A difference of sex development (DSD) distinct from complete AIS (CAIS) characterized by the presence of abnormal genital development in a 46,XY individual with normal testis development and partial responsiveness to age-appropriate levels of androgens.

Summary:
Epidemiology
There are no available data on the prevalence of PAIS in the general population. Nevertheless, resistance to androgens is the most frequent cause of XY DSD.
Clinical description
Patients have a highly variable genital appearance. The prototypic form of presentation is severe hypospadias, micropenis, and bifid scrotum in which the testes may or may not be descended. In the more severe form of PAIS, patients have female external genitalia with clitoromegaly, partial labial fusion and labial swellings comprising testes. A mild end of the spectrum, labeled MAIS (mild or minimal AIS), is a male with gynecomastia at puberty or an adult presenting with male factor infertility.
Etiology
The condition is due to missense mutations in the androgen receptor (AR) gene (Xq11-12) coding for the AR nuclear transcription factor, and results in variable degrees of AR function. An AR mutation is found in only approximately 20% of patients with PAIS.
Diagnostic methods
The diagnosis is based on clinical and biochemical findings in XY patients with varying degrees of under-masculinization. The typical hormone profile is increased luteinizing hormone (LH) and testosterone levels, which is used as a screening test for MAIS with male factor infertility. Serum anti-Mullerian hormone (AMH) levels may be normal or increased. A pelvic ultrasound, MRI or cysto-urethroscopy confirm the presence of Wolffian duct structures and the absence of Müllerian structures. A utriculus or vaginal remnant is often visualized on urethroscopy. Positive mutation analysis of the AR gene and the mutant AR confirmed to be pathogenic in a reporter gene assay confirms the diagnosis.
Differential diagnosis
Human chorionic gonadotropin (hCG) stimulation should be performed to exclude an androgen biosynthetic defect. A urinary steroid profile is reliable to exclude 5-alpha-reductase deficiency (see this term) after six months of age. Other differential diagnoses include 46,XY partial gonadal dysgenesis, congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency, Denys-Drash syndrome, Smith-Lemli-Opitz syndrome (see these terms), and PAIS with a normal AR. The latter condition is strongly associated with low birth weight due to fetal growth restriction.
Antenatal diagnosis
Antenatal diagnosis is seldom indicated.
Genetic counseling
The condition is X-linked recessive. Affected families should be offered genetic counseling only when an AR gene mutation has been identified and shown to be pathogenic. Counseling should be based on the variable expression of the same AR mutation between, and even within, affected families.
Management and treatment
Management depends on the sex of rearing that the parents and healthcare professionals should assign as early as possible in infancy. Those raised as male require hypospadias repair (two procedures or more) and orchiopexy for undescended testes. Those raised as female need gonadectomy before puberty and puberty induction with estrogen. The onset of puberty in PAIS patients raised male is unpredictable and large doses of androgens may be required to induce adequate virilization. Gynecomastia is treated by reduction mammoplasty. High dose androgens can rarely restore fertility in MAIS patients. Psychological support from birth to adulthood is necessary.
Prognosis
Prognosis is variable in terms of sexual function and quality of life in those raised male. Infertility is invariable. There is an increased risk of gonadal tumor, particularly if the testis remains undescended.

                            Last update:
                            January 2011

                            - Expert reviewer(s):
                            Pr Ieuan HUGHES


A rare congenital cardiac malformation that is a variant of an atrioventricular septal defect (AVSD) with an interatrial communication (ostium primum defect) just above the common atrioventricular (AV) valve, no interventricular communication just below the atrioventricular valve, a common atrioventricular junction but separate right and left atrioventricular valvar orifices, and a three-leaflet, left-sided component of the common atrioventricular valve (''cleft''). Shunting is restricted to the atrial level because of fusion of the leaflets of the common AV valve with the crest of the ventricular septum.

