplex without extracutaneous involvement

A rare, inherited, epidermolysis bullosa simplex characterized by primarily acral blistering with onset typically at birth. Patients have easy bruisability, hemorrhagic blistering, and onychogryphosis.


Plectin-related limb-girdle muscular dystrophy R17

A form of limb-girdle muscular dystrophy characterized by proximal muscle weakness presenting in early childhood (with occasional falls and difficulties in climbing stairs) and a progressive course resulting in loss of ambulation in early adulthood. Muscle atrophy and multiple contractures have also been reported in rare cases.


Pleomorphic liposarcoma (PLS), the rarest subtype of liposarcoma (LS; see this term), is an aggressive, fast growing tumor located usually in the deep soft tissues of the lower and upper extremities. It is characterized by a variable number of pleomorphic lipoblasts and, in contrast to dedifferentiated liposarcoma, it lacks any association with well-differentiated liposarcoma (see these terms).

Summary:
Epidemiology
The incidence is approximately 1/2,000,000 per year and it accounts for 5-10% of all LS cases.
Clinical description
PLS usually presents in older individuals with a typical age at diagnosis of 50-70 years. PLS is most commonly a firm, rapidly growing mass in the deep compartments of the lower and upper extremities but can also be located in the abdomen or chest wall in rare cases. PLS has a high (>50%) risk of metastasis, primarily to the lungs. Metastasis is rapid, often leading to death.
Etiology
The etiology is unknown. PLS is characterized by highly complex chromosome alterations, including polyploidy and various chromosomal duplications, deletions and complex rearrangements.
Diagnostic methods
When a mass is detected, computed tomography (CT) or magnetic resonance imaging (MRI) is performed. Chest and abdominal lesions do not require pretreatment biopsy unless resection is likely to be incomplete or highly morbid. Extremity lesions are generally sampled by multiple core biopsies to make the histological diagnosis of PLS. Histologically PLS contains a variable number of pleomorphic lipoblasts, with hemorrhage and necrosis commonly observed.
Differential diagnosis
PLS can often be mistaken for myxofibrosarcoma or pleomorphic undifferentiated sarcoma (see these terms).
Management and treatment
Treatment involves the surgical excision of the tumor and surrounding normal tissue. In rare cases amputation of the limb is necessary. Tumors that are large (>5-8 cm) or marginally resectable may be treated with preoperative chemotherapy. Adjuvant radiation is recommended if the surgical margin is narrow or positive for sarcoma. Lifelong follow-up is recommended in order to monitor for recurrence at the initial site as well as distant metastasis.
Prognosis
PLS has the poorest prognosis of all the LS subtypes. Five-year survival is 59%.

                            Last update:
                            January 2013

                            - Expert reviewer(s):
                            Dr Samuel SINGER


A rare soft tissue sarcoma characterized by a high-grade lesion occurring almost exclusively in adults, composed of bizarre polygonal, round, and spindle cells with evidence of skeletal muscle differentiation. Patients usually present with a rapidly growing, painful mass located in the deep soft tissues of the extremities, but also other anatomic regions. Prognosis is generally poor.


A rare tumor of salivary glands characterized by a benign, well-circumscribed, slow-growing, painless mass most commonly occurring in the parotid gland (but also the palate, submandibular gland, or nasal septal mucosa), histopathologically composed of epithelial and myoepithelial / stromal components. Possible signs and symptoms depend on the location of the tumor and include facial nerve weakness, mild dysphagia, or unilateral nasal obstruction. Recurrence rates are low, although tumor rupture and spillage have been reported. Malignant transformation may occur in a small percentage of cases.


A rare low-grade astrocytoma characterized by superficial location in the cerebral hemispheres with involvement of the meninges, composed of GFAP-expressing cells showing nuclear and cytoplasmic pleomorphism and xanthomatous change, surrounded by a reticulin network. The tumor corresponds to WHO grade II and typically affects children and young adults, who often present with a long history of seizures. Extent of resection and mitotic index are important prognostic factors.


A rare pulmonary condition characterized by accumulation of pus in the pleural cavity, most commonly as a consequence of pneumonia, but also trauma and surgical procedures. Clinical signs and symptoms depend on host factors, as well as the nature of the causative microorganism, among others, and include cough, chest pain, dyspnea, and fever.


Malignant mesothelioma is a fatal asbestos-associated malignancy arising in the lining cells (mesothelium) of the pleural and peritoneal cavities, as well as in the pericardium and the tunica vaginalis.

Summary:
Epidemiology
The exact prevalence is unknown but it is estimated that mesotheliomas represent less than 1% of all cancers. Its incidence is increasing, with an expected peak in the next 10-20 years.
Clinical description
Pleural malignant mesothelioma is the most common form of mesothelioma. Typical presenting features are chest pain and dyspnea. Breathlessness due to a pleural effusion without chest pain is reported in about 30% of patients. A chest wall mass, weight loss, sweating, abdominal pain and ascites (due to peritoneal involvement) are less common presentations.
Etiology
Mesothelioma is directly attributable to occupational asbestos exposure with a history of exposure in over 90% of cases. There is also evidence that mesothelioma may result from both para-occupational exposure and non-occupational 'environmental' exposure. Idiopathic or spontaneous mesothelioma can also occur in the absence of any exposure to asbestos, with a spontaneous rate in humans of around one per million.
Diagnostic methods
A combination of accurate exposure history, along with examination radiology and pathology are essential to make the diagnosis. The most suggestive CT findings indicating malignant pleural disease are 1) a circumferential pleural rind, 2) nodular pleural thickening, 3) pleural thickening of >1cm and 4) mediastinal pleural involvement.
Differential diagnosis
Distinguishing malignant from benign pleural disease can be challenging.
Management and treatment
Involvement of a multidisciplinary team is recommended to ensure prompt and appropriate management, using a framework of radiotherapy, chemotherapy, surgery and symptom palliation with terminal care. Compensation issues must also be considered.
Prognosis
Life expectancy in malignant mesothelioma is poor, with a median survival of about one year following diagnosis.

                            Last update:
                            December 2008

                            - Expert reviewer(s):
                            Pr John MOORE  - Dr Robert PARKER  - Pr John WIGGINS


Pleuro-pericardial cyst is a rare, mostly congenital, pericardium anomaly characterized by the presence of, usually asymptomatic, cysts which are typically located in the right costophrenic angle and are usually incidentally diagnosed. On occasion, it manifests with chest pain, dyspnea, tachycardia, persistent cough or cardiac arrhythmias. The condition is usually benign, but rare complications, such as cardiac tamponade, cardiogenic shock, mitral valve prolapse, hoarseness atrial fibrillation, right ventricular outflow, tract obstruction, spontaneous internal hemorrhage, pulmonary stenosis and sudden death, may occur.


A rare respiratory tumor characterized by an aggressive, malignant, dysontogenetic neoplasm of intrathoracic (pulmonary, pleural, or combined) mesenchyme occurring in young children. Three subtypes can be distinguished, type 1 being purely cystic, type 2 cystic and solid, and type 3 purely solid. Type 1 lesions may progress to the more malignant types 2 and 3, which are associated with central nervous system and bone metastasis. The tumor is often part of pleuropulmonary blastoma family tumor and dysplasia syndrome. It can also be associated with multilocular cystic nephroma or other neoplasms. Patients usually present with dyspnea or other respiratory problems, and sometimes pneumothorax.


PLIN1-related familial partial lipodystrophy

A rare genetic lipodystrophy characterized by loss of subcutaneous adipose tissue primarily affecting the lower limbs and gluteal region due to a defect in the PLIN1 gene. Associated features of insulin resistance, hepatic steatosis, dyslipidemia, hypertension, axillary acanthosis nigricans and muscular hypertrophy of the lower limbs are typical.


Plummer-Vinson or Paterson-Kelly syndrome presents as a classical triad of dysphagia, iron-deficiency anemia and esophageal webs.

Summary:
Epidemiology
Exact data about the epidemiology of the syndrome are not available; the syndrome is extremely rare.
Clinical description
Most of the patients are white middle-aged women, in the fourth to seventh decade of life, but the syndrome has also been described in children and adolescents. The dysphagia is usually painless and intermittent or progressive over years, limited to solids and sometimes associated with weight loss. Symptoms resulting from anemia (weakness, pallor, fatigue, tachycardia) may dominate the clinical picture. Additional features are glossitis, angular cheilitis and koilonychia. Enlargement of the spleen and thyroid may also be observed. One of the most important clinical aspects of Plummer-Vinson syndrome is the association with upper alimentary tract cancers.
Etiology
The etiopathogenesis of Plummer-Vinson syndrome is unknown. The most important possible etiological factor is iron deficiency. Other possible factors include malnutrition, genetic predisposition or autoimmune processes.
Management and treatment
Plummer-Vinson syndrome can be treated effectively with iron supplementation and mechanical dilation. In case of significant obstruction of the esophageal lumen by esophageal web and persistent dysphagia despite iron supplementation, rupture and dilation of the web are necessary. Since Plummer-Vinson syndrome is associated with an increased risk of squamous cell carcinoma of the pharynx and the esophagus, the patients should be followed closely.

                            Last update:
                            September 2006

                            - Expert reviewer(s):
                            Pr Gottfried NOVACEK


A rare congenital disorder of N-glycosylation and is characterized by cerebellar dysfunction, abnormal fat distribution, inverted nipples, strabismus and hypotonia. 3 forms of PMM2-CDG can be distinguished: the infantile multisystem type, late-infantile and childhood ataxia-intellectual disability type (3-10 yrs old), and the adult stable disability type. Infants usually develop ataxia, psychomotor delay and extraneurological manifestations including failure to thrive, enteropathy, hepatic dysfunction, coagulation abnormalities and cardiac and renal involvement. The phenotype is however highly variable and ranges from infants who die in the first year of life to mildly involved adults.


PMP2-related Charcot-Marie-Tooth disease type 1

A rare autosomal dominant hereditary demyelinating motor and sensory neuropathy characterized by progressive distal muscle weakness and atrophy, distal sensory impairment, and decreased or absent reflexes in the affected limbs, with an onset in the first or second decade of life. Median motor nerve conduction velocities are typically less than 38 m/s. Patients often have foot deformities. Sural nerve biopsy shows decrease in myelinated fibers, myelin abnormalities, and onion bulb formation. Fatty replacement of muscle tissue predominantly affects the anterior and lateral compartment of the lower legs.


