A rare overgrowth syndrome characterized by tall stature, learning difficulties and facial dysmorphism.


Overgrowth-metaphyseal undermodeling-spondylar dysplasia syndrome

A rare overgrowth syndrome with skeletal involvement characterized by pre- or postnatal onset of overgrowth, accelerated bone age in infancy and early childhood, tall stature, bony overgrowth of the skull base, spondylar dysplasia, and undermodeling of the tubular bones. Facial dysmorphism includes mild hypertelorism, depressed nasal bridge, short and broad nose, and full lower lip. Additional reported features are scoliosis, as well as delayed puberty, cryptorchidism, and hypospadias.


Overhydrated hereditary stomatocytosis (OHSt) is a disorder of red cell membrane permeability to monovalent cations and is characterized clinically by hemolytic anemia.

Summary:
Epidemiology
OHSt is very rare with only seven cases described in the literature so far.
Clinical description
Onset occurs during the neonatal period or infancy with hemolytic anemia that may require occasional blood transfusions. Splenomegaly or hepatosplenomegaly are present. The disease course is marked by the usual complications of hemolytic anemia (biliary lithiasis) and, remarkably, by a strong tendency for iron overload.
Etiology
In the majority of cases, OHSt is caused by mutations in the RHAG gene (6p21-qter) encoding the Rh-associated glycoprotein component of the Rh complex.
Diagnostic methods
Diagnosis is based on a massive right shift of the osmotic gradient ektacytometry curve indicating overhydrated red cells and decreased osmotic resistance, together with a substantial increase in the monovalent cation leak compared to controls, and a sharp decrease of the leak as a function of decreasing temperature. Blood smears show an elevated percentage of well formed stomatocytes. There is macrocytosis, a low mean cell hemoglobin concentration (MCHC) and a high reticulocyte count. Electrophoresis reveals that the membrane protein stomatin is absent or present at only low levels.
Differential diagnosis
The differential diagnosis should include the most common form of hereditary stomatocytosis, dehydrated hereditary stomatocytosis, as well as hereditary cryohydrocytosis with reduced stomatin (see these terms).
Genetic counseling
OHSt is transmitted as an autosomal dominant trait but de novo mutations are quite common.
Management and treatment
Treatment involves blood transfusions, when necessary, together with management of biliary lithiasis and iron overload. Splenectomy is contraindicated in OHSt patients as it may induce venous thromboembolic complications.
Prognosis
With correct management of the complications, the prognosis is good.

                            Last update:
                            October 2008

                            - Expert reviewer(s):
                            Pr Jean DELAUNAY


A rare idiopathic inflammatory myopathy (IIM) with a heterogeneous phenotype characterized by myositis with at least one clinical and/or autoantibody overlap feature. Possible clinical overlap features include polyarthritis, Raynaud's phenomenon, sclerodactyly, scleroderma (proximal to metacarpophalangeal joints), lung interstitial pneumonia, and/or clinical signs of systemic lupus erythematosus (SLE).

Summary:
Epidemiology
Prevalence and annual incidence are not known. Estimates are difficult to determine because of low recognition levels of this form of IIM. The disorder is more common in adult women and is frequently associated with other connective tissue disorders such as systemic sclerosis, SLE, rheumatoid arthritis, and Sjögren syndrome.
Clinical description
Overlap myositis (OM) is a clinically heterogeneous, poorly recognized subtype of idiopathic inflammatory myopathy. Patients with myositis and one clinical and/or autoantibody overlap feature are considered to have OM. Possible clinical overlap features include polyarthritis, Raynaud's phenomenon, sclerodactyly, scleroderma (proximal to metacarpalphalangeal joints), lung interstitial pneumonia, and/or clinical signs of systemic lupus erythematosus (SLE). Overlap autoantibodies include those observed with scleroderma (such as anti-Ku or anti-PMScl), mixed connective tissue disease (MCTD; with anti-RNP), SLE (frequent ANA positivity), and/or some inflammatory myopathies such as anti-synthetase syndrome (anti-JO1).
Etiology
OM covers a range of inflammatory myopathies and other connective tissue diseases for which the etiology is generally poorly understood.
Diagnostic methods
The precise diagnostic criteria are still debated. Sometimes OM is defined as the combination of myositis and another connective tissue disorder (systemic sclerosis, SLE, RA, Sjögren syndrome, etc.). Sometimes, OM is defined as a myositis with overlap features without fulfilling criteria of another connective tissue disorder. The diagnosis of this disorder improves with the increased screening for myositis-specific and myositis-associated autoantibodies. Some antibodies may delineate homogeneous subgroup of myositis patients, such as anti-RNP with specific extramuscular manifestations (puffy hands / Raynaud's phenomenon, arthralgia / ILD).
Differential diagnosis
The differential diagnoses include other IIM disorders (dermatomyositis, anti-synthetase syndrome, immune-mediated necrotizing myopathy and inclusion body myositis). There is still debate about OM as a distinct entity as opposed to a specific CTD with muscle involvement.
Management and treatment
There is no specific recommendation for therapeutic management. The treatment is usually based on the use of corticosteroids and/or other immunosuppressants.
Prognosis
Due to the heterogeneity of the diagnostic criteria and the small number of patients in the published studies, the specific prognosis of OM is not well known.

                            Last update:
                            March 2021

                            - Expert reviewer(s):
                            Dr Céline ANQUETIL  - Pr Olivier BENVENISTE


A rare, genetic, inborn error of metabolism disorder characterized by neonatal-onset of developmental delay, hypotonia, hepatomegaly, lactic acidemia, increased creatine kinase levels, elevated alpha-ketoglutaric acid in urine, and a decreased plasma beta-hydroxybutyrate-to-acetoacetate ratio. Pyruvate dehydrogenase deficiency can be associated, leading to hypoglycemia and neurologic anomalies, including seizures.


Pachydermoperiostosis (PDP) is a form of primary hypertrophic osteoarthropathy (see this term), a rare hereditary disorder, and is characterized by digital clubbing, pachydermia and subperiosteal new bone formation associated with pain, polyarthritis, cutis verticis gyrata, seborrhea and hyperhidrosis. Three forms have been described: a complete form with pachydermia and periostitis, an incomplete form with evidence of bone abnormalities but lacking pachydermia, and a forme frusta with prominent pachydermia and minimal-to-absent skeletal changes.

Summary:
Epidemiology
The prevalence is unknown. PDP occurs predominantly in men (male to female ratio: 7:1) and the disease is more severe in men than in women.
Clinical description
PDP typically begins during childhood or adolescence and may stabilize after 5-20 years of progression, or progress constantly. However, in the neonatal period, late closure of the fontanels and a patent arterial duct (see this term) may be observed. PDP presents with digital clubbing and dermatological (pachydermia, thickening and furrowing of the facial features, cutis verticis gyrata, seborrhea, edema, hyperhidrosis) and rheumatological symptoms (joint effusion, arthritis, acro-osteolysis, periosteal ossification). Patients may develop severe kyphosis, restricted motion and neurological manifestations. PDP may also be associated with congenital heart disease, particularly patent arterial duct.
Etiology
Mutations in the HPGD gene (4q33-q34) have been identified. The gene encodes 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the main enzyme of prostaglandin degradation. Patients with homozygous mutations have chronically elevated prostaglandin E2 levels.
Diagnostic methods
Diagnosis is based on clinical signs, X-ray exam, magnetic resonance imaging (MRI) and/or radionucleotide bone imaging showing typical bone abnormalities, such as diaphyseal periostosis and acro-osteolysis.
Differential diagnosis
Differential diagnoses include cranio-osteoarthropathy (see this term), secondary hypertrophic osteoarthropathy, chronic recurrent multifocal osteomyelitis, SAPHO and Camurati-Engelman disease (see these terms), thyroid acropachy and syphilitic periostosis.
Genetic counseling
PDP is inherited as an autosomal recessive trait; however, heterozygous carriers can have a mild phenotype. Genetic counseling should be offered to patients and their families.
Management and treatment
Rheumatologic symptoms can be improved by nonsteroidal anti-inflammatory drugs, corticosteroids or colchicine. Clinical improvement of the dermatological symptoms is achieved by retinoids. Plastic surgery may be helpful for facial involvement. Surgical reduction of finger clubbing has been performed with success.
Prognosis
PDP may progress constantly, leaving patients with chronic debilitating complications, such as clubbing and arthritis.

                            Last update:
                            January 2011

                            - Expert reviewer(s):
                            Pr Hermann GIRSCHICK


A rare, genetic neurological disorder characterized by the presence of diffuse pachygyria and arachnoid cysts, psychomotor developmental delay and intellectual disability. Seizures (absence, atonic and generalized tonic-clonic) and, on occasion, headache are also associated.


A rare genetic skin disease predominantly featuring painful palmoplantar keratoderma, thickened nails, cysts and white plaques affecting tongue and oral mucosa.

Summary:
Epidemiology
The prevalence is not known but over a thousand patients have been registered to date worldwide in the International Pachyonychia Congenita Research Registry (IPCRR). It is estimated that there are five to ten thousand cases worldwide.
Clinical description
Pachyonychia congenita (PC) presents clinically as a spectrum of conditions. PC onset is variable with most cases manifesting soon after birth, others becoming clinically apparent only in late childhood and rarely in adulthood. The first signs of the disease usually are thickened nails or neonatal teeth. At least 3 phenotypes of hypertrophic nail dystrophy of feet and hands can be observed: nail grows to full length but a distal prominent hyperkeratosis causes an upward slant with an accentuated curvature of the nail; nail plate terminates prematurely leaving a distal region of hyperkeratosis and an exposed fingertip; or nail plate is thin with little or no hyperkeratosis. When children start walking, typically in the first years of life, a focal palmoplantar keratoderma develops, with underlying blistering causing severe pain. In some cases, the onset of keratoderma is not seen until later childhood. By about 12 years of age the majority of patients have painful plantar keratoderma. Oral leukokeratosis occurs early, may possibly cause feeding difficulties and should be distinguished from oral candidiasis in infants. Laryngeal leukokeratosis may cause hoarseness, and rarely, causes airway obstruction. Follicular keratoses on the trunk and extremities may be seen at friction points such as waist, elbows and knees. Excessive sweating of palms and soles due to palmoplantar hyperhidrosis, widespread steatocystomas appearing during or after puberty, axillary and groin cysts are other findings observed in some PC patients.
Etiology
Although historically two subtypes have been described, PC-1 and PC2, it is today recommended to classify PC patients into five subgroups based on the underlying molecular etiology: PC-K6a, PC-K6b, PC-K6c, PC-K16 and PC-K17, as PC is caused by dominant negative mutations in at least 5 genes (KRT6A, KRT6B, KRT6C, KRT16 and KRT17) encoding keratins preferentially expressed in basal and suprabasal layers of palmoplantar skin, epidermal appendages and oral mucosa.
Diagnostic methods
Diagnosis is based on clinical examination and is confirmed by molecular genetic testing.
Differential diagnosis
The differential diagnosis includes variants of PC (steatocystoma multiplex, which develops at puberty with little or no nail dystrophy) and disorders manifesting with dystrophic nails such as epidermolysis bullosa, Clouston syndrome (distinguished by the presence of alopecia or hypotrichosis), autosomal recessive nail dysplasia (only nail involvement), other disorders presenting with palmoplantar keratoderma such as palmoplantar keratoderma-esophageal carcinoma syndrome, striate palmoplantar keratoderma and acquired disorders such as psoriasis and lichen planus.
Antenatal diagnosis
Antenatal molecular diagnosis is feasible provided the causative mutation is known.
Genetic counseling
Recent data suggesting the possibility that the disease may rarely be inherited in a semi-dominant fashion emphasizes the importance of accurate molecular diagnosis for proper genetic counseling.
Management and treatment
There is no curative treatment for PC yet. Treatment of manifestations will focus primarily on grooming of nails and management of pain due to palmoplantar keratoderma: it includes the use of emollients and oral retinoids to reduce hyperkeratosis and strategies to limit frictions and trauma of the feet. Novel treatment modalities under investigation include small interfering RNA (siRNA) strategies, the use of topical rapamycin, oral and topical erlotinib and injection of botulinum toxin.
Prognosis
Complications may include secondary infection that is usually well controlled by antibiotic therapy.