Summary:
Epidemiology
Partial atrioventricular septum defect (PAVSD) accounts for 1-2% of all congenital heart malformations and its prevalence is estimated to be 1/5,000-1/2,500.
Clinical description
Most patients with PAVSD are asymptomatic until late in life. The clinical presentation depends on the degree of mitral regurgitation and on the associated cardiac defects. The two most common clinical manifestations are impaired exercise capacity and exertional dyspnea. Rarely, cardiac failure may occur in infancy. Additional features in adults include palpitations, presyncope or syncope, and sustained atrial arrhythmias. The ventricles may be equal or nearly equal in size (balanced) or one of the ventricles may be significantly larger than the other (unbalanced). Unbalanced ventricles are associated with hypoplasia of the arterial valve above and aortic coarctation if the left ventricle is hypoplastic.
Etiology
CRELD1 (3p25.3), GATA4 (8p23.1-p22), GATA6 (18q11-q12) and NR2F2 (15q26) have been associated with a small fraction of PAVC cases. These genes encode developmental transcription factors that are critical for normal cardiac morphogenesis.
Diagnostic methods
Diagnosis of PAVC is established by means of 2D-echocardiography. Transesophageal echocardiography or cardiac catheterization can be useful in adults (to assess pulmonary vascular resistance and status of the left AV valve and, in patients > 40 years, to exclude coexisting coronary arterial disease). An elevated pulmonary arterial pressure and moderate to severe left atrioventricular valve regurgitation may be observed. First-degree AV block, right bundle branch block, and a superior QRS axis may be noted on electrocardiogram.
Differential diagnosis
Differential diagnosis includes the complete and intermediate forms of atrioventricular septal defects. Intermediate (transitional) atrioventricular septal defect is a variant of complete atrioventricular septal defect with a restrictive ventricular component due to multiple attachments of the bridging leaflets on the crest of the ventricular septum. PAVSD may be associated with syndromes including the RASopathies (particularly Noonan syndrome caused by mutations in PTPN11 and RAF1), Ellis Van Creveld and Down, and CHARGE syndrome.
Antenatal diagnosis
PAVSD may be detectable prenatally by 4-chamber view screening during obstetric ultrasonography.
Management and treatment
The early diagnosis of PAVSD requires cardiology follow-up and elective complete repair between 3 and 5 years of age, which involves closure of a primum atrial septal defect with an appropriately shaped patch through right atriotomy, and partial suture of the ''cleft'' of the left component of the common atrioventricular valve. A pacemaker insertion may be required for complete AV block, which may spontaneously develop after repair. A continuous lifelong follow-up is recommended to avoid late complications. Symptom free patients may be referred for PAVSD repair because of a substantial left-to right atrial shunt (pulmonary to systemic flow ratio 1.8:1) and echocardiographic evidence of right heart volume overload.
Prognosis
Long-term survival after repair of partial AVSD is the rule. The elective age for repair is 3-5 years, but some patients will not present until later in life. The later the repair is made, the greater the loss of ventricular function that occurs. High morbidity and need for reoperation, often related to residual problems of the systemic AV valve such as LAVV regurgitation, may be observed. Furthermore, the prognosis can be severely impaired if the left ventricle and left component of the common atrioventricular valve are hypoplastic or severely malformed. Norwood-type intervention in infancy can be required, as well as prosthetic replacement of the left AV valve.

                            Last update:
                            October 2020

                            - Expert reviewer(s):
                            Pr Lucile HOUYEL


Partial corpus callosum agenesis-cerebellar vermis hypoplasia with posterior fossa cysts syndrome is a rare, hereditary, cerebral malformation with epilepsy syndrome characterized by severe global developmental delay with no ability to walk and no verbal language, intractable epilepsy, partial agenesis of the corpus callosum and cerebellar vermis hypoplasia with posterior fossa cysts.


A form of hydatiform mole characterized by abnormal hyperplastic trophoblasts and hydropic villi due to fertilization of a normal ovocyte by two spermatozoa or one abnormal spermatozoon (allowing for some fetal development), and that manifests with vaginal bleeding accompanied by nausea and frequent vomiting, hyperemesis gravidarum, hyperthyroidism and risk of spontaneous miscarriage.