PMP22-RAI1 contiguous gene duplication syndrome

A rare partial duplication of the long arm of chromosome 17 characterized by a combination of features of 17p11.2 microduplication syndrome and Charcot-Marie-Tooth disease type 1A. Patients present with infantile onset of global developmental delay, hypotonia, feeding difficulties, and failure to thrive, as well as childhood onset of peripheral neuropathy with distal extremity weakness or atrophy, gait impairment, sensory loss, reduced or absent deep tendon reflexes of the ankles, and foot deformities. Facial dysmorphism, cardiac and renal anomalies, and syringomyelia may also be observed.


A rare infectious disease of the nervous system caused by the bacterium Streptococcus pneumoniae, which is commonly part of the bacterial flora colonizing the nasopharyngeal mucosa. The disease is clinically characterized by typical symptoms of acute leptomeningitis, like fever, headache, neck stiffness, vomiting, and clouding of consciousness. It is frequently fatal and, in surviving patients, often accompanied by long-term sequelae, especially focal neurological deficits, hearing loss, cognitive impairment, and epilepsy.


Human pneumocystosis is caused by an infectious agent, which (after recent nomenclature and taxonomy revisions) is now classed as the fungus Pneumocystis jiroveci. The prevalence is unknown. Pneumocystis jiroveci is an opportunistic infectious agent, developing in immunosuppressed patients. It is an air-borne infection, localised to the lungs. However, extrapulmonary involvement is seen in AIDS patients. The disease manifests progressively with coughing, respiratory problems (dyspnea) and fever, followed by acute respiratory insufficiency and death within a few weeks in untreated cases. The most reliable diagnostic method is bronchoalveolar lavage. The treatment of choice is cotrimoxazole.


Pneumonia caused by Pseudomonas aeruginosa infection

A rare pulmonary disease characterized by primary or nonbacteremic pneumonia most frequently arising in an intensive care setting, or bacteremic pneumonia, which is typically associated with neutropenia. Chronic lower respiratory tract infection with development of episodes of pneumonia is common in patients with cystic fibrosis. Acute infections are potentially life-threatening. Patients present with fever, chills, dyspnea, cyanosis, productive cough, as well as signs of severe systemic toxicity. Alveolar hemorrhage, necrosis, and, eventually, cavity formation, are commonly seen.


POEMS syndrome is a paraneoplastic syndrome characterized by polyradiculoneuropathy (P), organomegaly (O), endocrinopathy (E), clonal plasma cell disorder (M), and skin changes (S). Other features include papilledema, extravascular volume overload, sclerotic bone lesions, thrombocytosis/erythrocytosis, and elevated VEGF levels.

Summary:
Epidemiology
Exact prevalence and incidence rates are not known. The only estimates are from Japan. In this country, prevalence has been reported to be about 1/330,000. Male predilection has been reported (2.5:1).
Clinical description
The average age of onset is in the 5th or 6th decade. The disease covers a wide clinical spectrum depending on the systems involved. Neuropathy is the primary manifestation and is usually peripheral, ascending, and symmetrical with distal weakness and paresthesia. It is both sensory and motor and may cause pain, hyperesthesia, and areflexia. A clonal plasma cell disorder (PCD) is the second major feature. Organomegaly mainly includes hepatomegaly, splenomegaly, and/or lymphadenopathy (Castleman disease; see this term). Various and extensive endocrine disorders may be found causing hypogonadism, thyroid abnormalities, adrenal insufficiency, and/or erectile dysfunction and gynecomastia in men. The skin is commonly affected with development of hyperpigmentation, hemangiomas, hypertrichosis, leukonychia or nail clubbing, sclerodermoid changes, lipodystrophy, and flushing. The main ocular manifestation is papilledema. Extravascular overload mainly manifests as peripheral edema, and sometimes as pleural effusion, ascites, and pericardial effusions. An increased risk of arterial and/or venous thrombosis is reported (up to 20% of patients). Disease severity depends on the systems involved and the course is chronic. Some patients have a mild presentation while others have debilitating disease. 25% have respiratory manifestations including restrictive lung disease, pulmonary hypertension, and respiratory muscle weakness.
Etiology
The pathogenesis has not been clearly elucidated. Vascular endothelial growth factor (VEGF) appears to play a significant role in this plasma cell disorder.
Diagnostic methods
All of the clinical features are not required for diagnosis. Patients with three of the major criteria necessarily including polyradiculoneuropathy and clonal PCD (plus possibly Castleman, sclerotic bone lesions, VEGF elevation), plus at least one minor criterion can be diagnosed with POEMS. Minor criteria are organomegaly, endocrinopathy, papilledema, extravascular overload, and skin changes. Patient with POEMS features who do not have both peripheral neuropathy and PCD are considered as having the Castleman disease variant of POEMS. Radiographic assessment of bones, elevated VEGF, and bone marrow biopsy aid in confirming the diagnosis. VEGF levels correlate with disease activity.
Differential diagnosis
The main differential diagnoses are chronic inflammatory demyelinating polyneuropathy, AL amyloidosis and Guillain-Barré syndrome (see these terms). Monoclonal gammopathy of undetermined significance (MGUS) and should also be considered.
Management and treatment
Patients with dominant sclerotic plasmacytoma are treated with radiotherapy. Radiation is also used in patients with diffuse sclerotic lesions or disseminated bone marrow involvement. Some patients progress after radiation therapy and require systemic treatment. Alkylators are the main treatment, along with lenalidomide and to a lesser extent thalidomide and bortezomib. High-dose chemotherapy with peripheral blood stem cell transplant may be successful. Supportive care should also be provided (orthotics, physical therapy, and continuous positive airway pressure (CPAP)).
Prognosis
The prognosis is generally good if diagnosis is early and appropriate treatment is provided. Causes of death include progressive anasarca, thrombosis, and inanition.

                            Last update:
                            March 2015

                            - Expert reviewer(s):
                            Pr Angela DISPENZIERI


POGLUT1-related limb-girdle muscular dystrophy R21

A rare autosomal recessive limb-girdle muscular dystrophy characterized by adult onset of progressive muscle weakness and atrophy in the proximal upper and lower limbs, leading to scapular winging and loss of independent ambulation. Respiratory function may become impaired in the course of the disease. Fatty degeneration of internal regions of thigh muscles sparing external areas has been reported, as well as a reduction of alpha-dystroglycan in muscle biopsies.


Poikiloderma with neutropenia is a rare, genetic hereditary poikiloderma disorder characterized by early-onset poikiloderma (which typically begins in the extremities, progresses centripetally and eventually involves the trunk, face and ears) associated with chronic neutropenia, recurrent infections, pachyonychia and palmoplantar keratoderma. Growth and/or develomental delay and hepato- and/or splenomegaly are additional reported features.


A rare congenital malformation characterized by a unilateral, complete or partial, absence of the pectoralis major (and often minor) muscle, ipsilateral breast and nipple anomalies, hypoplasia of the pectoral subcutaneous tissue, absence of pectoral and axillary hair, and possibly accompanied by chest wall and/or upper limb defects.

Summary:
Epidemiology
The incidence is estimated at 1/30,000, but this is likely an underestimate. It affects more frequently men (male/female ratio of 2:1).
Clinical description
The major feature of Poland syndrome (PS) is complete or partial (sternocostal head) agenesis of the pectoralis major muscle, manifesting as an asymmetric appearance. Generally, the pectoralis minor muscle is also absent. The malformation is typically unilateral with the right side predominantly affected; bilateral involvement is possible but rare (1% of cases). The associated upper limb and rib anomalies determine the severity of PS. According to the combination of these additional features, three forms of PS can be described: type-1 (minimal form) is defined as an isolated pectoral muscle defect, type-2 (partial form) is defined by pectoral muscle defect associated with either upper limb (2a, upper limb variant) or rib (2b, thoracic variant) anomaly, and type-3 (complete form) by pectoral muscle defect associated with both upper limb and rib anomalies. Additional muscle involvement may include the serratus anterior, latissimus dorsi and trapezius. Chest defects can include absence of the anterior part of the rib with lung herniation, rib hypoplasia, contralateral pectus carinatum and/or pectus excavatum. Dextrocardia occurs in 10% of cases, associated with left rib agenesis. Upper limb anomalies are present in 56% of the patients, including brachydactyly, syndactyly or a combination of the two; aplasia/hypoplasia of the middle phalanges of the hand is frequently observed. Hypoplastic/absent hand(s) and short forearm are rarely observed. In all females, the breast and nipple areola complex is aplasitic or hypoplasitic with superolateral localization of the nipple.
Etiology
The etiology is unknown.
Diagnostic methods
Diagnosis is by clinical evaluation. The pectoral muscle anomaly is generally observed by asking the patient to push the palms of the hands against each other with the arms positioned in front of the body. Cough or other maneuvers increasing thoracic pressure will demonstrate lung herniation in case of rib agenesis. Echography can confirm the diagnosis and delineate the extent of the muscular anomaly and detect cartilage rib anomaly and, in postpubertal females, breast anomaly. Chest X-ray can confirm rib agenesis and dextrocardia.
Differential diagnosis
Differential diagnosis includes other chest wall anomalies, breast/nipple anomalies, isolated thoracic lipoatrophy, and isolated hand/upper limb anomalies without pectoralis major muscle involvement. Syndromes rarely associated with PS include Moebius, Klippe Feil, Pierre-Robin, Sprengel deformity and Carey-Fineman-Ziter.
Antenatal diagnosis
Antenatal diagnosis is rare; however, suspicion may arise if hand anomaly is detected.
Genetic counseling
PS is typically a sporadic condition but around 4% of cases are familial. Most cases are probably multifactorial with a low recurrence risk. Autosomal dominant and recessive patterns are described in literature.
Management and treatment
Usually, the aim of surgical treatment is cosmetic. However, in a minority of cases thoracic surgery is required to improve respiratory dynamics due to rib cage defect or heart compression by sternal compression. TNB (thorax, breast and nipple) classification guides surgical choice. Patients should be evaluated for surgery at the beginning of puberty (and before complete growth). A combined approach (pediatric/thoracic and plastic surgery) is beneficial. In case of multiple rib agenesis, non-absorbable mesh or metallic or custom prostheses can be used. Breast/pectoral, custom-made, implants can be used to correct the soft tissue and breast defect. Breast/pectoral expander can be used as first step. Fat grafting is beneficial either as first step or to improve final result. For symmetry reasons, surgery to the contralateral breast can be considered. Muscle transpositions require careful evaluation of the benefits and risks, and should only be considered in selected cases and never in children. Correction of syndactyly should generally begin between 12 and 24 months of life. In case of phalangeal absence, non-microvascular free phalangeal transfer from the foot, or microvascular digital transfer from the foot can be proposed.
Prognosis
Aesthetic achievement after surgery is typically satisfactory. Usually, there is not a significant muscle weakness.