                            Last update:
                            December 2022

                            - Expert reviewer(s):
                            Pr Edel O'TOOLE | ERN-Skin*

                                * European Reference Network


Paget disease of the nipple describes a rare presentation of breast cancer, seen most frequently in women aged 50-60, manifesting with nipple drainage and itching, erythema, crusty and excoriated nipple, thickened plaques, and hyperpigmentation (less frequently). It is due to tumor cells invading the nipple-areola complex and represents 1-3% of all new breast cancer diagnoses.


PAGOD syndrome is a severe developmental syndrome characterized by multiple congenital anomalies including cardiovascular defects, pulmonary hypoplasia, diaphragmatic defects and genital anomalies.

Summary:
Epidemiology
Since the first publication in 1991, only 11 patients have been described.
Clinical description
Neonates with PAGOD syndrome present with several visceral anomalies: hypoplasia of right or left lung, diaphragmatic hernia, omphalocele, various cardiac anomalies including, amongst others, atrial septal defect, left ventricular hypoplasia or ventricular septal defect, and great vessels anomalies such as aortic hypoplasia and pulmonary artery hypoplasia or atresia. Cardiac and mediastinal structures may be in dextroposition. Ambiguous external genitalia can be observed in some cases and all patients present gonadal agenesis or hypoplasia and developmental anomalies of Wolffian and Mullerian duct structures.
Etiology
Etiology is unknown but vitamin A deficiency has been suggested to play a role in the development of the syndrome.
Genetic counseling
Almost all cases are sporadic, except for 2 siblings, suggesting autosomal recessive inheritance.
Prognosis
Life expectancy is reduced due to cardiac and respiratory complications.

                            Last update:
                            December 2011


A rare frontonasal dysplasia characterized by median cleft of the upper lip (MCL), midline polyps of the facial skin, nasal mucosa, and pericallosal lipomas. Hypertelorism with ocular anomalies are also observed, generally with normal neuropsychological development.

Summary:
Epidemiology
Pai syndrome (PS) has been reported in 67 patients to date, however, the incidence seems to be underestimated.
Clinical description
PS presents at birth with a variable phenotype ranging from mild facial dysmorphism to more severe anomalies resembling frontonasal dysplasia. Most patients present with a marked hypertelorism with downward slanting palpebral fissures and may include a bifid nose in the most extreme cases. Midline cleft lip with midline nasal and facial polyps manifest generally as a bifid uvula with high palate, polyps are located over the nasal septum or extend from the nostril from an attachment to the nasal septum. These anomalies may lead to respiratory impairment, increased respiratory infections, speech impediments or early childhood difficulties in eating solids. Skin lipomas containing cartilage may be seen on the forehead. Ocular anomalies may include anterior segment dysgenesis, persistent papillary membrane, corneal leukoma, microcornea, posterior lenticonus, heterochromia iris and conjunctival lipoma. Coloboma of the iris has been reported. Neuropsychological development is usually normal, but some patients may present with epilepsy and impaired neuropsychological development. Sacral dimples may be observed at birth, and hypospadias has been reported in some male patients.
Etiology
The etiology of PS is unknown.
Diagnostic methods
PS is diagnosed strictly by clinical signs, the presence of a congenital nasal polyp plus one or more of the three following traits: MCL (with or without cleft alveolus), mid-anterior alveolar process congenital polyp and pericallosal lipoma. MRI may reveal pericallosal lipomas and an abnormal configuration of the third ventricle. An ophthalmological exam is recommended.
Differential diagnosis
Differential diagnoses include Loeys-Dietz syndrome, oculocerebrocutaneous syndrome, frontonasal dysplasia, Goldenhar syndrome, as well as a variety of chromosomal anomalies.
Genetic counseling
One case of father to son transmission has been reported to date, but no recurrence in sibs has ever been reported. Recurrence risk in families with no history of PS is therefore thought to be low.
Management and treatment
Detection of potential oral or respiratory difficulties in newborns must be treated immediately. Multistage craniofacial surgery may be necessary in many cases. Surgical restoration of orbicular muscle continuity and excision of skin lipomas may be performed early in childhood, correction of the nasal pyramid should be performed after the pubertal growth spurt. In patients presenting with ocular anomalies, corneal or cataract surgery may improve vision in some cases, and optical iridectomy may be necessary in cases presenting with corneal leukoma. All patients should be regularly monitored for increases in intraocular pressure.
Prognosis
Both cosmetic and functional restoration of buccal and nasal anomalies is feasible and the prognosis is good for most patients.

                            Last update:
                            October 2019

                            - Expert reviewer(s):
                            Dr Damien LEDERER


Painful orbital and systemic neurofibromas-marfanoid habitus syndrome is a rare, benign, peripheral nerve sheath tumor disorder characterized by multiple, painful, mucin-rich plexiform neurofibromas located in the orbits, cranium, large spinal nerves and mucosa, associated with a marfanoid habitus, enlarged corneal nerves, congenital neuronal migration anomalies and facial dysmorphism which includes ptosis, proptosis, prominent nose, full lips, gingival hyperplasia, and multiple subcutaneous and submucosal nodules in the lips and sublingual zone.


Palatal anomalies-widely spaced teeth-facial dysmorphism-developmental delay syndrome is a rare, genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay, axial hypotonia, palate abnormalities (including cleft palate and/or high and narrow palate), dysmorphic facial features (including prominent forehead, hypertelorism, downslanting palpebral fissures, wide nasal bridge, thin lips and widely spaced teeth), and short stature. Additional manifestations may include digital anomalies (such as brachydactyly, clinodactyly, and hypoplastic toenails), a single palmar crease, lower limb hypertonia, joint hypermobility, as well as ocular and urogenital anomalies.


Pallister-Hall syndrome (PHS), a pleiotropic autosomal dominant malformative disorder, is characterized by hypothalamic hamartoma, pituitary dysfunction, bifid epiglottis, polydactyly, and, more rarely, renal abnormalities and genitourinary malformations.

Summary:
Epidemiology
Approximately 100 patients have been reported to date.
Clinical description
Most patients with PHS present at birth with skeletal polydactyly of the third or fourth digit or postaxial polydactyly; either may be accompanied by cutaneous syndactyly and nail dysplasia. Facial features may include a short nose, flat nasal bridge, and low-set, posteriorly angled ears. Cleft palate, cleft uvula and multiple buccal frenula have been reported in some patients. An asymptomatic bifid epiglottis is nearly pathognomonic, however, some patients present with more severe posterior laryngeal clefts leading to potentially fatal respiratory insufficiency. Hypothalamic hamartoma is often asymptomatic, however, it may be associated with panhypopituitarism. Acute primary adrenal insufficiency (see this term) may also occur in severe cases, as well as milder forms of adrenal insufficiency. Precocious puberty manifests in some cases. Neurological involvement can include gelastic epilepsy (seizures that manifest as facial grimacing, smiling or laughter) or other seizure types. Renal agenesis or dysplasia as well as other genitourinary anomalies have been reported, including vaginal atresia or hydrometrocolpos, microphallus, or cryptorchidism. Other findings may include intrauterine growth retardation, abnormal lung lobation, generalized skeletal dysplasia with mesomelic shortening and radial bowing of limbs, imperforate anus and congenital heart defects (see this term).
Etiology
PHS is due to mutations of the GLI3 gene (7p13) that encodes a transcription factor activated by the sonic hedgehog pathway. Mutations lead to alterations in gene expression during development.
Diagnostic methods
Clinical diagnostic criteria of patients with at least one family member with PHS require two findings: hypothalamic hamartoma, visualized on magnetic resonance imaging (MRI) as a non-enhancing, midline hypothalamic mass that is isointense to gray matter on all pulse sequences, and mesoaxial polydactyly. This may be confirmed by full sequence analysis of GLI3.
Differential diagnosis
Differential diagnoses include oral-facial-digital syndrome type 6, Holzgreve-Wagner-Rehder syndrome, McKusick-Kaufman syndrome, Holt-Oram syndrome, Bardet-Biedl syndrome, Smith-Lemli-Opitz syndrome, as well as craniopharyngioma, Greig cephalopolysyndactyly syndrome Ellis Van Creveld syndrome (see these terms) and congenital hypothalamic hamartoma syndrome.
Antenatal diagnosis
Antenatal genetic testing may be considered in families harboring a known PHS causative mutation of GLI3 and fetal MRI can exclude hypothalamic hamartoma. However, familial occurrences of PHS are generally milder than sporadic ones.
Genetic counseling
PHS is autosomal dominant, passed on to 50% of offspring, but expression is highly variable and many cases are sporadic, due to de novo mutations.
Management and treatment
Treatment is symptomatic. Medical imaging should include MRI to assess the hypothalamic hamartoma, X-rays of hands and feet and a full-skeletal survey as well as renal ultrasound. Laboratory assessment including a full endocrinological function and cholesterol synthesis analysis should be performed. At birth, breathing of patients with polydactyly should be monitored and indirect laryngoscopy should be performed. Tracheotomy may be necessary. If present, surgical intervention for imperforate anus must be undertaken. Multiple lifelong hormone replacement therapies may be required.
Prognosis
Prognosis should be assumed to be excellent until proven otherwise. However, in its most severe forms, panhypopituitarism and severe airway malformations can be lethal; imperforate anus may also be lethal if not recognized. Intellectual deficits and behavioral alterations have not been directly correlated with the syndrome.