Partial agenesis of the pancreas is characterized by the congenital absence of a critical mass of pancreatic tissue.

Summary:
Epidemiology
It is a rare disorder with only around 50 cases being reported in the literature so far.
Clinical description
The severity of the disease depends on the amount of functional pancreatic tissue present. Pancreatic agenesis is commonly associated with other malformations, in particular pancreaticobiliary duct anomalies, leading to acute or chronic pancreatitis, hyperglycemia (50% of cases), or, more rarely, polysplenia. In the majority of cases, patients are diagnosed after reporting abdominal pain. Agenesis of the dorsal pancreas usually manifests as diabetes.
Etiology
Pancreatic agenesis has been associated with mutations in the PDX1 gene (13q12.2), which encodes the insulin promoter factor-1 (IPF-1) transcription factor. In addition, missense mutations in the PTF1A gene (10p12.3) have been found to be responsible for the autosomal recessive syndrome of neonatal diabetes mellitus associated with cerebellar and/or pancreatic agenesis (see this term).
Diagnostic methods
Diagnosis is made by imaging studies revealing the partial absence of the pancreas.
Differential diagnosis
The principle differential diagnosis is pancreas divisum.
Management and treatment
Management involves treatment of the diabetes and exocrine deficiency, when present.
Prognosis
The prognosis for patients is variable, depending on the quality of treatment received.

                            Last update:
                            May 2009

                            - Expert reviewer(s):
                            Pr Frédéric BARGY  - Pr Pierre BOUGNERES


Partial septate uterus is a rare, non-syndromic uterovaginal malformation characterized by a uterus that has a longitudinal septum which extends from the uterine fundus and does not reach the internal cervical os (variable lengths and widths may be observed). Although frequently asymptomatic, an increased risk of poor reproductive outcome has been observed. Urinary tract abnormalities are very rarely associated.


Partially involuting congenital hemangioma

A rare congenital hemangioma characterized by a superficial, red to violaceous lesion with overlying telangiectasia and a surrounding pale halo, which initially behaves like a rapidly involuting congenital hemangioma, beginning to involute shortly after birth. Involution is then aborted, and a residual tumor virtually indistinguishable from non-involuting congenital hemangioma remains. This lesion grows proportionally with the child and does not regress.


Partington syndrome is a form of syndromic X-linked mental retardation (S-XLMR) characterised by the association of mild to moderate intellectual deficit, dysarthria and dystonic hand movements. So far, less than 20 cases have been described in the literature. The syndrome is caused by mutations in the Aristaless-related homeobox (ARX) gene (Xp22.13). Transmission is X-linked recessive.


A rare skin disease belonging to the spectrum of autoinflammatory syndromes characterized by the triad of pyoderma gangrenosum (PG), suppurative hidradenitis (SH) and acne.


Patent ductus arteriosus-bicuspid aortic valve-hand anomalies syndrome

A rare heart-hand syndrome that is characterized by a variety of cardiovascular anomalies including patent arterial duct, bicuspid aortic valve and pseudocoarctation of the aorta in conjunction with hand anomalies such as brachydactyly and ulnar ray derivative i.e. fifth metacarpal hypoplasia.


Patent urachus is a type of congenital urachal anomaly (see this term) characterized by a persistent communication between the bladder and the umbilicus, secondary to non occlusion of the urachal lumen, manifesting as clear drainage from the umbilicus.


Paternal 20q13.2q13.3 microdeletion syndrome is a recently described syndrome characterized by severe pre- and post-natal growth retardation, microcephaly, intractable feeding difficulties, mild psychomotor retardation, hypotonia and facial dysmorphism.

Summary:
Epidemiology
It has been reported in 2 unrelated patients.
Clinical description
Facial dysmorphism includes high forehead, broad nasal bridge, thin upper lip, small chin and malformed ears. In addition, the patients presented with skin, iris and hair hypopigmentation and abnormal adipose tissue distribution.
Etiology
The syndrome is caused by an interstitial deletion of paternal origin at 20q13.2q13.3. In the 2 cases, the deletion was approximately 4.5Mb in size and encompassed the GNAS imprinted locus; the loss of the paternally expressed GNAS gene might account for the severe pre- and post-natal retardation and intractable feeding difficulties observed in the patients.