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Dr Maria Teresa DIVIZIA  - Dr Margherita LERONE  - Dr Aldamaria PULITI  - Dr Maria Victoria ROMANINI  - Dr Michele TORRE


Poliomyelitis is a viral infection caused by any of three serotypes of human poliovirus, which is part of the family of enteroviruses.

Summary:
Epidemiology
Progress in global poliomyelitis eradication, since its beginning in 1988, has been remarkable. In 1988, 125 countries were endemic for poliomyelitis and an estimated 1000 children were being paralyzed every day by wild poliovirus. By the end of 2003, six polio-endemic countries remained (Afghanistan, Egypt, India, Niger, Nigeria, Pakistan), and less than 3 children per day were being paralyzed by the poliovirus. The Global Poliomyelitis Eradication Initiative is ongoing. There remain only 4 endemic countries (Pakistan, Afghanistan, India, and Nigeria) and just 2000 reported cases globally in 2006.
Clinical description
It primarily affects children under the age of 5. Generally the infection is limited to the grastrointestinal tract and nasopharynx and is often asymptomatic. The central nervous system, primarily the spinal cord, may be affected, leading to rapidly progressive paralysis. Motor neurons are mainly affected. Encephalitis may also occur.
Etiology
Transmission is mainly person-to-person, principally through the fecal-oral route. The virus replicates in the nervous system and particularly affects motor neurons in the anterior horn of the spinal cord (`polio' means `gray').
Differential diagnosis
Poliomyelitis must be distinguished from other paralytic conditions by isolation of virus from stool.
Management and treatment
Prevention is the only cure for paralytic poliomyelitis. Two vaccines against poliomyelitis are available: an inactive injectable vaccine and a live attenuated vaccine that is taken orally. Europe was certified as polio-free in June 2002 and immunization and disease surveillance continue to ensure the region remains polio-free

                            Last update:
                            January 2010

                            - Expert reviewer(s):
                            Dr Bruce AYLWARD  - Dr David HEYMANN


A rare, clinically heterogeneous, systemic disease characterized by necrotizing inflammatory lesions affecting medium-sized blood vessels. It most commonly affects skin, joints, peripheral nerves and the gastrointestinal tract.

Summary:
Epidemiology
Prevalence of polyarteritis nodosa (PAN) has been estimated at 1/33,000 in France, Norway and Sweden. Changes in classification of systemic vasculitis and more precise delineation of these disorders make it difficult to determine exact epidemiological data.
Clinical description
PAN is defined as vasculitis affecting medium-sized vessels and has no pathognomonic clinical or laboratory features. There is a very broad range of clinical presentations depending on the underlying cause and age of onset, with different presenting features, courses, therapeutic implications, and prognoses. The most frequent form of the disease is a potentially life-threatening, idiopathic condition affecting mainly adults, and has a presentation with fever, fatigue, weight loss, myalgia and arthralgia, often with multisystem involvement (systemic PAN). In this form, cutaneous manifestations are common at onset. A limited form with subcutaneous nodules, indurated erythema, and livedo reticularis, and mild extracutaneous features has also been described, with no significant internal organ involvement (cutaneous PAN). Rare limited forms affecting the peripheral nerves, testicles, ureter, breasts, or ovaries have also been described and are known as single-organ PAN.
Etiology
The disease can be primary (primary PAN) or secondary, e.g. related to viral infection such as hepatitis B virus (secondary PAN).
Diagnostic methods
Diagnosis is based on the clinical features but often requires tissue biopsy showing necrotizing medium-sized vessel vasculitis, and/or angiography showing microaneurysms. Laboratory findings are non-specific and PAN is never associated with anti-neutrophil cytoplasm antibodies (ANCA).
Differential diagnosis
The main differential diagnoses are other medium-sized vessel vasculitides such as Kawasaki disease and also small-sized vessel necrotizing vasculitides, mainly microscopic polyangiitis.
Management and treatment
The main factors guiding treatment are the extent of organ involvement and disease progression. Glucocorticoids combined with 6 to 9 intravenous cyclophosphamide injections are prescribed to treat systemic PAN with factors of poor prognosis, as defined by the Five Factor Score (FFS). Milder cases (FFS=0) can be treated with glucocorticoids alone. Once remission is obtained, maintenance treatment with azathioprine is given for one year. When PAN is caused by HBV infection, treatment involves a combination of anti-viral drugs and plasma exchanges. Corticosteroids and immunosuppressants are not recommended because they stimulate viral replication and favor the development of liver cirrhosis.
Prognosis
Limited forms tend to have a favorable prognosis. Factors of poor prognosis are GI involvement, renal insufficiency, cardiac manifestations and central nervous system involvement. Causes of death include uncontrolled vasculitis and infections, as well as renal, gastrointestinal and cardiovascular manifestations.

                            Last update:
                            October 2020

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


Polyarticular juvenile idiopathic arthritis

A rare type of juvenile idiopathic arthritis characterized by arthritis with an onset prior to the age of 16 years persisting for longer than six weeks and affecting at least five joints during the first six months of the disease. Other possible causes of joint inflammation must be excluded. Two subgroups of the disease can be distinguished, based on the presence of absence of rheumatoid factor. Both subgroups are more common in girls and may be associated with mild fever, weight loss, anemia, moderate hepatosplenomegaly, and mild growth retardation.


A rare hematologic disease characterized by high serum viscosity due to polyclonal expansion of immunoglobulins, most commonly in the context of Waldenström's macroglobulinemia, as well as a variety of disorders of immune dysregulation. Patients present with signs and symptoms involving multiple organs, such as bleeding diathesis, mucosal bleeding, retinal hemorrhage, headache, stroke, pulmonary hypertension, and congestive heart failure.


Polycythemia vera (PV) is an acquired myeloproliferative disorder characterized by an elevated absolute red blood cell mass caused by uncontrolled red blood cell production, frequently associated with uncontrolled white blood cell and platelet production.

Summary:
Epidemiology
Annual incidence is estimated at approximately 1/36,000-1/100,000 and prevalence at 1/3,300. PV occurs at all ages but is most common in those aged 50-70 years.
Clinical description
Symptoms are often insidious at onset and may include headache, dizziness, vertigo, tinnitus, visual disturbances, and pruritus after bathing, a ruddy complexion that manifests in the face, palms, nailbeds, mucosa and conjunctiva. Complications may be associated including arterial thrombosis (in cerebrovascular, myocardial or peripheral territories), angina pectoris or intermittent claudications, or venous thromboses including deep vein thrombosis, pulmonary embolism, splanchnic thrombosis (portal vein thrombosis and Budd-Chiari syndrome; see these terms) and bleeding including gum bleeding, ecchymoses and gastrointestinal bleeding. PV may also be characterized by splenomegaly. Myelofibrosis and acute leukemia or a myelodysplastic syndrome occur in a minority of patients, usually late in the disease.
Etiology
Symptoms are related to blood hyperviscosity, which impairs microcirculation and is caused by a marked increase in the cellular elements of blood. This is due to the presence of abnormal clonal stem cell expansion that interferes with or suppresses normal stem cell growth and maturation. The exact origin of this stem cell transformation is still a matter of debate, however, a somatic mutation (JAK2-V617F) in exon 14 of the JAK2 gene (9p24) is present in the vast majority of patients and, less frequently, a somatic mutation in exon 12 of JAK2.
Diagnostic methods
Diagnosis is based on evidence of a combination of some of the following criteria: hematocrit (Hct) greater than 52% or hemoglobin (Hb) greater than 185 g/L in male patients, Hct greater than 48% or Hb greater than 165 g/L in female patients, an increased (greater than 125% of normal value) red blood cell mass, the presence of a V617F or an exon 12 mutation of JAK2, low circulating erythropoietin (EPO) levels, spontaneous colony formation by erythroid progenitor cells, and, in rare cases where a JAK2 mutation is lacking, evidence of a myeloproliferative disorder on bone marrow biopsy.
Differential diagnosis
Differential diagnosis includes elimination of Ph1 negative myeloproliferative disease (MPD) including essential thrombocytosis and agnogenic myeloid metaplasia (see these terms). In patients with polyglobuly without JAK2 mutation, causes of congenital primary erythrocytosis and secondary erythrocytosis (see these terms) should be considered. In patients with PV associated with MPD in the same family, the diagnosis of familial predisposition to MPD must be considered.
Management and treatment
Patients with PV should be individually assessed. Treatment is based on phlebotomy to improve blood circulation. The targeted Hct is 45%. In patients with an increased risk of thrombosis due to age over 60 years, previous thrombosis, peripheral vascular disease or hypertension, cytoreduction should be considered. Hydroxyurea remains the reference drug for elderly patients. In those with no specific contraindication, low-dose aspirin has been proved to reduce the risk of thrombosis. Treatment with interferon alpha may be proposed for pregnant patients. Anagrelide may also be used to decrease platelet counts.
Prognosis
PV is a chronic disease. Survival of treated patients in the literature is either identical to the general population or decreased (with mortality 1.6 times higher than that of the general population).

                            Last update:
                            July 2010

                            - Expert reviewer(s):
                            Pr Jean BRIERE


Polydactyly of a biphalangeal thumb and/or hallux

A rare non-syndromic limb malformation characterized by the duplication of one or more skeletal components of a biphalangeal thumb and/or hallux. Hands are preferentially affected (in bilateral), and the right hand is more commonly involved than the left. Hallux duplication may present concomitantly to, or independently of thumb polydactyly and is predominantly unilateral right.