                            Last update:
                            May 2013

                            - Expert reviewer(s):
                            Dr Leslie BIESECKER


Palmoplantar keratoderma, Nagashima type

A rare autosomal recessive, isolated diffuse palmoplantar keratoderma charactized by transgressive and nonprogressive palmoplantar keratoderma resembling a mild form of mal de Meleda.


Palmoplantar keratoderma-deafness syndrome is a keratinization disorder characterized by focal or diffuse palmoplantar keratoderma. A patchy distribution is observed with accentuation on the thenars, hypothenars and the arches of the feet. The disease becomes apparent in infancy and is associated with sensorineural hearing loss that shows a variable age of onset. Due to genetic and clinical similarities, it has been proposed that palmoplantar keratoderma-deafness syndrome, knuckle pads-leukonychia-sensorineural deafness-palmoplantar hyperkeratosis syndrome and keratoderma hereditarium mutilans may represent variants of one broad disorder of syndromic deafness with heterogeneous phenotype. The disease is transmitted in an autosomal dominant manner with incomplete penetrance.


Palmoplantar keratoderma-esophageal carcinoma syndrome

A rare genetic disease characterized by thickening of the skin on palms and soles restricted to areas of weight bearing and/or friction (focal, non-epidermolytic palmoplantar keratoderma) and oral and esophageal leukokeratosis, associated with a very high lifetime risk of developing squamous cell carcinoma of the esophagus. The skin lesions appear in childhood and can be complicated by fissuring and infection.


Palmoplantar keratoderma-hereditary motor and sensory neuropathy syndrome

A rare, genetic, autosomal dominant hereditary axonal motor and sensory neuropathy disorder characterized by childhood-onset palmoplantar keratoderma associated with motor and sensory polyneuropathy manifestating with late-onset, predominantly distal, lower limb muscle weakness and atrophy (later associating mild proximal weakness and upper limb involvement), moderate sensory impairment (hypoesthesia with stocking-glove distribution), and normal or near‐normal nerve conduction velocities. Additional variable manifestations include impaired vibratory sensation, reduced tendon reflexes, paresthesia, pain, talipes equinovarus, pes cavus, and nail dystrophy.


Palmoplantar keratoderma-spastic paralysis syndrome

A rare, genetic punctate palmoplantar keratoderma disease characterized by discrete, focal, punctate keratoderma on the palms and soles and/or slowly progressive spastic paralysis, predominantly affecting the lower limbs. Lesional histology reveals pronounced orthokeratosis, acanthosis, papillomatosis, and regular undulation to the surface keratin. There have been no further descriptions in the literature since 1983.


Palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome is characterised by sex reversal in males with a 46, XX (SRY-negative) karyotype, palmoplantar hyperkeratosis and a predisposition to squamous cell carcinoma. To date, five cases (four of whom were brothers) have been described. The aetiology is unknown.


A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by the association of pancreatic agenesis and lobar/semilobar holoprosencephaly. Insulin-dependent diabetes mellitus and pancreatic exocrine deficiency manifest early after birth. Additional reported manifestations include intrauterine growth retardation, muscle weakness, seizures, mild intellectual disability and dysmorphic craniofacial features, and agenesis of the gallbladder.


A rare disorder of lipid metabolism characterized by childhood onset of steatorrhea due to isolated pancreatic colipase deficiency, while other exocrine pancreatic enzymes are normal. Early formation of gallstones, as well as vitamin B12 deficiency with megaloblastic anemia have also been reported. There have been no further descriptions in the literature since 1982.


Pancreatic hypoplasia-diabetes-congenital heart disease syndrome

A rare, syndromic diabetes mellitus characterized by partial pancreatic agenesis, diabetes mellitus, and heart anomalies (including transposition of the great vessels, ventricular or atrial septal defects, pulmonary stenosis, or patent ductus arteriosis).


A rare syndromic mitochondrial disease characterized by exocrine pancreatic insufficiency, dyserythropoietic anemia, and calvarial hyperostosis.

Summary:
Epidemiology
It has been described in four children, three boys and one girl, from two consanguineous families.
Etiology
The disease is due to a mutation in the COX4I2 gene, encoding a mitochondrial cytochrome C oxidase sub-unit.
Genetic counseling
Transmission is autosomal recessive.

                            Last update:
                            October 2009


Pancreatic triacylglycerol lipase deficiency

A rare genetic disorder of lipid metabolism characterized by neonatal to childhood onset of impaired absorption of dietary fat with greasy/oily and voluminous stools, but normal growth and development. Decreased levels of fecal elastase, as well as low serum levels of the fat-soluble vitamins A, D, and E, have been reported.


A rare neoplastic gastroenterologic disease most often found in children, which usually presents with the non-specific symptoms of a palpable mass, vomiting, abdominal pain, jaundice, and weight loss/failure to thrive. Histologically, this malignant epithelial pancreatic neoplasm of the exocrine cells is characterized by multiple lines of differentiation (acinar, ductal, mesenchymal, neuroendocrine) and the presence of squamoid nests.

Summary:
Epidemiology
The incidence is less than 1/1,000,000 in Europe. Pancreatoblastoma accounts for 0.5% of all pancreatic exocrine tumors and occurs equally in females and males. It is the most common malignant pancreatic tumor in young children and has a mean age of diagnosis of 5 years.
Clinical description
Pancreatoblastoma most often presents in children under the age of 10 (mean of 5 years). Onset in adulthood (third/fourth decade) is extremely rare, and patients are more likely to develop metastases. Symptoms are often non-specific and include a large abdominal mass, abdominal distension/pain, failure to thrive, diarrhea, vomiting and jaundice. Tumors in the head of the pancreas can lead to mechanical obstruction of the upper duodenum and gastric outlet, as well as gastrointestinal bleeding. Local invasion and metastasis to the liver (most commonly), lungs and/or regional lymph nodes can often be discovered at diagnosis. Pancreatoblastoma can sometimes be associated with Beckwith-Wiedemann syndrome and familial adenomatous polyposis (FAP).
Etiology
The etiology is unknown but pancreatoblastoma can occur in any part of the pancreas. It is a malignant embryonal tumor that seems to recapitulate the embryogenesis of the pancreas, presumably because it originates from the pluripotent pancreatic stem cells during foregut development. Sporadic and FAP-associated pancreatoblastomas have frequent alterations in the adenomatous polyposis coli (APC)/beta-catenin pathway, and allelic loss in chromosome 11p.
Diagnostic methods
Diagnosis is based on histological characteristics. Pancreatoblastoma is usually a large (2 to 20 cm), encapsulated mass with a histological picture of multiple squamoid nests composed of whorls of spindle-shaped cells that are diagnostic of this tumor. It shows significant acinar cell differentiation but also ductal, mesenchymal and neuroendocrine differentiation. The tumor marker alpha-fetoprotein (AFP) is raised in 68% of cases, regardless of age. Full staging needs to be performed, including ultrasound and computed tomography (CT) or magnetic resonance imaging (MRI) scans of the primary tumor, as well as CT scans of the chest to detect any metastasis.
Differential diagnosis
Differential diagnoses include poorly differentiated adenocarcinomas, solid pseudopapillary tumors, pancreatic carcinoma, pancreatic neuroendocrine tumors and autoimmune pancreatitis.
Management and treatment
Treatment involves complete surgical resection of the tumor. Procedures include a distal pancreatectomy with or without splenectomy (for tumors in the body and tail of pancreas) and pancreaticoduodenectomy (for those in the head of the pancreas). Chemotherapy (usually cisplatin and doxorubicin) and radiotherapy are used in cases of unresectable, recurrent or metastatic tumors with variable results. In adults, 5-fluorouracil/doxorubicin/mitomycin and doxorubicin/carboplatin have been given as adjuvant therapy.
Prognosis
The prognosis for pediatric cases is usually good if the tumor is resectable, but recurrences still occur. If unresectable and in the presence of metastasis, pancreatoblastoma has an aggressive course and prognosis is poor. Adult cases usually have a poorer prognosis, with a median survival time of 15 months.

                            Last update:
                            August 2019

                            - Expert reviewer(s):
                            Pr Ewa BIEN  - Pr Bernadette BRENNAN


A rare syndrome with combined immunodeficiency characterized by a variable clinical presentation ranging from asymptomatic individuals to potentially life-threatening, recurrent bacterial infections associated with progressive loss of serum immunoglobulins and B cells.


A rare constitutional aplastic anemia characterized by progressive trilineage bone marrow failure (with hypocellularity), developmental delay with learning disabilities, and microcephaly. Mild facial dysmorphism and hypotonia have also been reported.


PANDAS is an acronym for Pediatric Autoimmune Neuropsychiatric Disorders Associated with a group A beta-hemolytic Streptococcal infection and applied to a subgroup of children with obsessive-compulsive disorder (OCD) and/or tic disorders.

Summary:
Epidemiology
The prevalence is unknown but the boy-to-girl ratio is 2.6:1.
Clinical description
The current diagnostic criteria for the PANDAS are: presence of OCD and/or a tic disorder, very young age at onset (prepubertal), sudden and dramatic onset of symptoms, association between streptococcal infections and episodic relapsing-remitting exacerbations manifesting as neuropsychiatric symptoms (motor hyperactivity or adventitious movements including choreiform movements or tics). The increased severity of symptoms usually persists for at least several weeks, but may last for several months or longer, followed by a slow, gradual improvement. The major distinctive feature of PANDAS is the temporal association between neuropsychiatric symptom exacerbations and streptococcal infections. Additional neuropsychiatric symptoms occur frequently: emotional lability, separation anxiety, anorexia, impulsivity, distractibility and motor hyperactivity characteristic of attention deficit hyperactivity disorder (ADHD). Comorbid disorders include major depression (36%), major dysthymia (6%) and separation anxiety disorder (20%).
Etiology
The etiology is uncertain. One theory is that streptococcal infections trigger an antibody response in some children that causes changes in the basal ganglia. No specific genetic factors have been identified.
Diagnostic methods
Diagnosis of PANDAS is clinical. Neuroimaging studies may reveal increased basal ganglia volumes.
Management and treatment
Management includes standard interventions for obsessive-compulsive and tic disorders: cognitive-behavioural therapy, reversal therapy in the case of tic disorders and pharmacologic therapy (neuropsychiatric drugs, antibiotics to prevent infections and intravenous immunoglobulin therapy).

                            Last update:
                            November 2006


A type of primary hypophysitis characterized by an inflammation of the entire pituitary gland. Common clinical presentation is diabetes insipidus with polyuria and polydipsia and partial or panhypopituitarism. Other symptoms may include headaches, nausea/vomiting, visual disturbances and fatigue.