                            Last update:
                            June 2011

                            - Expert reviewer(s):
                            Dr Nicole MORICHON-DELVALLEZ


Paternal uniparental disomy of chromosome 1 is an uniparental disomy of paternal origin that most likely does not have any phenotypic expression except from cases of homozygosity for a recessive disease mutation for which only father is a carrier.


Paternal uniparental disomy of chromosome 13 is an uniparental disomy of paternal origin that most likely does not have any phenotypic expression except from cases of homozygosity for a recessive disease mutation for which only father is a carrier.


Paternal uniparental disomy of chromosome 20 is a very rare chromosomal anomaly in which both copies of chromosome 20 are inherited from the father. The main features described are high birth weight and/or early-onset obesity, relative macrocephaly, and tall stature. Most patients were ascertained during sporadic pseudohypoparathyroidism type 1b (see this term) testing and have UPD involving variable segments of the long arm of chromosome 20.


Paternal uniparental disomy of chromosome 21 is an uniparental disomy of paternal origin that most likely does not have any phenotypic expression except from cases of homozygosity for a recessive disease mutation for which only father is a carrier.


Paternal uniparental disomy of chromosome 5 is an uniparental disomy of paternal origin that most likely does not have any phenotypic expression except from cases of homozygosity for a recessive disease mutation for which only father is a carrier.


Paternal uniparental disomy of chromosome 6 is an uniparental disomy of paternal origin characterized by intrauterine growth retardation, transient neonatal diabetes mellitus, and macroglossia.


Paternal uniparental disomy of chromosome 7 is an uniparental disomy of paternal origin that most likely do not have any phenotypic expression except from cases of homozygosity for a recessive disease mutation for which only father is a carrier (e.g., cystic fibrosis, congenital chloride diarrhea, sensorineural hearing loss).


Paternal uniparental disomy of chromosome X

A uniparental disomy of paternal origin that does not seem to have an adverse impact on the phenotype of an individual. There is a possibility of homozygosity for a recessive disease mutation for which the father is a carrier and specific phenotype depends on the inherited disorder.


Patterson-Stevenson-Fontaine syndrome is a very rare variant of acrofacial dysostosis characterized by mandibulofacial dysostosis and limb anomalies.

Summary:
Epidemiology
It has been described in less of ten patients.
Clinical description
The mandibulofacial dysostosis consists of retrognathism, complete or occult posterior cleft palate, and anomalies of the external ears. Limb anomalies consist of split-foot deformity with syndactyly of some toes.
Genetic counseling
The condition is transmitted as an autosomal dominant trait with variable penetrance and expressivity.

                            Last update:
                            October 2010


Pauci-immune glomerulonephritis with ANCA

A form of pauci-immune glomerulonephritis characterized by a rapidly progressive glomerulonephritis in association with the presence of circulating antineutrophilic cytoplasmic antibodies (ANCA), mostly directed against proteinase-3 (PR3) and myeloperoxidase (MPO). Patients usually present with urinary abnormalities and rapidly declining renal function, often leading to dialysis within weeks without treatment. Cutaneous, pulmonary, musculoskeletal and nervous involvement may be observed in case of systemic disease, and the correlation between ANCA titer and disease activity has been demonstrated.


Pauci-immune glomerulonephritis without ANCA

A form of pauci-immune glomerulonephritis characterized by rapidly progressive glomerulonephritis and the absence of antineutrophilic cytoplasmic antibodies (ANCA). In comparison with pauci-immune GN with ANCA, patients lacking ANCA may be younger at onset of the disease, have fewer extra renal manifestations (e.g. involvement of lung, eye, ear, nose and throat), fewer constitutional symptoms (e.g. fever, weight loss, muscle pain and arthralgia) and a high prevalence of nephrotic syndrome and chronic renal lesions. The prognosis is generally poorer.