Polydactyly of a triphalangeal thumb or PPD2 is a form of preaxial polydactyly of fingers (see this term), a limb malformation syndrome, that is characterized by the presence of a usually opposable triphalangeal thumb with or without additional duplication of one or more skeletal components of the thumb. The thumb appearance can differ widely in shape (wedge to rectangular) or it can be deviated in the radio-ulnar plane (clinodactyly). PPD2 is also associated with systemic syndromes, including Holt-Oram syndrome and Fanconi anemia (see these terms).


Polydactyly of an index finger or PPD3 is a form of preaxial polydactyly of fingers (see this term), a limb malformation syndrome, where the thumb is replaced by one or two triphalangeal digits with dermatoglyphic pattern specific of the index finger. Two forms of PPD3 have been characterized: unilateral and bilateral (see these terms). There have been no further descriptions in the literature since 1962.


Polydactyly-myopia syndrome is an exceedingly rare autosomal dominant developmental anomaly reported in 1986 in nine individuals among four generations of the same family. The syndrome is characterized clinically by four-limb postaxial polydactyly and progressive myopia. There have been no further descriptions in the literature since 1986.


A rare malignant germ cell tumor characterized by predominant composition of embryoid bodies consisting of a central core of embryonal carcinoma cells, an amnion-like cavity, and a yolk sac tumor component. The tumor usually occurs as the dominant component of a mixed germ cell tumor, with teratoma being the most common associated element. It may manifest as an abdominal mass or with abdominal pain, menstrual irregularities, or precocious puberty in women, while men typically present with testicular enlargement. Serum alpha-fetoprotein and/or beta-human chorionic gonadotropin can be elevated.


A rare genetic disease characterized by childhood onset of multiple endocrine manifestations in combination with central and peripheral nervous system abnormalities. Reported signs and symptoms include postnatal growth retardation, moderate intellectual disability, hypogonadotropic hypogonadism, insulin-dependent diabetes mellitus, central hypothyroidism, demyelinating sensorimotor polyneuropathy, and cerebellar and pyramidal signs. Progressive hearing loss and a hypoplastic pituitary gland have also been described. Brain imaging shows moderate white matter abnormalities.


Polyglucosan body myopathy type 1 is a rare, genetic, glycogen storage disorder characterized by polyglucosan accumulation in various tissues, manifesting with progressive proximal muscle weakness in the lower limbs and rapidly progressive, usually dilated, cardiomyopathy. Hepatic involvement and growth retardation may be associated. Early-onset immunodeficiency and autoinflammation, presenting with recurrent bacterial infections, have also been reported.


A rare glycogen storage disease characterized by slowly progressive myopathy with storage of polyglucosan in muscle fibers. Age of onset ranges from childhood to late adulthood. Patients present proximal or proximodistal weakness predominantly of limb-girdle muscles. Variable features include exercise intolerance or myalgia. Serum creatine kinase is normal or mildly elevated. There is usually no overt cardiac involvement.


Polymalformative genetic syndrome with increased risk of developing cancer (PGSIRC) comprises a wide range of syndromes characterized by congenital malformations with a high risk of developing tumors including up to 50 different rare diseases.

Summary:
Epidemiology
There are no published data on the prevalence of the set of all syndromes included in this category but, as each syndrome has its specific prevalence, it can be roughly estimated at 1/10,000.
Clinical description
PGSIRC encompasses different syndromes: the Overgrowth Syndromes, among which the Beckwith-Wiedemann syndrome with a 10% cumulative risk of cancer at 4 years of age mainly hepatoblastoma and Wilms' tumor, Costello syndrome with up to 10% risk of rhabdomyosarcoma, and other syndromes such as Simpson-Golabi-Behmel or Perlman (see these terms). Some other genetic rare diseases associated with an increased risk of cancer include tuberous sclerosis, Xeroderma pigmentosum or WAGR syndrome (see these terms). Because of this predisposition, it is essential to establish an early multidisciplinary follow-up protocol for each patient after the diagnosis. The clinical characteristics are specific to each syndrome.
Etiology
The etiology is specific to each syndrome. The genetic alterations associated with tumorigenesis can occur in the germ-line, resulting in hereditary predisposition to cancer, or have their monoclonal origin in somatic cells, resulting in sporadic tumors. The exact mechanism by which alterations in cancer-related genes (i.e. RAS genes) produce both congenital polymalformative abnormalities as well as sporadic tumors is still under investigation.
Genetic counseling
The inheritance pattern is specific to each syndrome. In most cases of familial cancer, those not associated with congenital abnormalities, tumor susceptibility is inherited in an autosomal dominant pattern. In cancer associated to genetic rare diseases characterized by congenital malformations, the overall tumor susceptibility is inherited mainly in an autosomal recessive pattern, regardless of the inheritance pattern associated with the specific rare disease.

                            Last update:
                            February 2013

                            - Expert reviewer(s):
                            Dr Víctor MARTÍNEZ-GLEZ


A rare, genetic, complex cerebral cortical malformation characterized by generalized or focal dysgyria (also named polymicrogyria-like cortical dysplasia) or alternatively by microlissencephaly with dysmorphic basal ganglia and dysgenesis of the corpus callosum. Clinical manifestations are variable and include microcephaly, seizures, hypotonia, developmental delay, severe psychomotor delay, ataxia, spastic diplegia or tetraplegia, and ocular abnormalities (strabismus, ptosis or optic atrophy).


Polymicrogyria with optic nerve hypoplasia is a rare genetic syndrome with central nervous system malformations characterized by severe developmental delay, neonatal hypotonia, seizures, optic nerve hypoplasia and distinct central nervous system malformations including extensive bilateral polymicrogyria, dysplastic or absent corpus callosum and malformed brainstem with loss of demarcation of the pontomedullary junction.


A heterogenous group of cerebral cortical malformations characterized by excessive cortical folding and abnormal cortical layering that, depending on its topographic distribution, presents with variable combinations of neurological symptoms of varying severity such as epilepsy, developmental delay, intellectual disability, motor dysfunction (e.g. spasticity), and pseudobulbar palsy.


A rare idiopathic inflammatory myopathy (IIM) historically characterized by symmetric proximal muscle weakness, elevated muscle enzymes (creatine kinase), myopathic findings on electromyography, and muscle biopsy showing endomyial infiltration composed mainly of macrophages and lymphocytes. The features are non-specific, thus the disease should be distinguished from similar entities with specific clinical, immunological, histological features, notably dermatomyositis, immune-mediated necrotizing myopathy, anti-synthetase syndrome, inclusion body myositis, and myositis associated with other connective tissue disorder.


Polyneuropathy associated with IgM monoclonal gammopathy with anti-MAG

A demyelinating polyneuropathy characterized clinically by sensory ataxia, tremor, paresthesia, and impaired gait.


Polyneuropathy-hearing loss-ataxia-retinitis pigmentosa-cataract syndrome

This rare neurologic disease is a slowly-progressive Refsum-like disorder associating signs of peripheral neuropathy with late-onset hearing loss, cataract and pigmentary retinopathy that become evident during the third decade of life.

Summary:
Epidemiology
The syndrome has been described in three patients from a consanguineous family (one brother, one sister and a male cousin).
Clinical description
The disease manifests during childhood with pes cavus and tendoachilles contractures. A disorder of gait, due to ataxia and spasticity, develops during adulthood. Contrarily to Refsum disease, plasmatic phytanic and pristanic acid levels as well as alpha-oxidation enzymatic activity are normal.
Etiology
The disease was mapped on chromosome 20 (20p11.21-q12).
Genetic counseling
Transmission is autosomal recessive.

                            Last update:
                            October 2009


Polyneuropathy-intellectual disability-acromicria-premature menopause syndrome is a rare genetic syndromic intellectual disability characterized by intellectual disability, polyneuropathy, short stature and short limbs, brachydactyly, and premature ovarian insufficiency. Only one familial case with three affected females was described and there have been no further descriptions in the literature since 1971.


A rare, major congenital malformation characterized by complete duplication of the nose resulting in twofully developed noses often associated with choanal atresia, causing respiratory distress and necessitating surgical repair.


A rare, life-threatening developmental defect during embryogenesis characterized by polysyndactyly of fingers and toes as well as complex congenital heart defects (e.g. atrioventricular septal defects, aortic dextroposition, single ventricle, hypo- or hypertrophy of one side of the heart). Additional features may include dysmorphic traits (large fontanel, high forehead, ptosis, hypertelorism, epicanthus, low-set malformed ears, prominent root of the nose, bulbous nose, anteverted nares, long and smooth philtrum, thin upper lip, micrognathism, hirsutism, single transverse crease) nail hypoplasia, phalange agenesis/hypoplasia, flexion contractures, polysplenia, multiple hepatic/renal cysts, atrophic biliary vesicle, ductal plate malformation and genital anomalies (e.g. micropenis, undescended testes, hypoplastic scrotum). The syndrome is usually fatal in utero or in infancy, but survival cases have been reported.


Polysyndactyly or PPD4 is a form of preaxial polydactyly of fingers (see this term), a limb malformation syndrome, characterized by the presence of a thumb showing the mildest degree of duplication, being broad, bifid or with radially deviated distal phalanx. Syndactyly of various degrees of third-and-fourth fingers is occasionally present.


POMGNT1-related limb-girdle muscular dystrophy R15

A form of limb-girdle muscular dystrophy characterized by an onset in childhood or adolescence of rapidly progressive proximal limb muscle weakness (particularly affecting the neck, hip girdle, and shoulder abductors), hypertrophy in the calves and quadriceps, ankle contractures, and myopia.


POMGNT2-related limb-girdle muscular dystrophy R24

A rare autosomal recessive limb-girdle muscular dystrophy characterized by infantile to adolescent onset of a milder form of limb-girdle muscular dystrophy with or without intellectual disability. Patients present variable proximal limb muscular weakness with calf hypertrophy and elevated serum creatine kinase.


POMT1-related limb-girdle muscular dystrophy R11

A form of limb-girdle muscular dystrophy characterized by the onset of slowly progressive proximal muscle weakness during childhood (with fatigue and difficulty running and climbing stairs) and developmental delay. Mild intellectual deficit and microcephaly, without any obvious structural brain abnormality, are found in all patients. Mild pseudohypertrophy and joint contractures of the ankles have also been reported.