A rare osteochondrosis of the capitellum of the humerus, characterized by involvement of the dominant upper limb and onset before the age of 10 years. It results from lateral compression injuries of the elbow typically occurring in children practising sports such as baseball and throw. It should be distinguished from osteochondritis dissecans of the capitellum, occurring later, in adolescents.


Panniculitis-induced localized lipodystrophy is a rare, acquired, localized lipodystrophy disorder characterized by eruption of tender, occasionally painful, erythematous nodules and plaques which enlarge radially and resolve into lipoatrophic lesions, often located in the upper and lower limbs. Histologically, lesions are characterized by lipophagic, lobular panniculitis and absence of vasculitis.


Pantothenate kinase-associated neurodegeneration (PKAN) is the most common type of neurodegeneration with brain iron accumulation (NBIA; see this term), a rare neurodegenerative disorder characterized by progressive extrapyramidal dysfunction (dystonia, rigidity, choreoathetosis), iron accumulation on the brain and axonal spheroids in the central nervous system.

Summary:
Epidemiology
Prevalence is estimated at 1-2/1,000,000.
Clinical description
Classic PKAN (75% of cases) is characterized by early onset, usually before six years of age, and rapid progression. Atypical PKAN (25% of cases) has later onset, between 13 and 14 years of age, and slower progression. Patients present with symptoms anywhere along a continuum between the two. In classic PKAN, patients present with impaired gait and falling, often related to dystonia, rigidity, impaired balance, or spasticity, and usually lose the ability to ambulate by 10-15 years after onset. Episodes of rapid decline, which may include status dystonicus, occur interspersed with longer periods of relative stability. Developmental delay (primarily motor, sometimes global) may occur. Patients frequently develop pigmentary retinal degeneration and dysarthria. Later in disease course common complications include dysphagia, gastro-oesophageal reflux, chronic constipation, aspiration pneumonia and malnutrition. In atypical PKAN, patients present with speech difficulty, mild gait abnormalities, prominent psychiatric symptoms that may include depression, emotional lability, impulsivity, or violent outbursts, pigmentary retinal degeneration (less frequently than in classic PKAN) and both verbal and motor tourettism. Motor involvement is generally less severe and loss of ambulation occurs within 15-40 years of onset. The association of hyperprebetalipoproteinemia, acanthocytes and retinitis pigmentosa (HARP syndrome) is within the PKAN spectrum.
Etiology
PKAN is caused by mutations in the PANK2 gene (20p13-p12.3).
Diagnostic methods
PKAN is usually suspected following MRI evidence of the classic `eye-of-the-tiger' sign, a central region of hyperintensity surrounded by a rim of hypointensity on coronal or transverse T2-weighted images of the globus pallidus. Genetic analysis is required to confirm diagnosis.
Differential diagnosis
Differential diagnoses include Wilson disease (see this term), which is excluded by normal plasma ceruloplasmin concentration or copper metabolism, and other types of NBIA, which can be differentiated using MRI findings and genetic testing.
Antenatal diagnosis
Prenatal testing is available if both disease-causing mutations have been identified in an affected family member.
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Treatment aims to alleviate symptoms, including baclofen (oral or intrathecal pump) and trihexyphenidyl for dystonia and spaciticy, and botulinum toxin for patients whose quality of life is improved by treating a limited body region. Patients with PKAN do not typically benefit from L-dopa. Deep brain stimulation (DBS) may relieve some symptoms. Frequent contact with patients and treatment adjustments are required to maintain as high a quality of life as possible. Dietary assessment, gastrostomy tube feeding and dental extraction (in cases with severe orobuccolingual dystonia) may be required.
Prognosis
PKAN is a progressive disorder and lost skills are usually not regained. Rate of progression correlates with age at onset; those with early symptoms decline more rapidly. Life span is variable but premature death does occur.

                            Last update:
                            March 2010

                            - Expert reviewer(s):
                            Dr Allison GREGORY  - Pr Susan HAYFLICK


Pyogenic arthritis-pyoderma gangrenosum-acne syndrome is a rare pleiotropic autoinflammatory disorder of childhood, primarily affecting the joints and skin.

Summary:
Epidemiology
To date, only 34 patients with PAPA syndrome have been reported worldwide, from five families (two in the USA, one in Italy, one in the Netherlands, and one in New Zealand).
Clinical description
The first affected family contained ten affected members from three generations and manifested variable expression of a pauciarticular, nonaxial, arthritis that began in childhood; pyoderma gangrenosum; and severe cystic acne in adolescence and beyond. PAPA syndrome is a self-limiting disease, but it can lead to severe joint destruction. Synovial fluid is purulent with neutrophil accumulation, but cultures are invariably negative. Recurrent sterile arthritis usually occurs after minor trauma, but can also occur spontaneously. Other less commonly associated features include adult-onset insulin-dependent diabetes mellitus, proteinuria, and abscess formation at the site of parenteral injections (pathergy).
Etiology
The gene responsible for the syndrome, the proline-serine-threonine phosphatase interacting protein 1 (PSTPIP1) gene (previously known as the CD2 binding protein 1 (CD2BP1) gene), was cloned in 2002. Only two mutations account for the known cases. Recently, the PSTPIP1 protein has been demonstrated to bind pyrin/marenostrin (P/M), the protein encoded by the MEFV gene, mutations in which cause Familial Mediterranean Fever. PAPA-associated PSTPIP1 mutants exhibit increased binding to P/M.
Differential diagnosis
Differential diagnosis for PAPA syndrome should include juvenile idiopathic arthritis and periodic fever.
Genetic counseling
PAPA syndrome is inherited in an autosomal dominant manner.
Management and treatment
Arthritis and skin lesions have sometimes been reported to be responsive to glucocorticoids. However, two alternative therapeutics have been suggested so far. In one report, the disease underwent rapid and sustained clinical remission after treatment withthe tumor necrosis factor inhibitor, etanercept. Another recent paper described the effect of recombinant human interleukin (IL)-1 receptor antagonist (anakinra), which appeared to be an effective therapy to treat disease flares in PAPA syndrome.

                            Last update:
                            October 2006

                            - Expert reviewer(s):
                            Pr Isabelle TOUITOU


A rare mixed neuronal-glial tumor characterized by a supratentorial space-occupying lesion in periventricular location, often with prominent cystic change. The histological hallmark of this low-grade neoplasm is its pseudopapillary appearance with a single layer of cuboidal cells around hyalinized blood vessels, associated with sheets or focal collections of neuronal cells. Clinical presentation is variable and non-specific, most frequently with headache and seizures. Prognosis is favorable after complete resection.


A rare vascular tumor characterized by an ill-defined, slowly growing, asymptomatic cutaneous plaque or nodule mostly involving the limbs, in fewer cases the trunk. The tumor is composed of lymphatic-like channels with prominent intraluminal papillary tufts with hyaline cores lined by hobnail endothelial cells. It is locally aggressive, while metastasis is rare. Infants and children are much more often affected than adults.


Papillary renal cell carcinoma is a rare subtype of renal cell carcinoma, arising from the renal tubular epithelium and showing a papillary growth pattern, which typically manifests with hematuria, flank pain, palpable abdominal mass or nonspecific symptoms, such as fatigue, weight loss or fever. Symptoms related to metastatic spread, such as bone pain or persistent cough, are frequently associated since early diagnosis is not common. It is typically multifocal, bilateral, and in most cases sporadic, although different hereditary syndromes, such as Hereditary leiomyoma renal cell carcinoma, Birt-Hogg-Dubé syndrome and Tuberous sclerosis, may predispose to the development of papillary renal cell carcinoma.


Papillary tumor of the pineal region (PTPR) is a very rare neoplasm of the pineal region that is thought to arise from the specialized ependymocytes of the subcommissural organ and that manifests with visual disturbances, headaches, loss of coordination and balance, nausea and vomiting due to obstructive hydrocephalus.


A rare benign type of choroid plexus tumor often occurring in the fourth ventricle (in adults) and the lateral ventricle (in children) but sometimes arising ectopically in the brain parenchyma, and presenting with nausea, vomiting, papilledema, abnormal eye movements, as well as enlarged head circumference, seizures and gait impairment due to an increase in intracranial pressure.


Papillon-Lefèvre syndrome (PLS) is a rare ectodermal dysplasia characterized by palmoplantar keratoderma associated with early-onset periodontitis.

Summary:
Epidemiology
The prevalence is estimated between 1/250,000 and 1/1,000,000 individuals. The male to female ratio is 1:1. PLS is found in all ethnic groups.
Clinical description
Diffuse palmoplantar keratoderma (see this term) with erythematous plaques develops between the first and fourth years of life, with the soles being usually more severely affected than the palms. Psoriasiform hyperkeratosis can overflow onto the dorsal surfaces of the hands and feet (transgredient spread) and, less frequently, lesions can be seen on the limbs (knees, elbows). Skin lesions are followed by intense gingivitis that rapidly progresses into periodontitis with alveolar bone lysis and early loss of primary dentition. The skin lesions are aggravated by cold and during episodes of severe periodontitis. During childhood, the phenomenon of periodontal disease recurs with rapid loss of permanent dentition. Cases of PLS with mild and/or late-onset periodontal disease have been reported occasionally. PLS is accompanied, in half of the patients, by enhanced susceptibility to cutaneous and systemic infections (furunculosis, skin abscesses, pyoderma, hidradenitis suppurativa (see this term), respiratory tract infection...). Patients may also present with malodorous hyperhidrosis, follicular hyperkeratosis, nail dystrophy or dural calcifications. The association of PLS with malignant melanoma or squamous cell carcinoma has been reported in very rare occasions.
Etiology
PLS is due to mutations in the CTSC gene (11q14.2) that codes for cathepsin C (also known as dipeptidyl peptidase I), a lysosomal protease playing a role in epidermal differentiation and desquamation and in activation of serine proteases expressed in cells of the immune system. CTSC mutations lead to an almost total loss of cathepsin C activity which seems to result in susceptibility to specific virulent pathogens. It is also suggested that other immune-mediated deficiencies in the host defense mechanism could be involved in the pathogenesis of PLS.
Diagnostic methods
Diagnosis is based on clinical signs. Dental radiography shows atrophy of the alveolar bone. Neutrophil function tests reveal anomalies of chemotaxis and phagocytosis by polymorphonuclear leukocytes. Skin biopsy shows hyperkeratosis with focal parakeratosis, moderate perivascular infiltration, hypergranulosis, and acanthosis. Biochemical analysis reveals a loss of CTSC activity. Diagnosis is confirmed by genetic testing.
Differential diagnosis
Differential diagnosis includes two rare disorders that are allelic variants of PLS, Haim-Munk syndrome (see this term) and prepubertal/aggressive periodontitis. Other diseases with similar dermatologic features include localized epidermolytic palmoplantar keratoderma (Vörner), mal de Meleda, Howel-Evans syndrome, transgrediens et progrediens palmoplantar keratoderma (Greither's disease) (see these terms), and keratosis punctata.
Antenatal diagnosis
Antenatal diagnosis is theoretically possible but has never been reported.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to the parents of an affected individual informing them of the 25% risk their offspring has of inheriting the disease causing mutation.
Management and treatment
Treatment is based on oral retinoids which attenuate the palmoplantar keratoderma and slow the alveolar bone lysis. Antibiotics, along with oral hygiene and use of mouth rinses, are also recommended for slowing the progression of periodontitis. Ultimately, primary or remaining teeth are extracted and are replaced by dental implants. Antibiotherapy is also used in the treatment of recurrent infections. Etretinate (a synthetic retinoid) shows promising results in the treatment of PLS.
Prognosis
Despite meticulous dental care, all patients eventually become edentulous at the beginning of adulthood. Life expectancy is normal.