A rare small vessel vasculitis associated with rapidly progressive glomerulonephritis (GN) and clinically characterized by renal manifestations such as urinary abnormalities (hematuria and/or proteinuria) and hypertension leading to renal failure within days or weeks, and distinguished by the absence of immune deposits on immunofluorescent microscopy. The disease can occur as a renal-limited disease or as a component of systemic necrotizing small-vessel vasculitis.

Summary:
Epidemiology
Pauci-immune GN is the most common cause of rapidly progressive glomerulonephritis. The incidence of pauci-immune GN in the United States is estimated at 3.1/1,000,000, with significantly higher rates for Caucasians, males and individuals over 65. In the European population, the incidence is estimated between 1-2/100,000, with an increasing trend in recent years.
Clinical description
Patients with pauci-immune GN may present with different clinical pictures, and predominantly occurs in patients over 55 years of age, although rarely it may occur earlier. Most patients report a prodromal 'flu-like' illness preceding the overt vasculitic syndrome. Pauci-immune GN can occur as a renal-limited disease or as a component of systemic vasculitis. Systemic symptoms including fever, asthenia, arthralgias, weight loss, and myalgias can precede the renal presentation of the disease. Clinically, it is characterized by renal manifestations such as urinary abonormalities (hematuria and/or proteinuria) and hypertension leading to renal failure within days or weeks. It can also be associated with extrarenal manifestations depending on the disease process and may involve the upper and lower respiratory tract, nerves, skin, and musculoskeletal system. Risk factors for progression to end stage renal disease (ESRD) include increased initial serum creatinine or decreased estimated glomerular filtration rate (eGFR) at baseline, older age, presence of pulmonary hemorrhage, and dialysis-dependent acute kidney injury.
Diagnostic methods
The disease is associated with the presence of serum anti-neutrophil cytoplasmic antibodies (ANCAs) in a high percentage of subjects. Renal biopsy is essential for the diagnosis and subsequent management of pauci-immune GN, and is used to to determine the activity and chronicity of the renal lesions as well as the risk associated with immunotherapy of ANCA pauci-immune necrotizing glomerulonephritis. The histological hallmarks of the disease are the presence of extracapillary proliferation and segmental necrosis on light microscopy, and the absence of immune deposits on immunofluorescence microscopy. Immunologic classification is based on the presence or absence of circulating ANCAs, namely pauci-immune-GN with ANCAs and pauci-immune GN without ANCAs. Other laboratory data such as erythrocyte sedimentation rate, C-reactive protein (CRP) and urine test are not specific but can help with the diagnosis.
Differential diagnosis
Differential diagnosis includes other forms of crescentic GN.
Management and treatment
Conventional induction therapies for pauci-immune GN have been defined and include Cyclophosphamide (CYC) for at least 3 months, with a corticosteroid taper followed by maintenance immunosuppression for up to 2 years with azathioprine or mycophenolate mofetil. Clinical trials have shown that rituximab (RTX) is an effective induction therapy for pauci-immune ANCA-associated GN. Since preventing relapses and maintaining remission are critical to slowing chronic kidney disease (CKD) progression to ESRD in this group of patients, a number of trials have focused on repeat doses of RTX at 4/6 month intervals. As with other forms of CKD, patients with stable but decreased eGFR usually benefit from blood pressure control with long-term inhibition of RAAS axis to reduce glomerular hyperfiltration, a low-sodium diet, and moderate protein intake.
Prognosis
Despite the substantial progress in treatment, pauci-immune glomerulonephritis remain a group of diseases with significant morbidity and mortality related to the disease itself. Renal involvement is one of the most threatening aspects

                            Last update:
                            June 2020

                            - Expert reviewer(s):
                            Dr Roberta FENOGLIO | ERKNet* - Pr Dario ROCCATELLO | ERKNet*

                                * European Reference Network


PCNA-related progressive neurodegenerative photosensitivity syndrome

A rare developmental defect during embyogenesis caused by homozygous mutations in the PCNA gene and characterized by neurodegeneration, postnatal growth retardation, prelingual sensorineural hearing loss, premature aging, ocular and cutaneous telangiectasia, learning difficulties, photophobia, and photosensitivity with evidence of predisposition to sun-induced malignancy. Progressive neurologic deterioration leads to gait disturbances, muscle weakness, speech and swallowing difficulties and progressive cognitive decline.