POMT2-related limb-girdle muscular dystrophy R14

A form of limb-girdle muscular dystrophy characterized by proximal weakness (manifesting as slowness in running) presenting in infancy, along with calf hypertrophy, mild lordosis, scapular winging and normal intelligence (or mild intellectual disability).


Pontiac fever (PF) is a mild form of legionellosis (see this term) manifesting with flu-like symptoms such as nausea, myalgia, fever, cough and headache but without pneumonia.

Summary:
Epidemiology
The incidence is unknown. Due to the disease's mild and non-specific manifestations it is thought to be underreported. PF is characterised by a high attack rate (number of patients affected / number of people exposed) of up to 95%.
Clinical description
Pontiac fever has a short incubation period ranging from 30-90 hours after infection and affects mainly adults but also children. The disease manifests as an influenza-like syndrome with fever, headache, myalgia and fatigue. In some cases, patients may also experience thoracic pain, dyspnea, diarrhea and vomiting, ocular redness with photophobia and arthralgia. These symptoms usually last 2-7 days and patients recover without treatment.
Etiology
PF is caused by an infection with Legionella pneumophila and Legionella non-pneumophila by inhalation of aerosols from contaminated water, most frequently from showers, whirlpools, spas and hot tubs. The bacteria are found in wet soil and water. It is currently unknown why infection with Legionella evolves into LD or PF in any given case, but as PF is usually observed in immunocompetent patients, immune system status could play a role.
Diagnostic methods
Laboratory diagnosis is rarely performed and is usually done retrospectively by detecting seroconversion or high titers of antibody to Legionella in serum samples. The diagnosis can also be made by detection of the L. pneumophila antigen in urine samples.
Differential diagnosis
Influenza closely resembles PF and must therefore be excluded.
Management and treatment
No treatment is needed for PF and recovery without treatment is the rule.
Prognosis
There is no fatality associated with PF.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Dr Sophie JARRAUD


Pontine autosomal dominant microangiopathy with leukoencephalopathy

A rare genetic cerebral small vessel disease characterized by recurrent ischemic strokes, often with a predilection for the pons, with typical onset in the fourth or fifth decade of life. Patients present progressive cognitive and motor impairment with pyramidal, bulbar, and cerebellar symptoms, among others. Brain imaging shows multiple lacunar infarcts, typically with involvement of the pons, as well as variable leukoencephalopathy of the cerebral hemispheres.


A rare, central nervous system malformation characterized by specific pattern of congenital anomalies affecting the pons, medulla, and cerebellum. Clinical manifestations of multiple cranial nerves deficits, pyramidal and cerebellar signs include neonatal hypotonia, ataxia, sensorineural deafness, reduced vision, language and speech disorders, feeding and swallowing difficulties, facial paralysis and intellectual disability. Various cardiac, gastrointestinal, genitourinary and skeletal defects have been sometimes reported.


A severe, genetic form of pontocerebellar hypoplasia (PCH) characterized by spinal cord anterior horn cell degeneration in addition to pontocerebellar hypoplasia. Clinically, patients manifest with a severe global development deficit that is evident early on from difficulties in feeding and swallowing

Summary:
Epidemiology
About 115 patients with pontocerebellar hypoplasia type 1 (PCH1) have been reported.
Clinical description
The clinical course is severe. Neonates with PCH1 present with hypotonia, impaired swallowing with subsequent feeding difficulties, and progressive, postnatal microcephaly. A severe psychomotor deficit subsequently becomes apparent. If patients survive past infancy, patients have oculomotor manifestations including strabismus, nystagmus and oculomotor apraxia. The most severe cases of PCH1 manifest prenatally with polyhydramnios and arthrogryposis multiplex congenital.
Etiology
PCH1 is genetically heterogeneous. Recessive mutations in the EXOSC3 gene (9p13.2) are found in 40-50% of patients and are the most prevalent cause of PCH1. Mutations in EXOSC8 (13q13.3) and EXOSC9 (4q27) are recently described as a rare cause of PCH1. Mutations in 3 families have been identified in SLC25A46 (5q22.1) and VRK1 (14q32.2) in 2 families. In single cases, recessive mutations have been found in TSEN54 (17q25.1) and RARS2 (6q15). From the small groups reported, severity is suggested to depend on genotype.
Diagnostic methods
MRI shows pontocerebellar hypoplasia with cerebellar hemispheres variably affected. Variable findings include spinal anterior horn degeneration and absence of pontine hypoplasia. Lack of awareness often results in a delay in diagnosis or a diagnosis is never made.
Differential diagnosis
PCH type 2 and 4 (TSEN54-related PCH) can be considered. PCH2 is the most common type of PCH, characterized by dyskinesia and seizures. Brain MRI typically shows pontocerebellar hypoplasia with relative sparing of the vermis compared to the hemispheres, similar to PCH1. In PCH1 however, the pons may be unaffected while in PCH2 the ventral pons is flattened. PCH4 is a more severe than PCH2 and often associated with congenital contractures and polyhydramnios. Spinal Muscular Atrophy (SMA) type 1, caused by biallelic pathogenic variants in SMN1, is characterized by anterior horn cell degeneration, similar to that observed in PCH1. Cognitive function is normal in SMA.
Antenatal diagnosis
Prenatal detection of PCH by ultrasound is unreliable, since cerebellar abnormalities are often not detected at time of the routine screening for structural abnormalities at 20 weeks of gestation. In families in which the causal mutation is detected, prenatal testing or pre-implantation genetic diagnosis (PGD) should be offered.
Genetic counseling
PCH1 is inherited in an autosomal recessive manner. Genetic counseling is recommended for families of individuals with PCH1. For parents of an affected individual, there is a 25% recurrence risk of having another affected child.
Management and treatment
Treatment is symptomatic in PCH.
Prognosis
Prognosis is poor; the majority of patients will only live into infancy. Patients with EXOSC3 mutation have a less severe prognosis.

                            Last update:
                            January 2021

                            - Expert reviewer(s):
                            Pr F. [Frank] BAAS  - Dr Tessa VAN DIJK


A rare, genetic, pontocerebellar hypoplasia subtype characterized by severe psychomotor developmental delay, progressive microcephaly, progressive spasticity, seizures, and brain abnormalities consisting of mild atrophy of the cerebellum, pons and corpus callosum and cortical atrophy with delayed myelination. Patients may present dysmorphic facial features (high arched eyebrows, prominent eyes, long palpebral fissures and eyelashes, broad nasal root, and hypoplastic alae nasi) and an axonal sensorimotor neuropathy.


A rare, genetic form of pontocerebellar hypoplasia characterized by pontocerebellar hypoplasia and progressive neocortical atrophy that manifests clinically with uncoordinated sucking and swallowing, and generalized clonus in the neonate. In early childhood, spasticity, chorea/dyskinesia, seizures and progressive microcephaly develop. Voluntary motor development is lacking.

Summary:
Epidemiology
Pontocerebellar hypoplasia type 2 (PCH2) is reported in at least 81 families to date. It is the most common form of pontocerebellar hypoplasia.
Clinical description
After an uneventful pregnancy and birth without dysmorphic features, affected neonates present usually, but not always, with dysphagia due to bucco-pharyngeal incoordination, respiratory and feeding difficulties and generalized clonus. Extrapyramidal dyskinesia with mixed spasticity such as chorea, athetosis and dystonia develop later. From infancy onward, affected children develop progressive microcephaly, central visual impairment, seizures and a severe impairment of cognitive and motor development, marked by an impaired motor development with failing head control, lack of voluntary hand control and the absence of speech and communication. PCH2 is often fatal in early childhood.
Etiology
PCH2 is generally caused by homozygous mutations in the TSEN54 gene (17q25.1), most frequently a founder mutation, prevalent in families of European extraction: p.A307S/A307S or missense mutations. Rarely mutations in the TSEN2 (3p25.2), TSEN34 (19q13.42), TSEN15 (1q25.3), SEPSECS (4p15.2) or VPS53 (17p13.3) genes are reported.
Diagnostic methods
Diagnosis is made is based on a combination of neuroradiologic and clinical findings : MRI demonstrates variable neocortical atrophy, progressive in time, flattening of the caudate nuclear heads, and pontocerebellar hypoplasia with a typical dragonfly-like cerebellar pattern on coronal sections caused by the flat hemispheres heavily reduced in size together with a comparatively spared vermis. Genetic testing is recommended to confirm the diagnosis.
Differential diagnosis
Due to phenotypic overlap, other subtypes of PCH should be considered, as well as mutations in the CASK gene. Congenital Disorder of Glycosylation type 1A (CDG1A) caused by mutations in the PMM2 gene can resemble PCH. Extreme prematurity (gestational age <32 weeks) can cause cerebellar hypoplasia of variable degrees.
Antenatal diagnosis
In case of risk for recurrence of PCH2, genetic prenatal diagnosis, by amniocentesis or chorionic villus sampling and cytogenetic analysis, may be offered. Prenatal detection of PCH by ultrasound is unreliable, since cerebellar abnormalities are often not detected at time of the routine screening for structural abnormalities at 20 weeks of gestation. In families in which the causal mutation is detected, prenatal testing or pre-implantation genetic diagnosis (PGD) should be offered.
Genetic counseling
PCH2 is inherited in an autosomal recessive manner. Genetic counseling is recommended for families of individuals with PCH2. For parents of an affected individual, there is a 25% recurrence risk of having another affected child.
Management and treatment
Treatment is symptomatic in PCH and involves medication for treatment of dystonia, dyskinesia and seizures and percutaneous endoscopic gastrostomy tube feeding.
Prognosis
Prognosis is variable; the majority of patients will not reach puberty. Life threatening complications include sleep apnea, rhabdomyolysis and malignant hyperthermia. Cot death is possible.

                            Last update:
                            January 2021

                            - Expert reviewer(s):
                            Pr F. [Frank] BAAS  - Dr Tessa VAN DIJK


A rare, genetic form of pontocerebellar hypoplasia (PCH) characterized by neocortical and pontocerebellar hypoplasia with pons and cerebellum equally affected and that clinically manifests with neonatal hypotonia and impaired swallowing followed by seizures, optic atrophy and short stature from infancy onward. Movement disorders, as seen in other forms of PCH, are absent.