                            Last update:
                            November 2012

                            - Expert reviewer(s):
                            Dr Fanny MORICE-PICARD  - Pr Alain TAIEB


A rare, acquired, dermis elastic tissue disorder characterized by multiple, asymptomatic, firm, well-demarcated, nonfollicular, hypopigmented or skin-colored papules, with a diameter of less than 1 cm, distributed symmetrically over trunk and/or proximal limbs (rarely, head, neck, shoulders, armpits, thighs), with no extracutaneous manifestations. Histopathology typically reveals decreased and fragmented elastic fibers, thickened and/or homogenized collagen bundles and, in some, a mild, perivascular, lymphocytic infiltrate in the dermis.


Papular mucinosis of infancy is a rare pediatric non progressive form of localized lichen myxedematosus (see this term) characterized by the development of firm opalescent mucinous papules on the upper arms and the trunk.


Papular xanthoma is a form of non-Langerhans cell histiocytosis characterized by cutaneous presentation of solitary or disseminated yellow to orange-brown papular or papulonodular, noncoalescent, asymptomatic skin lesions located predominantly on the head, neck, trunk and extremities (rarely on oral mucosa), in the presence of normolipidemia. Microscopically, the lesions consist of monomorphous infiltrate of xanthomatized macrophages and numerous Touton giant cells, with scant or absent inflammatory infiltrate. It is usually not associated with systemic disease.


A rare intoxication due to a medical product occurring as a result of accidental or intentional overdosing of paracetamol (acetaminophen). Patients may develop gastroenteritis within hours and hepatotoxicity within 24 to 72 hours after ingestion, potentially leading to acute liver injury and liver failure. Possible non-hepatic sequelae include renal failure, thrombocytopenia, pancreatitis, and subendocardial myocyte necrosis. Chronic paracetamol poisoning may be asymptomatic or include all signs and symptoms potentially occurring in acute poisoning.


Parachute tricuspid valve is a rare congenital heart malformation defined as an insertion of the chordal apparatus into a single papillary muscle or a muscle group, making a pathognomonic 'pear' shape sign in the four-chamber echocardiographic view with the atrium forming the larger base of the pear and the leaflets the apex. Isolated parachute tricuspid valve may be asymptomatic or present with symptoms of tricuspid stenosis (diastolic inspiratory murmur, pulsation of jugular veins, hepatomegaly, edema, epigastric discomfort, right atrial enlargement, right ventricular hypertrophy, electrocardiography abnormalities). It may also be associated with other heart malformations and present with symptoms of the complex of malformations.


A rare mycosis characterized by an acute form mostly occurring in children and young adults presenting with fever, weight loss, lymph node enlargement, hepatosplenomegaly, and bone marrow dysfunction, versus a chronic form which usually involves the lungs and mucosae of the upper respiratory tract, skin, lymph nodes, and adrenal glands, but may affect any part of the body. The most common sequelae are chronic respiratory insufficiency and Addison's disease. The infectious agent, Paracoccidioides brasiliensis, is a fungus limited to Latin America.


Paramedian nasal cleft is a rare developmental defect during embryogenesis characterized by a unilateral or bilateral coloboma of the nose, ranging in severity from a small notch, resulting in minor deviation of the nasal septum, to variable-sized clefts of the nasal ala which may be associated with small cysts or sinuses in the nasal midline. Defect may be isolated or may occur in association with cleft lip and/or other craniofacial anomalies (e.g. hypertelorism, broadening of nasal root, midline cleft). Dorsum and apex of nose are usually well preserved.


A rare genetic skeletal muscle ion channel disorder, part of the non-dystrophic myotonias, characterized by exercise and/or cold-exacerbated myotonia.

Summary:
Epidemiology
The exact prevalence is unknown but is estimated to be < 1/100,000 people in Europe (0.17/100,000 in UK).
Clinical description
Symptoms usually manifest in the first decade of life with an usual onset in early childhood. The major clinical manifestation is episodic muscle stiffness as a consequence of myotonia which, in paramyotonia congenita (PC), is called « paradoxical » because of its worsening with repeated exercice. Muscle stiffness commonly follows severe attacks of stiffness in case of prolonged exercise and/or prolonged cold exposure, it presents an extreme cold sensitivity and can be also exacerbated by other factors, like fasting and some hormonal conditions (menstruation, pregnancy). Myotonia can last seconds to minutes whereas weakness may persist for hours, even if the muscles are rewarmed. Facial, tongue, and hand muscles are predominantly affected whereas the lower limbs are generally only mildly affected.
Etiology
PC is a muscle sodium channelopathy due to missense mutations of the SCN4A gene (17q23.3) encoding the alpha subunit of the skeletal muscle voltage-gated sodium channel Nav1.4. Pathological variants of SCN4A lead to an increased membrane excitability. The rapid inactivation phase of the sodium channels, which normally follows muscle contraction, is altered. The sodium channels are prematurely reactivated, and new action potentials are generated, resulting in myotonic bursts.
Diagnostic methods
Diagnosis is based on clinical history, physical exam, electromyographic and genetic tests. EMG records myotonic discharges and reveals specific muscle excitability anomalies after provocative test, showing gradual decrease of compound motor muscle action potential (CMAP) after repeated short exercise tests at room temperature and after cooling. CPK levels vary depending on the myotonia severity. Long exercise test may show progressive and prolonged decrease in the amplitude of CMAPs. Muscle biopsy is not useful for diagnosis. It can reveal a vacuolar myopathy in case of associated attacks of weakness.
Differential diagnosis
The differential diagnosis includes the other non-dystrophic myotonic syndromes such as Thomsen and Becker disease, other sodium channel myotonias, and hyperkalemic periodic paralysis with paradoxical myotonia.
Antenatal diagnosis
Prenatal and preimplantation genetic testing are possible when the pathogenic variant has been identified in an affected family member, but are rarely performed because of the non life-threatening prognosis.
Genetic counseling
PC is transmitted as an autosomal dominant disease with a complete penetrance. Sporadic cases and de novo mutations have been reported. Genetic counseling should be offered to patients informing them that there is a 50% risk of having an affected child at each pregnancy.
Management and treatment
Management of patients consists in medical therapy and avoidance of triggering factors (cold exposure, fasting and strenuous/prolonged exercice). Muscle stiffness (myotonia) responds well to sodium channel blockers. Mexiletine or carbamazepine are treatments of choice. Acetazolamide can be useful to prevent attacks of weakness and may also improve myotonia in some cases. Physiotherapy with massages and stretching may be useful against pain and retractions. Close monitoring is necessary during surgery and anesthesia. Depolarizing agents can induce masseter spasms and stiffness of respiratory and other muscles and can therefore impair intubation and mechanical ventilation. Depolarizing muscle relaxants are therefore contraindicated. Myotonic patients are considered to be susceptible to malignant hyperthermia; volatile anesthetics and suxamethonium should be prohibited.
Prognosis
Prognosis is good and symptoms are stable during life. There is no impact on life expectancy. Even if the disease is nonprogressive and not life-threatening, the disability resulting from the symptoms can have a significant functionnal impact on daily life activities, affecting quality of life, personal, social, and professional spheres.

                            Last update:
                            July 2023

                            - Expert reviewer(s):
                            Dr Savine VICART | EURO-NMD* - Dr Nur VILLAR | EURO-NMD*

                                * European Reference Network


A rare genetic skin disorder characterized by very early-onset of progressive skin thickening over the entire body (except for eyelids, neck and ears), progressively limited joint mobility with gradual freezing of joints, and eventual severe chest and abdomen movement restriction, manifesting with restrictive pulmonary disease, which may lead to death. Additional features include severe growth restriction and osteoporosis. There have been no further descriptions in the literature since 1974.


Paraneoplastic neurological syndromes (PNS) can be defined as remote effects of cancer that are not caused by the tumor and its metastasis, or by infection, ischemia or metabolic disruptions.

Summary:
Epidemiology
PNS are rare, affecting less than 1/10,000 patients with cancer.
Clinical description
Only the Lambert-Eaton myasthenic syndrome is relatively frequent, occurring in about 1% of patients with small cell lung cancer. The other most common PNS are subacute cerebellar ataxia, limbic encephalitis (LE), opsoclonus-myoclonus (OM), retinopathies (cancer-associated retinopathy (CAR) and melanoma-associated retinopathy (MAR), Stiff-Person syndrome (SPS), chronic gastrointestinal pseudoobstruction (CGP), sensory neuronopathy (SSN), encephalomyelitis (EM) and dermatomyositis (see these terms). PNS can affect any part of the central or peripheral nervous system, the neuromuscular junction, and muscle. They can be isolated or occur in association. PNS are usually severely disabling.
Etiology
They are caused by autoimmune processes triggered by the cancer and directed against antigens common to both the cancer and the nervous system (onconeural antigens).
Diagnostic methods
In most patients, the neurological disorder develops before the cancer becomes clinically overt and the patient is referred to the neurologist for identification of the neurological disorder as paraneoplastic. Due to their high specificity, the best way to diagnose a neurological disorder as paraneoplastic is to identify one of the well-characterized anti-onconeural protein antibodies in the patient's serum. In addition, as these antibodies are associated with a restricted range of cancers, they can guide the search for the underlying tumor at a stage when it is frequently not clinically overt.
Management and treatment
This is a critical point as, to date, the best way to stabilize PNS is to treat the cancer as soon as possible. Unfortunately, about one-third of patients do not have detectable antibodies and 5% to 10% have an atypical antibody that is not well-characterized. As PNS are believed to be immune-mediated, suppression of the immune response represents another treatment approach.