PDE4D haploinsufficiency syndrome is a rare syndromic intellectual disability characterized by developmental delay, intellectual disability, low body mass index, long arms, fingers and toes, prominent nose and small chin.


A rare mitochondrial oxidative phosphorylation disorder due to large-scale single deletion of mitochondrial DNA characterized by hyporegenerative anemia in early infancy with vacuolization of bone marrow precursors, lactic acidosis and multi-organ dysfunctions such as exocrine pancreatic dysfunction, and renal tubulopathy.

Summary:
Epidemiology
Approximately 200 cases have been reported in the literature. Both males and females are affected. The prevalence of Pearson syndrome is approximately 1/1,000,000.
Clinical description
Most patients present with sideroblastic anemia in infancy. Additional symptoms comprise failure to thrive, neurological (hypotonia, speech delay, muscular hypertrophy) and gastrointestinal (vomiting, chronic diarrhea and feeding difficulties) symptoms. All organs can be affected and various complications develop during the course, which are generally irreversible. Hepatic dysfunction (hepatomegaly, splenomegaly), exocrine pancreatic insufficiency and renal tubulopathy are common early complications, while ophthalmological complications (such as retinitis pigmentosa and cataract) and cardiac conduction defects usually occur at a later stage of the disease. Patients often develop multiple endocrine disorders. Interestingly, hematological recovery spontaneously occurs in a majority of patients at 1-3 years of age, while some patients develop myeloid neoplasms in early childhood. Patients who survive early infancy can demonstrate a Kearns-Sayre syndrome-like phenotype.
Etiology
Pearson syndrome is caused by large-scale mitochondrial DNA (mtDNA) deletions which lead to a deficiency in mitochondrial respiratory chain function. Heteroplasmy (mixture of both wild-type and deleted mtDNA in the same cell) can be observed in patients and explains the high variability in clinical expression, both between patients and between the various organs of an affected subject. Cellular dysfunction appears only if the level of heteroplasmy exceeds a certain critical threshold.
Diagnostic methods
The diagnosis of Pearson syndrome is usually suspected based on the typical bone marrow cytology with vacuolization in erythroid and myeloid precursors. Iron staining reveals ring-sideroblasts in 70-85% of patients. The diagnosis should be confirmed by genetic testing (detection of large-scale mtDNA deletion).
Differential diagnosis
Patients with Pearson syndrome can be misdiagnosed as Diamond-Blackfan anemia, a congenital hypogenerative anemia that presents in infancy.
Genetic counseling
Most cases are sporadic. Although deleted mtDNA can be maternally inherited, the unpredictable heteroplasmy status in a child makes genetic counseling challenging.
Management and treatment
Similar to the majority of patients with primary mitochondrial diseases, there is no curative therapy for children with Pearson syndrome. Therapy is largely supportive and includes blood transfusions, treatment of infections, prevention of metabolic decompensations, and therapy for various organ complications such as pancreatic insufficiency and endocrine disorders. Most patients receive supplements such as coenzyme Q10, L-carnitine and/or various vitamins, despite limited evidence for efficacy.
Prognosis
Patients with Pearson syndrome have a dismal prognosis. About half of patients die by 4 years of age. Patients who reach 15 years of age are rare. The most common cause of death is metabolic decompensation with lactic acidosis. Patients who survive early infancy typically undergo phenotypic change: hematological manifestations spontaneously resolve, whereas neurological and myopathic signs either appear or worsen. Some patients develop Kearns-Sayre syndrome (KSS) with ophthalmoplegia, ataxia, pigmentary retinitis, conduction defects and myopathy.