Summary:
Epidemiology
Pontocerebellar hypoplasia type 3 (PCH3) is reported in only 3 families.
Clinical description
Neonatally, PCH3 is characterized by hypotonia and impaired swallowing. From infancy onwards, the main features of PCH3 include progressive microcephaly with brachycephaly, optic atrophy, seizures during the first year of life, severe developmental delay, truncal hypotonia, with increased limb deep tendon reflexes and signs of spasticity of the limbs. Other characteristics such as facial dysmorphism (low set ears and prominent eyes), short stature and low weight are also reported. None of the clinical findings are specific. Characteristic movement disorders, as seen in PCH type 2, appear to be absent.
Etiology
Mutations in the PCLO gene (7q21.11) has been identified in a family from the Sultanate of Oman. It is however unclear if PCLO mutations are causative in the other reported PCH3 families reported in literature. PCH3 is inherited in an autosomal recessive manner.
Diagnostic methods
MRI demonstrates neocortical and pontocerebellar hypoplasia with pons and cerebellum equally affected, a small brainstem, prominent sulci and lateral ventricles and decreased cerebral white matter volume. Genetic testing is recommended to confirm the diagnosis.
Differential diagnosis
Due to phenotypic overlap, other subtypes of PCH should be considered, as well as mutations in the CASK gene. Congenital disorder of glycosylation type 1A (CDG1A) caused by mutations in the PMM2 gene can resemble PCH.
Antenatal diagnosis
Prenatal detection of PCH by ultrasound is unreliable, since cerebellar abnormalities are often not detected at time of the routine screening for structural abnormalities at 20 weeks of gestation. In families in which the causal mutation is detected, prenatal testing or pre-implantation genetic diagnosis (PGD) should be offered.
Genetic counseling
PCH3 is inherited in an autosomal recessive manner. Genetic counseling is recommended for families of individuals with PCH3. For parents of an affected individual, there is a 25% recurrence risk of having another affected child.
Management and treatment
Treatment is symptomatic in PCH.
Prognosis
There is no information on life expectancy, but reported PCH3 patients do not appear to regress.

                            Last update:
                            January 2021

                            - Expert reviewer(s):
                            Pr F. [Frank] BAAS  - Dr Tessa VAN DIJK


A severe, genetic form of pontocerebellar hypoplasia (PCH) characterized by delayed neocortical maturation with underdeveloped cerebral hemispheres and pontocerebellar hypoplasia and a severely affected vermis. Clinically, the disorder manifests with prenatal onset of polyhydramnios and contractures followed by hypertonia, severe clonus, primary hypoventilation leading to an early postnatal death.

Summary:
Epidemiology
Pontocerebellar hypoplasia type 4 (PCH4) has been reported in 10 families to date.
Clinical description
PCH4 is characterized prenatally by polyhydramnios. Neonates present with microcephaly, central apnea requiring respiratory support, dysmorphism (sloping forehead, midface hypoplasia, micrognathia), congenital arthrogryposis (50%), severe clonus, and hypertonia. Weaning from mechanical ventilation is difficult and usually fails. Survival beyond the neonatal period is rare.
Etiology
PCH4 is caused by a compound heterozygosity for p.A307S plus non-sense or splice site mutations in the TSEN54 gene (17q25.1).
Diagnostic methods
MRI (usually performed at autopsy) demonstrates microcephaly due to delayed neocortical maturation with underdeveloped cerebral hemispheres, increased volume of extracerebral cerebrospinal fluid, wide midline cava, pontocerebellar hypoplasia with large denuded areas without folia of the cerebellar hemispheric cortex and a severely affected vermis. Genetic testing is recommended to confirm the diagnosis.
Differential diagnosis
Other types of PCH at the severe end of the spectrum should be considered, such as severe forms of PCH1 or SLC25A46-related PCH.
Antenatal diagnosis
In families in which the causal mutation is detected, prenatal genetic testing or pre-implantation genetic diagnosis should be offered. In general, prenatal detection of PCH by ultrasound is unreliable, since cerebellar abnormalities are often not detected at time of the routine screening for structural abnormalities at 20 weeks of gestation.
Genetic counseling
PCH4 is inherited in an autosomal recessive manner. Genetic counseling is recommended for families of individuals with PCH4. For parents of an affected individual, there is a 25% recurrence risk of having another affected child.
Management and treatment
Treatment is symptomatic in PCH.
Prognosis
Survival beyond the neonatal period is rare in PCH4.

                            Last update:
                            January 2021

                            - Expert reviewer(s):
                            Pr F. [Frank] BAAS  - Dr Tessa VAN DIJK


A rare, genetic form of pontocerebellar hypoplasia (PCH) characterized by neocortical and severe cerebral cortical atrophy associated with pontocerebellar hypoplasia with the pons and cerebellum equally affected. Clinically the disorder manifests at birth with hypotonia, clonus, epilepsy, impaired swallowing and from infancy by progressive microcephaly, spasticity and lactic acidosis.

Summary:
Epidemiology
Pontocerebellar hypoplasia type 6 (PCH6) is reported in at least 31 cases to date.
Clinical description
PCH6 manifests at birth by generalized hypotonia, lethargy and dysphagia. The clinical profile is characterized from infancy by a profound developmental delay, progressive microcephaly, hypotonia or spasticity and treatment-resistant epilepsy.
Etiology
PCH6 is caused by nonsense, missense and splice site mutations in the mitochondrial arginyl-transfer RNA synthetase (RARS2) gene located to 6q16.1.
Diagnostic methods
MRI demonstrates neocortical and severe cerebral cortical atrophy (more severe than in other types of PCH) as well as pontocerebellar hypoplasia with the pons and cerebellum equally affected. In some patients, early MRI is normal or only shows mild vermal hypoplasia, followed by rapidly progressive brain atrophy. Lactic acid is elevated in cerebrospinal fluid in the majority of patients, which can be accompanied by respiratory chain enzyme deficiency in muscle or fibroblasts. Genetic testing is recommended to confirm the diagnosis
Differential diagnosis
Due to phenotypic overlap, other subtypes of PCH should be considered, as well as mutations in the genes encoding mitochondrial aminoacyl-tRNA synthetases, which can also cause early onset mitochondrial epileptic encephalopathies.
Antenatal diagnosis
Prenatal detection of PCH by ultrasound is unreliable, since cerebellar abnormalities are often not detected at time of the routine screening for structural abnormalities at 20 weeks of gestation. In families in which the causal mutation is detected, prenatal genetic testing or pre-implantation genetic diagnosis should be offered.
Genetic counseling
PCH6 is inherited in an autosomal recessive manner. Genetic counseling is recommended for families of individuals with PCH6. For parents of an affected individual, there is a 25% recurrence risk of having another affected child.
Management and treatment
Treatment is symptomatic in PCH.
Prognosis
Prognosis is poor, exact life expectancy is unknown but in most cases does not exceed infancy.

                            Last update:
                            January 2021

                            - Expert reviewer(s):
                            Pr F. [Frank] BAAS  - Dr Tessa VAN DIJK


Pontocerebellar hypoplasia type 7 (PCH7) is a novel very rare form of pontocerebellar hypoplasia (see this term) with unknown etiology and poor prognosis reported in four patients and is characterized clinically during the neonatal period by hypotonia, no palpable gonads, micropenis and from infancy by progressive microcephaly, apneic episodes, poor feeding, seizures and regression of penis. MRI demonstrates a pontocerebellar hypoplasia. PCH7 is expressed as PCH with 46,XY disorder of sex development (see this term) in individuals with XY karyotype, and may be expressed as PCH only in individuals with XX karyotype.


Pontocerebellar hypoplasia type 8 (PCH8) is a novel very rare form of pontocerebellar hypoplasia (see this term) characterized clinically by progressive microencephaly, feeding difficulties, severe developmental delay, although walking may be achieved, hypotonia often associated with increased muscle tone of lower extremities and deep tendon reflexes, joint deformities in the lower extremities, and occasionally complex seizures. PCH8 is caused by a loss-of-function mutation in the CHMP1A gene. MRI demonstrates a pontocerebellar hypoplasia with vermis and hemispheres equally affected and mild to severely reduced cerebral white matter volume with a fully formed very thin corpus callosum.


A rare, genetic, non-syndromic pontocerebellar hypoplasia characterized by progressive cerebellum and brainstem atrophy, corpus callosum hypo-/aplasia and progressive post-natal microcephaly. Patients typically present profound global developmental delay, spastic tetraparesis, seizures, cortical visual impairment and, on neuroimaging, abnormal brain morphology that includes pontocerebellar hypoplasia, ''figure of 8'' midbrain appearance, and, more variably, interhemispheric cysts, ventriculomegaly and cerebral dysmyelination.


Porencephaly-cerebellar hypoplasia-internal malformations syndrome is rare central nervous system malformation syndrome characterized by bilateral porencephaly, absence of the septum pellucidum and cerebellar hypoplasia with absent vermis. Additionally, dysmorphic facial features (hypertelorism, epicanthic folds, high arched palate, prominent metopic suture), macrocephaly, corneal clouding, situs inversus, tetralogy of Fallot, atrial septal defects and/or seizures have been observed.


Porencephaly-microcephaly-bilateral congenital cataract syndrome

A rare, genetic, central nervous system malformation syndrome characterized by bilateral congenital cataracts and severe hemorrhagic destruction of the brain parenchyma with associated massive cystic degeneration, enlarged ventricles and subependymal calcification. Patients typically present generalized spasticity, increased deep tendon reflexes and seizures. Hepatomegaly and renal anomalies have also been reported.


A rare, genetic or acquired, cerebral malformation characterized by an intracerebral fluid-filled cyst or cavity with or without communication between the ventricle and subarachnoid space. Clinical manifestations depend on location and severity and may include hemiparesis, seizures, intellectual disability, and dystonia.