                            Last update:
                            May 2007

                            - Expert reviewer(s):
                            Pr Jean-Christophe ANTOINE  - Pr Jérôme HONNORAT


A rare form of autoimmune bullous skin disease characterized by polyformative skin lesions, typically beginning on the oral mucus membranes, and generally associated with lymphoma or chronic lymphoid leukemia.

Summary:
Epidemiology
The prevalence of this form of pemphigus is unknown. About 500 cases of paraneoplastic pemphigus have been reported worldwide in the literature. This form accounts for 3-5% of all pemphigus cases.
Clinical description
Paraneoplastic pemphigus occurs in a background of suspected or proven neoplasia. The associated cancers are mostly lymphomas, chronic lymphoid leukaemia and in some cases, Kaposi sarcoma, Castelman's disease, thymomas, carcinomas, and poorly differentiated sarcomas. The disease almost always begins with severe diffuse blisters in the mouth, on the lips and on the oesophagus. Eyes are frequently involved. Skin lesions vary and can be misleading, presenting as bullous lichenoid lesions, evocative of urticaria or polymorphous erythema. Lungs can also be involved (in 30% to 40% of cases), as well as the gastrointestinal tract.
Etiology
The etiology and pathogenesis of paraneoplastic pemphigus are poorly understood.
Diagnostic methods
Histopathological analysis shows intra-epidermal acantholysis with the presence of necrotic keratinocyte cells, vacuolisation of the basal layer and dermic lichenoid inflammatory infiltrate. Direct immunofluorescence test usually shows granular-linear IgG and/or C3 deposits in the epidermal intercellular spaces, and/or at the dermo-epidermal junction (basement membrane zone). IgA and IgM can also be detected. Anti-plakine antibodies can be present (desmoplakin, periplakin, envoplakin), as well as anti-plectin, anti-desmoglein 1 and 3 antibodies, anti-BP180, and anti-BP230 antibodies.
Differential diagnosis
Differential diagnosis includes some forms of bullous pemphigoid, pemphigus vulgaris, drug-induced rash (toxic epidermal necrolysis, Stevens-Johnson syndrom), erythema multiforme, Graft Versus Host Disease (GVHD), lichen planus, or major aphthous stomatitis.
Management and treatment
The progression of paraneoplastic pemphigus rarely parallels neoplastic progression. The most commonly used treatment is systemic corticosteroids, but immunosuppressant drugs are often required. Some patients have been treated with intravenous immunoglobulin, plasmapheresis, and monoclonal antibodies. However, the efficacy of treatment varies depending on the underlying malignancy.
Prognosis
Paraneoplastic pemphigus is often fatal (in 90% of cases), however, the prognosis depends on the nature of the underlying malignancy and is improved when the associated tumor is benign. The high mortality rate is explained by the occurrence of severe infections (sometimes due to immunosuppressive drugs), the evolution of the underlying malignancy, or bronchiolitis obliterans which is related to the autoimmune response in paraneoplastic pemphigus.

                            Last update:
                            May 2020

                            - Expert reviewer(s):
                            Dr Marion CASTEL | ERN-Skin* - Pr Pascal JOLY | ERN-Skin*

                                * European Reference Network


A rare ophthalmic disorder characterized by a non-infectious uveitis potentially involving all parts of the uveal tract and due to a paraneoplastic autoimmune reaction. The signs and symptoms usually precede the tumor diagnosis and may include ocular redness and pain, light sensitivity, blurred vision, floaters, and decreased vision. The most classic form is the intermediate uveitis associated with anti-CV2 antibodies in small-cell lung cancer or other neoplasms. Other ocular and/or extra-ocular manifestations are commonly present in addition.


Paraparetic variant of Guillain-Barré syndrome is a rare variant of Guillain-Barré syndrome characterized by isolated leg weakness, areflexia and radicular leg pain that may simulate a cauda equina or spinal cord syndrome. The arms, ocular, facial, and oropharyngeal muscles are spared, and sphincteric function is normal.


A rare X-linked syndromic intellectual disability characterized by intellectual impairment of variable severity, progressive lower limb spasticity, and diffuse palmoplantar hyperkeratosis. Additional manifestations include pes cavus, extensor plantar responses, hand tremor, and mild dysmorphic facial features.


A rare intoxication with paraquat (a non-selective bipyridilium herbicide that has been banned in Europe), usually occurring through ingestion of the poison, and that presents with caustic injury of the oral cavity and pharynx, as well as nausea, vomiting, epigastric pain, lethargy, loss of consciousness and fever. Patients may develop potentially life-threatening complications such as hepatic dysfunction, acute tubular necrosis and renal insufficiency, and respiratory failure (due to pulmonary fibrosis) due to its inherent toxicity and lack of effective treatment. Intoxication via inhalation, injection and dermal or mucus contact have also been reported.


A rare, locally invasive or malignant, urogenital tumor characterized by a gland-forming epithelial neoplasm arising from paratesticular structures, typically manifesting with a palpable scrotal mass, with or without hydrocele, and/or testicular pain.


A rare endocrine tumor characterized by a malignant neoplasm derived from parathyroid parenchymal cells, localized in one of the normally located parathyroid glands or other sites where parathyroid tissue may be present. Signs and symptoms are predominantly due to excess secretion of parathyroid hormone, with marked hypercalcemia and renal and bone involvement. In rare cases, the tumor may be non-functioning and only present as a palpable mass in the neck region. Recurrent laryngeal nerve paralysis is also observed. The tumor can occur sporadically or on a genetic background. The extent of invasion of adjacent structures positively correlates with the development of recurrent or metastatic disease.


A rare form of salmonellosis caused by Salmonella enterica serovar Paratyphi A, B and C, characterized by typical symptoms of enteric fever including high fever, headache, abdominal pain and intestinal symptoms, dry cough, chills, and rashes, followed by a long period of recovery. The infection can be complicated by intestinal hemorrhage and perforation, as well as cardiac involvement, and may even be fatal. Transmission of the pathogen is via the fecal-oral route, with humans as the sole reservoir of infection.


PARC syndrome is a rare genetic developmental defect during embryogenesis syndrome characterized by the association of congenital poikiloderma (P), generalized alopecia (A), retrognathism (R) and cleft palate (C). There have been no further descriptions in the literature since 1990.


A rare hepatic disease characterized by intrahepatic cholestasis and deterioration of liver function in patients receiving parenteral nutrition for extended periods of time (signs may appear as early as within the first two weeks of initiation of parenteral nutrition). The condition commonly occurs in neonates and usually resolves with transition to enteral feeding, although severe cases may progress to liver fibrosis, cirrhosis, and portal hypertension.


Parietal foramina with clavicular hypoplasia

A rare genetic bone development disorder characterized by parietal foramina in association with hypoplasia of the clavicles (short abnormal clavicles with tapering lateral ends, with or without loss of the acromion). Additional features may include mild craniofacial dysmorphism (macrocephaly, broad forehead and frontal bossing). No dental abnormalities were reported.


Paris-Trousseau thrombocytopenia (TCPT) is a contiguous gene syndrome characterized by mild bleeding tendency, variable thrombocytopenia (THC), dysmorphic facies, abnormal giant alpha-granules in platelets and dysmegakaryopoiesis.


A rare congenital complex vascular malformation syndrome characterized by overgrowth of a limb (most commonly a leg) involving bones and soft tissue, in association with capillary malformations usually in the form of port-wine stains and multiple arteriovenous fistulas with high-flow arteriovenous shunting. The latter can also lead to other severe complications including abnormal bleeding and heart failure. Lymphatic malformations may also be present.


A rare neurodegenerative disease characterized by extrapyramidal symptoms (rigidity, tremor, bradykinesia) and dementia, typically beginning in the fifth or sixth decade of life and progressing to a vegetative state with pelvicrural flexion contractures within few years. Oculomotor signs, olfactory dysfunction, and autonomic disturbances may also be observed. Neuropathological hallmarks are frontotemporally accentuated cerebral atrophy, as well as neurofibrillary tangles and neuronal loss in a characteristic distribution in cortical and subcortical regions. The disease is endemic to the Pacific island of Guam.


Parkinsonian-pyramidal syndrome is a rare, genetic, neurological disorder characterized by the association of both parkinsonian (i.e. bradykinesia, rigidity and/or rest tremor) and pyramidal (i.e. increased reflexes, extensor plantar reflexes, pyramidal weakness or spasticity) manifestations, which vary according to the underlying associated disease (e.g. neurodegenerative disease, inborn errors of metabolism).


Paroxysmal cold hemoglobinuria (PCH) is a very rare subtype of autoimmune hemolytic anemia (AIHA, see this term), caused by the presence of cold-reacting autoantibodies in the blood and characterized by the sudden presence of hemoglobinuria, typically after exposure to cold temperatures.

Summary:
Epidemiology
PCH is thought to account for at most 2-10% of cases of AIHA, whose annual incidence is estimated to be between 1/35,000-1/80,000 in North America and Western Europe.
Clinical description
Acute cases almost exclusively affect children and are often preceded by symptoms of infection. Chronic idiopathic cases also occur but are extremely rare. Acute cases of the disease are characterized by an abrupt onset with features of severe intravascular hemolysis including high fever, chills, back and/or leg pain. Other symptoms may include nausea, headache, vomiting and diarrhea. Typically hemoglobinuria occurs, producing dark red to black urine. Hemolysis can be severe and even life-threatening and results from exposure to cold, which may even be localized (eg from drinking cold water, from washing hands in cold water). Chronic forms of PCH are characterized by recurrent episodes of hemolysis precipitated by cold exposure.
Etiology
PCH is most often acute and occurs secondary to an infection, mainly upper respiratory, and the causative agent is often not identified. Late-stage or congenital syphilis was historically linked to cases of PCH in adulthood but this is becoming less and less common.
Diagnostic methods
Diagnosis is based on evidence of anemia linked to hemolysis, the presence of hemoglobin in urine, a positive result from the Donath-Landsteiner (DL) test and evidence of anti-P specificity of the IgG autoantibodies.
Differential diagnosis
The main differential diagnosis is acute cold AIHA (see this term) induced by an infection (for example Mycoplasma pneumoniae or the Epstein Barr virus) due to the presence of IgM autoantibodies which are cold agglutinins.
Management and treatment
Most cases of PCH are self-limited so treatment is usually symptomatic, including keeping the patient warm and red blood cell transfusion if necessary. Patients with few clinical symptoms and slight anemia may not require drug therapy. Corticosteroids and splenectomy are usually ineffective and should not be considered. In cases of life-threatening PCH, plasmapheresis can temporarily dampen the hemolysis. Some patients may respond to rituximab, although responses are usually short-lived. If syphilis is present, treatment with antibiotics generally eliminates the concurrent hemolysis.