                            Last update:
                            May 2023

                            - Expert reviewer(s):
                            Pr Sarah GRÜNERT | MetabERN* - Dr Ayami YOSHIMI | PaedCan-ERN*

                                * European Reference Network


Pectus excavatum-macrocephaly-dysplastic nails syndrome is a rare multiple congenital anomalies syndrome characterized by relative macrocephaly, pectus excavatum, short stature, nail dysplasia, and motor developmental delay (that resolves during childhood). There have been no further descriptions in the literature since 1992.


A rare neurologic condition characterized by focal cerebral ischemia and infarction due to blockage of a brain artery with subsequent impairment of blood supply and oxygenation of brain tissue. Most children present with hemiparesis with or without facial palsy at stroke onset. In addition, compared to adults, children more often suffer strokes in the posterior circulation, leading to ataxia or oculomotor disturbance. Likewise, aphasia is more frequent in pediatric patients. Other signs and symptoms include seizures, headache, vomiting, and alterations in the level of consciousness. Children under one year of age are more likely to present with seizures and altered level of consciousness, while older children more often show focal neurological deficits.


A rare gastroenterologic disease characterized by the histopathological finding of a thickened (> 10 µm) gastric subepithelial collagen layer in association with an inflammatory infiltrate in the lamina propria. Patients typically present with upper abdominal pain and severe iron deficiency anemia. The condition is not commonly associated with autoimmune diseases, and involvement of the colon is less frequent than in the adult form. The disease takes a generally benign course with limited long-term morbidity and no increased mortality.


A rare, aggressive and malignant hepatic tumor arising from the hepatocytes. It develops mainly in children over 10 years of age, either in a cirrhotic background, or more commonly in a non-cirrhotic background (70% of cases).

Summary:
Epidemiology
Primary liver malignancies are rare in children and adolescents. Hepatocellular carcinoma (HCC) constitutes less than 25% of them. Annual incidence is about 1/2,000,000, with higher incidence rates found in sub-Saharan Africa and Southeast Asia as a result of endemic hepatitis B (HBV) and aflatoxin exposure. HCC is found more frequently in males (2-3:1). Incidence is higher among adolescents (1/1,250,000).
Clinical description
HCC mostly develops in pediatric patients with no underlying liver disease, unlike in adults, when it is usually associated with hepatic cirrhosis due to alcohol intake. Pediatric HCC is mostly found in children and adolescents and rarely in children under 5 years of age. The main presenting manifestations are abdominal mass with pain, swelling and discomfort, weight loss, and anorexia. Splenomegaly, nausea, vomiting and jaundice are less commonly observed. Metastases to the mediastinal lymph nodes, lungs, brain and bone marrow are common in advanced disease (25% at presentation). HCC may be associated with congenital diseases, such as biliary atresia, tyrosinemia type 1 (in 50% of cases), alpha-1-antitrypsin deficiency, progressive familial intrahepatic cholestasis, Alagille or Gardner syndrome, Wilson or glycogen storage diseases I-IV, Fanconi anemia, familial adenomatous polyposis (FAP), focal nodular hyperplasia and hemochromatosis. A specific HCC variant, fibrolamellar carcinoma (FLC), occurs in older children and young adults, and has an equally dismal prognosis despite a slower growth and less tendency to metastasize.
Etiology
The pathophysiology of HCC is not well understood. Underlying liver dysfunction is the main predisposing condition (HBV, HCV). Children with neonatal hepatitis, intrahepatic cholestasis, biliary atresia, glycogen-storage diseases and other types of cirrhotic diseases are predisposed to the tumor. The Wnt/beta-catenin pathway is frequently activated via stabilizing mutations in beta-catenin: some patients have been found to harbor mutations in the CTNNB1 (3p21) and MET (7q31) genes. TP53 (17p13.1) gene and the TERT promoter are mutated in 25-30% and 60% of HCC cases, respectively. However, so far, the key genomic alteration in HCC has not yet been identified, and no mutation is used in clinical practice to predict a therapeutic response.
Diagnostic methods
Diagnosis is based on the clinical manifestations, elevated alpha-fetoprotein (AFP) in 50% of cases, histological findings, and on liver imaging. A slowly enlarging mass may be found on physical examination. Abnormal levels of beta human chorionic gonadotropin (b-hCG) may also be detected (rare). Ultrasound typically shows a heterogeneous hyperechoic mass with increased vascularity. Chest CT and abdominal CT/MRI scans with intravenous contrast should be performed for initial staging. Other imaging techniques may also be required to determine possible metastatic spread.
Differential diagnosis
The main differential diagnosis is hepatoblastoma, the most common hepatic tumor in the pediatric population in Western countries. Others include focal nodular hyperplasia (FNH), hepatic adenoma and undifferentiated embryonal sarcoma, as well as other less common liver malignancies.
Management and treatment
At-risk patients should be monitored closely. Screening for HBV and HCV should be performed. Monitoring with ultrasound and AFP every 6 months for all cirrhotic children, those with chronic HBV infection, inherited metabolic diseases or congenital porto-systemic shunts is suggested. The mainstay of curative therapy in non-metastatic patients is primary complete surgical resection (possible in about 25% of presenting children), delayed surgical resection (after neo-adjuvant chemotherapy) or liver transplantation (often across the Milan criteria). Transarterial chemo-embolization (TACE), radio-embolization (TARE) and radiofrequency ablation (RFA) are possible palliative options. Immunotherapies (CAR T cells, PD-1/PD-L1 and CTLA-4 checkpoint inhibitors) are newly emerging field for HCC.
Prognosis
The prognosis currently depends on success rates of resection in resectable tumors. 5-year survival rates are moderate in low stage tumors but these rates drop below 20-30% in advanced disease.