Summary:
Epidemiology
Point prevalence of acquired and genetic forms is unknown. However, birth prevalence of porencephaly is estimated at 1/19,000 in Japan and 1/28,500 in the USA.
Clinical description
Porencephaly may manifest before or after birth. The cysts or cavities can be located anywhere within the cerebral parenchyma and are typically lined by smooth walls and surrounded by an atrophic cortex. The clinical picture is highly variable, even within affected families, with severe cases presenting major disability to mild cases with only slight, or even undetected, neurological involvement. The main clinical manifestations include hypotonia, microcephaly, spastic hemiparesis or quadriparesis, seizures, and global developmental delay. Intellectual disability is also a common finding and ranges from very mild to severe.
Etiology
Prenatal- and postnatally-acquired cysts (acquired porencephaly) may be due to a number of causes including hemorrhage, local damage from ischemia or traumatic brain injury. Mutations in the COL4A1 (13q34) and COL4A2 (13q34) genes have been identified in familial (Familial porencephaly) and de novo  cases. In these genetic cases, porencephaly results from antenatal or perinatal hemorrhage and is often associated with other brain abnormalities (bilateral white matter changes, calcifications, microbleeds) and ocular involvement (congenital cataract, retinal arterial tortuosity).
Diagnostic methods
The diagnosis is suspected based on the clinical manifestations and is confirmed radiologically by computed tomography (CT), magnetic resonance imaging (MRI), or ultrasonography showing characteristic intracerebral lesions. Cysts or cavities are well demarcated, contain cerebrospinal fluid and do not show contrast enhancement.
Differential diagnosis
Differential diagnoses include arachnoid cyst, schizencephaly, ependymal cyst, encephalomalacia, hydranencephaly, and other COL4A1 or COL4A2 related diseases, including childhood stroke, CADASIL and retinal vasculopathy with cerebral leukodystrophy.
Antenatal diagnosis
Ultrasonography may detect porencephaly prenatally after the 30th week of gestation.
Genetic counseling
The pattern of inheritance for familial porencephaly is autosomal dominant. Genetic counseling should inform parents of the 50% risk of transmission for future offspring. Occasionally, genetic cases arise de novo.
Management and treatment
No specific treatment is available for porencephaly. Treatment is therefore symptomatic and supportive and may include physical therapy, speech therapy, and anticonvulsant medication to treat seizures.
Prognosis
Prognosis is variable and depends on the site and extent of the lesion.

                            Last update:
                            June 2019

                            - Expert reviewer(s):
                            Pr Patrick VAN BOGAERT


A rare skin disease that is characterized by the presence of brownish single or multiple annular plaques of varying size, that are sometimes confluent, with a distinctive sharply-defined keratotic border.

Summary:
Epidemiology
Porokeratosis of Mibelli (PM) prevalence is unknown. It is more prevalent in males than females with a ratio of 2-3:1.
Clinical description
Disease onset usually occurs in children, adolescents or young adults (sometimes immunosuppressed). It presents with brownish dry hyperkeratotic plaques of varying size that may coalesce. The lesions have a sharply-defined keratotic border and are usually asymptomatic, but rarely pruritic. They most commonly occur on the limbs (hands and feet) but other areas such as the trunk, palms and soles and genitalia can also be affected. Facial and mucosal lesions are rare. In around 7% of cases, PM lesions undergo malignant transformation, mostly toward squamous cell carcinoma, or less commonly, basal cell carcinoma.
Etiology
The exact etiology is unknown but the lesions are thought to originate from the localized expansion of a clone of abnormal keratinocytes. Contributing factors include immunosuppression, exposure to ultraviolet radiation and drugs, as well as genetic factors (mutations in mevalonate kinase gene).
Diagnostic methods
Diagnosis is based on physical examination and a cutaneous biopsy showing the distinctive cornoid lamella, i.e. a narrow, vertical stack of parakeratotic corneocytes within the horny layer seated on a depression of the underlying epidermis.
Differential diagnosis
The main differential diagnoses are actinic keratosis, elastosis perforans serpiginosa, annular lichen planus, circumscribed palmoplantar hypokeratosis, psoriasis, focal palmoplantar keratoderma and Bowen's disease.
Genetic counseling
Autosomal dominant inheritance has been reported, although PM is often sporadic.
Management and treatment
PM lesions can be treated with surgical excision. Alternative, albeit less efficient, options include topical 5-fluorouracil (5-FU), imiquimod, cryotherapy, dermabrasion, carbon dioxide laser ablation and photodynamic therapy. However the lesions often recur after treatment. Regular follow-up is recommended to monitor the development of any possible malignancies, and sun exposure should be limited in order to decrease their risk.
Prognosis
PM is a chronically progressive disease and can have a negative impact on a patient's quality of life due to the presence of lesions. Rarely (in around 7% of cases), long-standing lesions may transform into squamous cell carcinoma, which has exceptionally proven fatal.

                            Last update:
                            August 2020

                            - Expert reviewer(s):
                            Pr Jean KANITAKIS


A rare genetic disease which is a rare form of porokeratosis occurring mainly in adolescence and characterized by small pruritic or painful keratotic papules that first appear on the palms and soles, and may gradually spread to other body zones.

Summary:
Epidemiology
Porokeratosis plantaris palmaris et disseminata (PPPD) prevalence is unknown but it is one of the rarest forms of porokeratosis. The disease is more frequently seen in males.
Clinical description
The disease often begins in adolescence but some cases have presented in adulthood. Keratotic papules are first noticed on the palms and soles but later spread over the entire body, although lesions on the trunk might be less keratotic. The lesions are usually punctate on the palms and soles and annular on the rest of the body with the characteristic hyperkeratotic border. Foot pain is common due to plantar keratoses. Men are more often affected than women.
Etiology
The exact etiology is unknown. A possible locus for PPPD has been found on chromosome 12q24.1-q24.2.
Diagnostic methods
Diagnosis is based on physical examination and a cutaneous biopsy showing the distinctive pathologic finding known as cornoid lamella. The characteristic clinical findings of papular-keratotic, rather than annular, lesions and an initial onset on the palms and soles also aids in the diagnosis.
Differential diagnosis
Differential diagnoses include other (genetic) punctate palmoplantar keratodermas such as acrokeratoelastoidosis of Costa, hyperkeratosis-hyperpigmentation syndrome, punctate palmoplantar keratoderma type 1 and hereditary papulotranslucent acrokeratoderma.
Genetic counseling
PPPD usually follows a dominant (autosomal or X-linked) pattern of inheritance. Sporadic cases have been reported and may be due to spontaneous mutations resulting in abnormal proliferating clones of epidermal cells.
Management and treatment
There is no standard treatment for PPPD. Oral retinoids combined with topical 5-fluorouracil (5-FU) have been successful in reducing the number of lesions in some patients, but relapses are common. Physical methods (shave excision, cryotherapy, curettage, dermabrasion and linear excision) have had varying degrees of success in removing lesions but are not a feasible option in cases where the lesions are generalized.
Prognosis
PPPD has a negative impact on a patient's quality of life as the lesions are tender or painful, limiting the patient's ability to walk, and their treatment is often unsuccessful.

                            Last update:
                            August 2020

                            - Expert reviewer(s):
                            Pr Jean KANITAKIS


A rare hepatic porphyria with cutaneous expression (PCT) characterized by bullous photodermatosis.

Summary:
Epidemiology
This is the most common form of cutaneous porphyria. Its prevalence in Western Europe is around 1/25,000. Men are more affected than women.
Clinical description
Occurring in adults, PCT is acquired (75% of cases) or familial (25% of cases). Manifestations generally appear earlier in familial cases. Some risk factors can trigger symptoms: excessive alcohol consumption, hepatitis C, estrogen intake, iron metabolism gene mutations with overload (hemochromatosis). The main clinical symptoms include extreme skin fragility, followed by bullous skin lesions on sun-exposed surfaces (hands, face). Healing is slow and often followed by hyper- and hypopigmentation. Skin lesions of varying ages are highly characteristic of the disease. These symptoms may be accompanied by hypertrichosis (especially facial) and, more rarely, by sclerodermiform lesions. Hepatopathy should be investigated (siderosis, steatosis, chronic inflammatory disorders, etc.).
Etiology
PCT is caused by a deficiency in uroporphyrinogen decarboxylase (UROD, the fifth enzyme in the heme biosynthesis chain). In the familial form of the disease, this deficiency is due to heterozygous mutations in the UROD gene (NM_000374.5), which codes for UROD and leads to an accumulation of porphyrins (uro- and hepta-carboxylic porphyrins) in the liver.
Diagnostic methods
Diagnosis is based on high concentrations of porphyrins in plasma, with a fluorimetric peak at 620 nm, and high concentrations of isocoproporphyrins in stools, which is specific to PCT. UROD deficiency in red blood cells confirms the diagnosis of familial PCT. In contrast, normal UROD activity in red blood cells is in favor of sporadic PCT. Skin biopsy is not very informative and is not recommended.
Differential diagnosis
Differential diagnosis mainly includes variegate porphyria (diagnosed on the basis of a characteristic fluorometric peak in plasma), hereditary coproporphyria, the photodermatosis of acute intermittent porphyria (in renal failure condition), and pseudo-porphyrias.
Antenatal diagnosis
Antenatal diagnosis is theoretically possible in familial forms, but is not offered.
Genetic counseling
The pattern of transmission for familial PCT is autosomal dominant, with low penetrance. Therefore, genetic counseling should be offered to those families to identify individuals likely to develop or transmit the disease.
Management and treatment
Management includes removal of triggers, management of underlying liver disease, phlebotomy and/or low-dose chloroquine (100 mg twice weekly) to achieve complete remission whether or not there is iron overload. A relapse is possible, and the treatment will be the same. Discontinuation of alcohol and estrogen-progestin therapy, and treatment of concomitant hepatitis C, are essential for remission.
Prognosis
PCT is not life-threatening and its prognosis is good. It is, however, a risk factor for the development of hepatocellular carcinoma.

                            Last update:
                            March 2024

                            - Expert reviewer(s):
                            Dr Neila TALBI | MetabERN*

                                * European Reference Network


Porphyria due to ALA dehydratase deficiency

A rare acute hepatic porphyria characterized by neurovisceral attacks without skin symptoms.