                            Last update:
                            August 2010

                            - Expert reviewer(s):
                            Pr Marc MICHEL


Paroxysmal dyskinesia (PD) is a rare heterogenous group of movement disorders manifesting as abnormal involuntary movements that recur episodically and last only a brief time. PD includes paroxysmal kinesigenic dyskinesia (PKD), paroxysmal non-kinesigenic dyskinesia (PNKD), paroxysmal exertion-induced dyskinesia (PED) and a variant form of PKD, infantile convulsion and choreoathetosis (ICCA syndrome) (see these terms).

Summary:
Epidemiology
The prevalence of PD is still unknown. The worldwide prevalence of PKD and PNKD is estimated to be 1/150,000 and 1/1,000,000 respectively.
Clinical description
The age of onset is typically in childhood. The paroxysmal movements are mainly dystonic and choreic but can be ballistic or a mixture of these. There is no alteration in consciousness. PD can be classified according to duration and precipitating factors and is thus divided into: paroxysmal kinesigenic dyskinesia (PKD), paroxysmal non-kinesigenic dyskinesia (PNKD) and paroxysmal exertion-induced dyskinesia (PED). Between attacks, patients are generally completely normal and neurological examination is typically normal. Infantile convulsion and choreoathetosis (ICCA syndrome) is considered a variant form of PKD.
Etiology
The exact etiology of PD is still elusive and the causes multifactorial. A number of genes have been associated with different forms of PD, namely: PNKD (2q35) mutations have been found to cause PNKD in families whose attacks can be triggered by caffeine and alcohol, PRRT2 (16p11.2) mutations account for some families with PKD or ICCA syndrome, and SLC2A1 (solute carrier family 2 (facilitated glucose transporter), member 1) (1p34.2 ) mutations have been identified to cause PED.
Diagnostic methods
Diagnosis of PD is essentially based on medical history and clinical examination which includes recordings of dystonia, abnormal postures and tremor, electroencephalogram, brain imaging (computed tomography or magnetic resonance imaging) and blood chemistry. Diagnosis is confirmed by the detection of known pathogenic mutations.
Differential diagnosis
PD can occur secondary to other disorders such as multiple sclerosis, Aicardi-Goutières syndrome (see these terms), myelopathy, cerebral palsy, cerebral infarcts and hemorrhages, focal seizures, encephalitis, radiculopathy, hypoparathyroidism, hypoglycemia and reflex sympathetic dystrophy.
Antenatal diagnosis
Prenatal diagnosis for pregnancies at increased risk for PRRT2, PNKD, and SLC2A1 mutations associated with familial PKD or ICCA syndrome, PNKD, and PED respectively is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at 15-18 weeks' gestation) or chorionic villus sampling (usually performed at 10-12 weeks' gestation). The disease-causing mutation of an affected family member must be identified in the family before prenatal testing can be performed.
Genetic counseling
PD can be sporadic or familial with autosomal dominant inheritance. Genetic counseling should be offered to all patients and families.
Management and treatment
Treatment is different for each of the 4 subtypes. Attacks may be controlled with anticonvulsant drugs such as carbamazepine and phenytoin. Deep brain stimulation may act as a potential therapeutic option in medically refractory PD.
Prognosis
The frequency of attacks typically diminishes with age in the familial cases and the disease often completely remits. There are no long term implications for life expectancy.

                            Last update:
                            November 2013

                            - Expert reviewer(s):
                            Dr Sian SPACEY


Paroxysmal dystonic choreathetosis with episodic ataxia and spasticity

A rare, genetic, paroxysmal dystonia disorder characterized by childhood to adolescent-onset of episodic paroxysmal choreoathetosis, triggered mainly by sudden movements, prolonged exercise, anxiety and emotional stress, in association with progressive spastic paraparesis (onest in adulthood), gait ataxia, mild to moderate cognitive impairment, and/or epileptic seizures. Episodes typically last from a few minutes to hours, have a variable frequency (daily to yearly), and are relieved by rest. Frequency of episodes tends to decrease with age.


Paroxysmal exertion-induced dyskinesia (PED) is a form of paroxysmal dyskinesia (see this term), characterized by painless attacks of dystonia of the extremities triggered by prolonged physical activities.

Summary:
Epidemiology
The prevalence is unknown but 20 sporadic cases and 9 families have been described to date.
Clinical description
The age of onset is usually in childhood, but may range from 1 to 30 years. PED is characterized by dyskinesias induced by prolonged exercise of 15-60 minutes of duration. The attacks last between 5 minutes and 2 hours and are typically restricted to the exercised limbs. The dystonic movements are usually bilateral and are aggravated by cold, psychological stress, fatigue and lack of sleep. The frequency of attacks varies between one per day to one per month. Brisk, deep tendon reflexes, developmental delay and intellectual disability (most frequently mild) may also be observed. In some familial forms, epilepsy or migraine can co-occur. PED can be associated with paroxysmal dystonic choreathetosis with episodic ataxia and spasticity, benign familial infantile seizures (BFIE), infantile convulsions and choreoathetosis (ICCA syndrome) or rolandic epilepsy - paroxysmal exercise-induced dystonia - writer's cramp (see these terms).
Etiology
The pathophysiology of PED is still unknown but some familial cases were found to be associated with mutations in the SLC2A1 (solute carrier family 2 (facilitated glucose transporter), member 1) gene (1p34.2). SLC2A1 encodes the glucose transporter GLUT1. All mutations in this gene responsible for PED have been found to affect the ability of GLUT1 to transport glucose. It has thus been proposed that an energy deficiency upon exertion caused by a reduced glucose transport rate is a cause of this paroxysmal movement disorder in SLC2A1 related cases.
Diagnostic methods
The diagnosis of PED relies on clinical examination and laboratory investigations showing hypoglycorrhachia and hypoglycemia. Electroencephalography (EEG) and brain imaging are normal. The diagnosis is confirmed by molecular genetic screening of SLC2A1 gene.
Differential diagnosis
The differential diagnosis includes paroxysmal kinesigenic dyskinesia (PKD), young adult-onset Parkinsonism and encephalopathy due to GLUT1 deficiency (see these terms).
Antenatal diagnosis
Prenatal diagnosis for pregnancies at increased risk of PED is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at 15-18 weeks' gestation) or chorionic villus sampling (usually performed at 10-12 weeks' gestation). The disease-causing mutation of an affected family member must be identified in the family before prenatal testing can be performed.
Genetic counseling
Sporadic and familial cases with autosomal dominant mode of inheritance have been reported for PED. Genetic counseling should be offered to patients and families.
Management and treatment
There is no specific cure or treatment but avoiding precipitating events such as prolonged physical exercise may largely improve the symptoms. Moreover, a ketogenic diet for patients may prevent attacks and may lead to improvement of developmental delay in affected children.

                            Last update:
                            November 2013

                            - Expert reviewer(s):
                            Dr Sian SPACEY


A rare, genetic, neurological disorder characterized by severe episodic perirectal pain accompanied by skin flushing that is typically precipitated by defecation. Ocular and submaxillary pain, associated with triggers including cold or other irritants, may become more prominent with age.

Summary:
Epidemiology
This disorder is rare but about a dozen families have been described.
Clinical description
This condition presents at childbirth or in the first year of life with episodes of severe rectal and peri-rectal pain following bowel movements. This is often accompanied by reflex anoxic seizures (RAS). Finally, there can be a color change down one half of the body; either horizontally from the waist down or involving one half of the body as in the harlequin phenomenon. Adults experience similar attacks although they are rare. Triggers include defecation, tactile stimulation in the peri-rectal area, unexpected falls, sexual activity and vivid dreams. Older children and adult patients are affected by painful eye and jaw crises. Other symptoms that may accompany the pain include tonic nonepileptic seizures, tachycardia and bradycardia, bronchospasm, lacrimation, hypersalivation, and rhinorrhea. Patients may have any or all of these in different episodes. The pain is typically felt in the deep tissues and can start with an itch-like sensation, which becomes burning and escalates to sharp, lancinating or a stabbing sensation. Pain appears suddenly and can last from seconds to several minutes.
Etiology
This disorder is caused by mutations in the sodium channel gene SCN9A (2q24.3). The mutations confer a gain-of-function by impairing fast-activation of sodium channel NaV1.7, which is preferentially expressed in dorsal root ganglion and sympathetic ganglion neurons.
Diagnostic methods
Diagnosis is based on a careful history, a normal examination and normal electroencephalography (EEG), electrocardiogram (ECG) and nerve conduction studies. Screening for SCN9A mutations can provide confirmatory information.
Differential diagnosis
Differential diagnoses include primary erythermalgia and hyperekplexia.
Genetic counseling
Paroxysmal extreme pain disorder follows an autosomal dominant pattern of inheritance.
Management and treatment
In children it is important to manage the inevitable constipation that ensues from stool withholding secondary to fear of defecation. The frequency of painful episodes may be reduced by medications used in the management of chronic neuropathic pain disorders, namely anticonvulsants. Carbamazepine, an activity-dependent sodium channel blocker, is the most effective of these treatments.
Prognosis
With maturation, rectal pain may be accompanied by or replaced by periocular or perimandibular pain.

                            Last update:
                            May 2019

                            - Expert reviewer(s):
                            Pr Stephen G WAXMAN  - Dr Betsy R SCHULMAN


A rare primary headache disorder characterized by multiple attacks of unilateral pain that occur in association with ipsilateral cranial autonomic symptoms. The hallmarks of this syndrome are the relative shortness of the attacks and the complete response to indomethacin therapy.

Summary:
Epidemiology
Paroxysmal hemicrania (PH) prevalence is unknown. There is a male-to-female ratio of 1:1.
Clinical description
The mean age of onset is 40 years (range 3-81 years). PH patients experience purely unilateral, severe to very severe attacks of head pain. The pain is often in the temporal, orbital or supraorbital region. The pain has an abrupt start and cessation and is accompanied by ipsilateral autonomic features, including lacrimation, conjunctival injection, rhinorrhoea, nasal congestion, periorbital oedema, facial flushing, miosis and/or ptosis. PH attacks last 2-30 minutes and occur more than 5 times a day up to 40 times a day with a mean of 11 a day. Patients can have unilateral photophobia and phonophobia ipsilateral to the side of the attack. Osmophobia, nausea or vomiting during the attacks has been reported. Although attacks are most usually spontaneous, attacks can be triggered by neck movements, or pressure over the neck or greater occipital nerves. PH can be classified as episodic or chronic, depending on the duration of pain-free period when untreated. Episodic paroxysmal hemicrania patients have bouts lasting from 7 days to 1 year and separated by pain-free periods more than 3 months, whereas in chronic patients the pain-free period is less than 3 months. As this is a primary headache disorder, patients have normal neurological tests.
Etiology
Etiology remains unclear.
Diagnostic methods
Diagnosis is based on clinical history and response to indomethacin. Patients with suspected paroxysmal hemicrania should undergo an oral indomethacin trial or placebo-controlled intramuscular indomethacin test. In adults, one could start with 25mg three times a day, titrating up to 75mg three times a day over the course of 3 weeks. With intramuscular indomethacin 100-200 mg could be used.
Differential diagnosis
Cluster headache is the main differential diagnosis, given the overlap in duration of the attacks. It is very important to differentiate PH from cluster headache, as treatment differs greatly.
Genetic counseling
Rare cases of familial PH have been reported.
Management and treatment
A complete response to indomethacin confirms the diagnosis of PH. Treatment with indomethacin with a median dose of 150 mg/day (ranging from 30-300mg/day) results in dramatic relief of the disabling symptoms caused by PH.
Prognosis
This is a debilitating headache condition if not accurately diagnosed and managed.