Summary:
Epidemiology
Fewer than a dozen cases have been reported in the literature to date.
Clinical description
The disease is reported among children. Patients suffer acute neuro-visceral episodes that can last several weeks, manifesting as intense abdominal pain, neurological disorders and psychological disturbances.
Etiology
Doss porphyria is due to a deficiency in delta aminolevulinic acid dehydratase (ALAD, the second enzyme in the heme biosynthesis pathway), which leads to an accumulation of porphyrin precursors (delta aminolevulinic acid, ALA) in the liver. The enzyme deficiency is due to mutations in the ALAD gene (NM_000031) coding for ALAD (to date, 9 mutations known and expressed). Patients most often have a compound heterozygosity. The transmission pattern is autosomal recessive.
Diagnostic methods
The diagnosis is made on the basis of massive accumulation of ALA in the urine, with no increase in PBG. Diagnosis is based on the identification of a causal mutation in the ALAD gene.
Differential diagnosis
Differential diagnosis should consider acute hepatic porphyria (in acute attack situations), type I tyrosinemia, and lead poisoning.
Antenatal diagnosis
Prenatal diagnosis is theoretically possible in families at risk, but is not offered.
Genetic counseling
Genetic counseling is recommended to patients and families to identify individuals at risk of developing or transmitting the disease, and to advise them on measures to take to reduce the risk of an episode It should also be offered to at-risk couples (both individuals are carriers of a heterozygous pathogenic variant) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Administration of human hemin is of limited effectiveness in acute episode as is liver transplantation. In 2020, treatment with weekly blood transfusions and hydroxyurea was successfully attempted.
Prognosis
In some patients, acute attacks are recurrent and disabling, sometimes fatal. In some cases, they can lead to severe paralysis. The disease is often progressive.

                            Last update:
                            March 2024

                            - Expert reviewer(s):
                            Dr Neila TALBI | MetabERN*

                                * European Reference Network


A group of rare hereditary metabolic diseases characterized by intermittent neurovisceral manifestations and/or skin lesions.

Summary:
Epidemiology
Prevalence depends on the type of porphyria.
Clinical description
The group includes eight diseases with different manifestations. Symptoms mainly appear in adulthood, but some also affect children. Porphyrias can be classified into two groups, hepatic and erythropoietic, depending on the tissue predominantly affected by the metabolic abnormality. Clinical signs of hepatic porphyrias with cutaneous expression and erythropoietic porphyrias are bullous cutaneous lesions and/or acute pain in areas exposed to the sun (painful lesions). They are not associated with acute neurovisceral attacks. On the contrary, acute hepatic porphyrias can be associated with neurovisceral attacks manifested by intense abdominal pain (very often accompanied with nausea, vomiting and severe constipation), neurological disorders and mental disturbances. Two acute hepatic porphyrias (variegate porphyria and hereditary coproporphyria) can present with cutaneous photosensitivity as well.
Etiology
All porphyrias are caused by a deficiency or a gain-of-function in one of the enzymes involved in heme biosynthesis. These deficiencies or gains of function lead to an accumulation of porphyrins and/or their precursors (delta aminolevulinic acid, ALA, and porphobilinogen, PBG) in the liver or bone marrow. Precursors, and especially ALA, are responsible for neurological manifestations (direct or indirect neurotoxicity). The deficits or gains in enzyme function are the result of mutations of the coded corresponding genes.
Diagnostic methods
Diagnosis is essentially based on the measurement of porphyrins and their precursors in biological samples (urine, stools, blood).
Differential diagnosis
The differential diagnosis includes Guillain-Barré syndrome, and all causes of abdominal pain when the patient presents with acute pain, and photodermatoses when the patient presents with cutaneous symptoms.
Antenatal diagnosis
Antenatal diagnosis may be proposed for the families at risk of congenital erythropoietic porphyria and homozygous acute hepatic porphyrias.
Genetic counseling
Transmission of hereditary porphyrias is autosomal and either dominant with low penetrance or recessive with complete penetrance. One type of porphyria is X-linked dominant. The risk of transmitting the disease varies from 25% to 50%, depending on the type of porphyria. Penetrance varies from less than 2% to 100%, depending on the type of porphyria and the affected family members. Genetic counselling should be offered to affected families to identify individuals likely to develop or transmit the disease.
Management and treatment
Acute attacks must be considered as medical emergencies and treated by injection of human hemin and/or perfusion of carbohydrates. Cutaneous manifestations are mainly treated by phlebotomy and/or low-dose regimen of chloroquine.
Prognosis
Prognosis depends on the type of porphyria.

                            Last update:
                            March 2024

                            - Expert reviewer(s):
                            Dr Neila TALBI | MetabERN*

                                * European Reference Network


Port-wine nevi-mega cisterna magna-hydrocephalus syndrome

A rare developmental defect during embryogenesis syndrome characterized by a glabellar capillary malformation, congenital communicating hydrocephalus, and posterior fossa brain abnormalities, including Dandy-Walker malformation, cerebellar vermis agenesis, and mega cisterna magna. Seizures are occasionally associated. There have been no further descriptions in the literature since 1979.


A group of rare immunodeficiency-associated lymphoproliferative disorders characterized by lymphoid or plasmacytic proliferations developing in the context of immunosuppression in a recipient of a solid organ or stem cell allograft. The group includes non-destructive post-transplant lymphoproliferative disorders (PTLDs), polymorphic PTLD, monomorphic PTLDs, and classic Hodgkin lymphoma PTLD. Patients may have more than one type of PTLD in a single or in different locations. The most commonly involved sites are lymph nodes, gastrointestinal tract, lungs, and liver, although the disease may occur almost anywhere in the body. In solid organ transplant recipients, PTLD may also involve the allograft.


A rare, acquired, endocrine disorder characterized by deficiency of one or more of the pituitary hormones resulting as a consequence of traumatic or medically-induced injury of the pituitary gland. Clinical presentation is variable depending on the nature and acuity of the injury and the resulting order and amount of hormone deficiency.


A rare acrofacial dysostosis that is characterized by mandibular and malar hypoplasia, small and cup-shaped ears, lower lid ectropion, and symmetrical postaxial limb deficiencies with absence of the fifth digital rays and ulnar hypoplasia.

Summary:
Epidemiology
Less than 30 cases of Postaxial acrofacial dysostosis (POADS) have been described in the literature.
Clinical description
Clinical features further include cholestasis, bilateral inguinal hernia and cleft palate. The patients can develop myopic astigmatism and speech delay can be present. Facial features include sparse eyebrows, almond shaped eyes with up-slanting palpebral fissures, malar hypoplasia, long philtrum, small mouth, and low-set, malformed ears.
Etiology
The disease arises from biallelic gene mutations for the enzyme dihydroorotate dehydrogenase (DHODH, 16q22.2), involved in pyrimidine biosynthesis. Nonetheless, despite demonstrated loss of enzyme activity, dihydroorotate (DHO) has not been shown to accumulate.
Diagnostic methods
DHODH mutations can be determined by PCR and Sanger sequencing. Analysis of DHO and orotic acid (OA) in urine, plasma and blood-spot test can be performed using liquid chromatography-tandem mass spectrometry.
Differential diagnosis
The clinical phenotype of Miller syndrome overlaps with mandibulofacial and other acrofacial dysostosis syndromes including Treacher Collins, Guion-Almeida (mandibulofacial dysostosis with microcephaly) and Nager syndromes.
Antenatal diagnosis
Due to postaxial oligodactyly of fingers and toes, the diagnosis can be established prenatally on clinical grounds and confirmed by molecular testing.
Genetic counseling
Inheritance appears to be autosomal recessive. For parents of an affected individual, there is a 25% risk of having and affected child at each pregnancy. Recurrence risk for children of an affected individual is low if there is no consanguinity.
Management and treatment
The patients do not usually need surgical treatment, but sometimes need hearing aids. Logopedic treatment might be helpful.
Prognosis
There is usually no reduced life expectancy, but intrauterine death has been described.

                            Last update:
                            December 2020

                            - Expert reviewer(s):
                            Pr Dagmar WIECZOREK | ITHACA*

                                * European Reference Network


A rare congenital limb malformation characterized by duplication of the fifth digit in a hand or foot, with an extra, well-formed, functional digit at the metacarpophalangeal/metatarsophalangeal or carpometacarpal/tarsometatarsal joint. The malformation can be an isolated finding or be associated with a large number of other anomalies.


A rare congenital limb malformation characterized by duplication of the fifth digit in a hand or foot, the sixth digit being rudimentary, poorly developed, and non-functional, frequently consisting of additional soft tissue on a pedicle. The anomaly can be unilateral or bilateral.


Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome is a rare, genetic developmental defect during embryogenesis disorder characterized primarily by congenital hypopituitarism and/or postaxial polydactyly. It can be associated with short stature, delayed bone age, hypogonadotropic hypogonadism, and/or midline facial defects (e.g. hypotelorism, mild midface hypoplasia, flat nasal bridge, and cleft lip and/or palate). Hypoplastic anterior pituitary and ectopic posterior pituitary lobe are frequent findings on MRI examination.


Postaxial polydactyly-dental and vertebral anomalies syndrome is a rare, genetic, developmental defect during embryogenesis syndrome characterized by postaxial polydactyly and other abnormalities of the hands and feet (e.g. brachydactyly, broad toes), hypoplasia and fusion of the vertebral bodies, as well as dental abnormalities (fused teeth, macrodontia, hypodontia, short roots). There have been no further descriptions in the literature since 1977.


Postaxial tetramelic oligodactyly is a rare, genetic, congenital limb malformation disorder characterized by isolated, postaxial oligodactyly in all four extremities. Patients present a consistent pattern of malformation ranging from complete absence of the 5th metacarpals, metatarsals and phalanges to complete absence of the 5th metacarpals and metatarsals, with some residual distal 5th phalanges. There have been no further descriptions in the literature since 1993.


Postcardiotomy right ventricular failure

A rare cardiac condition characterized by acute severe right ventricular failure with subsequent hemodynamic instability following a cardiac surgical procedure. Predisposing factors include suboptimal myocardial protection during surgery, long cardiopulmonary bypass time, right ventricular myocardial ischemia or infarction, atrial arrhythmias, reperfusion lung injury with secondary pulmonary hypertension, post-operative pulmonary micro- or macro-embolism, and pre-existing pulmonary vascular disease, among others.