                            Last update:
                            October 2019

                            - Expert reviewer(s):
                            Pr Peter GOADSBY  - Dr Diana WEI


Paroxysmal kinesigenic dyskinesia (PKD) is a form of paroxysmal dyskinesia (see this term), characterized by recurrent brief involuntary hyperkinesias, such as choreoathetosis, ballism, athetosis or dystonia, triggered by sudden movements.

Summary:
Epidemiology
The prevalence is estimated to be 1/150,000 worldwide. PKD is the most common form of paroxysmal dyskinesia. Males are more commonly affected than females (sex ratio of 3 or 4 to 1) in the sporadic form.
Clinical description
The age of disease onset is typically in childhood or adolescence with a peak in puberty. PKD is triggered by a sudden movement from rest (such as rising from a chair or starting to walk, or by exercise) and is characterized by brief attacks of dystonia, chorea or athetosis movements preceded by aura (that usually last less than 1 min), without alteration of consciousness. Attacks are often unilateral, but can alternate or be bilateral, and their frequency is variable. Some patients have additional neurologic disorders such as benign familial infantile epilepsy (BFIE) (see this term). Infantile convulsion and choreoathetosis (ICCA; see this term) is considered to be a variable form of PKD.
Etiology
The exact etiology of PKD is still unknown but the PRRT2 (proline-rich transmembrane protein 2) gene (16p11.2) is believed to be the major causative gene. The PRRT2 gene encodes a protein that is hypothesized to interact with the SNAP25 protein which plays a role in presynaptic neurotransmitter release. It has been postulated that mutations in PRRT2 lead to a reduction of SNAP25 resulting in the dysregulation of neurotransmitter release, thus causing the symptoms seen in PKD.
Diagnostic methods
The clinical diagnosis of PKD relies on the following proposed criteria: (1) identification of kinesigenic trigger of the attacks; (2) short duration of attacks (<1min); (3) no loss of consciousness or pain during attacks; (4) exclusion of other organic diseases and normal neurologic examination in the case of primary PKD; (5) control of attacks with phenytoin or carbamazepine, if attempted; and (6) age of onset between 1 year and 20 years, if no family history of PKD. Moreover, molecular genetic screening of the PRRT2 gene may help to confirm the diagnosis.
Differential diagnosis
The differential diagnosis of PKD includes paroxysmal non-kinesigenic dyskinesia, juvenile myoclonic epilepsy, hyperekplexia, episodic ataxia, autosomal dominant nocturnal frontal lobe epilepsy, encephalopathy due to GLUT1 deficiency (see these terms) and shuddering attacks.
Genetic counseling
More than 60% of the patients with PKD have a family history of a similar disorder. PKD is mainly a familial disorder with autosomal dominant inheritance and incomplete penetrance, but sporadic cases occur. Individuals with onset before 20 years of age, and having a positive family history, should be screened for PRRT2 mutations.
Management and treatment
Attacks are suppressed or dramatically reduced by low-dose anticonvulsant medication such as carbamazepine or phenytoin. Moreover, treatment based on caffeine citrate, that may help to reduce the severity and frequency of attacks, has been described in a single case report.
Prognosis
The prognosis of PKD is usually favorable, with improvement of the attacks and even remission in adulthood. A gender difference in prognosis is also observed, with woman having a better prognosis and a higher chance of complete remission. An improvement of attacks can also be observed during pregnancy.

                            Last update:
                            November 2013

                            - Expert reviewer(s):
                            Dr Sian SPACEY


Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic stem cell disorder characterized by corpuscular hemolytic anemia, bone marrow failure and frequent thrombotic events.

Summary:
Epidemiology
Although PNH has been described worldwide, exact prevalence data are not available. It is estimated at 1/80,000 in France. An incidence estimate of about 1/770,000/year has been reported with a predicted prevalence of approximately 1/62,500 in Great Britain. Higher frequency is suggested in Southeast Asia and in the Far East. Men and women are equally affected.
Clinical description
The disease may occur at any age but it preferentially affects young adults. The variable clinical manifestations include hemolytic anemia, medium and large vessel thrombosis (mainly involving the hepatic, abdominal, cerebral, and dermal veins), and moderate to severe hematopoietic deficiency that may lead to pancytopenia. Pallor, fatigue and stress dyspnea with activity are the usual manifestations. Hemoglobinuria results in the production of classically dark urine during the night and in the morning (about 25 % of patients), and patients may present with renal insufficiency. Jaundice may be present. Depending on their localization, thromboses (which affect 30-40 % of untreated patients) may manifest as abdominal pain, hepatomegaly, ascites and headaches. PNH is a chronic disease with hemolytic crises that may be triggered by several factors such as common infection, vaccination, surgery or certain antibiotics. Bone marrow failure may occur prior, along, or as a late complication of the disease (40-50 % of cases).
Etiology
PNH is caused by somatic mutations in the PIGA gene (Xp22.1), encoding a protein involved in the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor. The mutation occurs in one or several hematopoietic stem cell(s) and leads to a lack (total or partial) of all GPI-anchored cell membrane proteins (the most important being CD55 and CD59, involved in the regulation of hemolysis due to complement).
Diagnostic methods
Diagnosis is based on the clinical features and presence of hemolytic anemia, especially since it is associated with thrombosis and/or peripheral blood cytopenia. Diagnosis is confirmed by flow cytometry to detect GPI-linked antigen deficiency in red cells, monocytes and granulocytes. Molecular analysis is unreliable for diagnosis as the causative mutations are non-homogenous and non-repetitive.
Differential diagnosis
Differential diagnoses include all the other forms of anemia (in particular autoimmune hemolytic anemia) and other causes of deep vein thromboses, according to their clinical presentation.
Management and treatment
Until 2007, treatment was primarily symptomatic: transfusions, use of anticoagulants and treatment of an associated aplasia. In June 2007, the monoclonal antibody Eculizumab received an orphan drug designation in Europe for the treatment of PNH. It reduces significantly the hemolysis, the need of transfusions, fatigue, the occurrence of thrombosis, the risk of renal failure, and improves the patients' survival. Bone marrow transplantation can cure PNH but is only indicated in case of severe associated medullar aplasia, due to the severe complications of this technique in this context.
Prognosis
The 6-year survival of patients treated since 2005 is 92 %, and median survival has increased significantly due to the use of Eculizumab and improvements in both supportive measures and management of disease complications.

                            Last update:
                            October 2017

                            - Expert reviewer(s):
                            Pr Régis PEFFAULT DE LA TOUR  - Dr Flore SICRE DE FONTBRUNE  - Pr Gérard SOCIE


Paroxysmal non-kinesigenic dyskinesia (PNKD) is a form of paroxysmal dyskinesia (see this term), characterized by attacks of dystonic or choreathetotic movements precipitated by stress, fatigue, coffee or alcohol intake or menstruation.

Summary:
Epidemiology
The prevalence of PNKD is estimated to be 1/1,000,000 worldwide. A male preponderance is observed (1.4:1).
Clinical description
The age of onset is variable ranging from 1 to 77 years. PNKD is characterized by attacks of spontaneous or induced (by alcohol, caffeine, stress, menstruation, sleep deprivation or exercise) dystonia, chorea, athetosis and ballism in the limbs, face, and trunk lasting from minutes to hours without a change in the level of alertness. The movements can be partial and unilateral, but are mostly bilateral and generalized. The frequency of the attacks varies from 1-3 per day to months of attack-free intervals. Dysarthria and oculogyric crisis can also be observed during episodes of severe attacks. An aura-like sensation (paresthesia, tension in the limbs or dizziness) prior to the onset of the motor manifestations and migraine headaches may be observed. Symptomatic PNKD is most commonly reported in association with multiple sclerosis (see this term) or vascular thalamic lesions.
Etiology
The pathophysiology of PNKD still remains to be elucidated but approximately 60% of patients exhibit mutations in the PNKD gene (2q35), encoding the PNKD protein (formerly named myofibrillogenesis regulator 1 protein, MR-1). Furthermore, subsequent linkage analysis in a Canadian kindred identified a novel gene locus at chromosome 2q31 (named PNKD2).
Diagnostic methods
The diagnosis is purely clinical and molecular screening of the PNKD gene can help to confirm the diagnosis.
Differential diagnosis
Differential diagnosis of PNKD includes: Wilson disease, paroxysmal kinesigenic dyskinesia (PKD), infantile convulsions and choreoathetosis (ICCA syndrome), paroxysmal exertion-induced dyskinesia (PED), autosomal dominant nocturnal frontal lobe epilepsy, paroxysmal dystonic choreathetosis with episodic ataxia and spasticity, and Huntington disease (see these terms).
Antenatal diagnosis
Prenatal diagnosis for pregnancies at increased risk of having PNKD mutations associated with familial PNKD is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at 15-18 weeks' gestation) or chorionic villus sampling (usually performed at 10-12 weeks' gestation). The disease-causing mutation of an affected family member must be identified in the family before prenatal testing can be performed.
Genetic counseling
Although sporadic cases have been reported, PNKD is usually inherited as an autosomal dominant trait with high penetrance. Haplotype analysis in the PNKD2 family demonstrated a disease penetrance of 89%.
Management and treatment
PNKD patients do not respond to antiepileptic drugs such as carbamazepine, but clonazepam or other benzodiazepines can be helpful in some PNKD mutation carrier patients. Because PNKD may be triggered by emotional stress, fatigue, alcohol or caffeine, the avoidance of these possible precipitating factors is recommended. Deep brain stimulation may act as a potential therapeutic option in medically refractory PNKD.
Prognosis
No long-term sequelae are associated with PNKD. Moreover, 61% of patients with PNKD show a tendency to decrease the frequency of their attacks with age. However, in some patients, episodes may remain unchanged or worsen with age. Disappearance of attacks during pregnancy has also been described.

                            Last update:
                            November 2013

                            - Expert reviewer(s):
                            Dr Sian SPACEY