                            Last update:
                            October 2019

                            - Expert reviewer(s):
                            Pr Piotr CZAUDERNA  - Dr Maciej MURAWSKI


Pediatric multiple sclerosis (MS) is a rare multiple sclerosis variant characterized by the onset of multiple sclerosis (i.e. one or multiple episodes of clinical CNS symptoms consistent with acquired CNS demyelination, with radiologically proven dissemination of inflammatory lesions in space and time, following exclusion of other disorders) before the age of 18 years old. Pediatric MS patients present a predominantly relapsing-remitting course with first attack usually consisting of optic neuritis, transverse myelitis, acute disseminated encephalomyelitis and monofocal or polyfocal neurological deficits. A high burden of T2-hyperintense lesions on initial MRI, primarily of the supratentorial region and/or of the cervical spinal cord, has been reported.


A rare, systemic, autoimmune disease characterized by inflammation in any organ system, with onset prior to adulthood, presenting highly variable clinical manifestations, which usually have a more aggressive course and higher rate of major organ involvement than adult-onset systemic lupus erythematosus, resulting in potential damage to a variety of organs (e.g. the skin, kidneys, lungs, nervous system).


Pediatric-onset glaucoma of genetic origin

A clinically diverse group of rare eye disorders with genetic predisposition characterized by elevated intraocular pressure (IOP) and glaucomatous changes of the optic nerve head, leading to field defects, visual loss and blindness. It can be sub-classified as primary (congenital glaucoma, juvenile glaucoma) or secondary according to the presence or absence of systemic or other ocular anomalies (iridogoniodysgenesis, Stickler syndrome, Coats syndrome). The clinical presentation is variable and is based on age, severity of glaucoma, presence of ocular abnormalities and development of secondary IOP related abnormalities.


A rare endocrine disease characterized by the presence of serum autoantibodies against thyroid-stimulating hormone receptors, leading to increased thyroid hormone production and secretion, causing diffuse toxic goiter. Patients present in childhood with signs of thyrotoxicosis (such as tachycardia, weight loss, hand tremor, and sweating), diffuse enlargement of the thyroid gland, and orbitopathy. Additional signs and symptoms include decreased academic and athletic performance, accelerated growth, restlessness, fatigue, sensitivity to heat, and amenorrhea, among others.


A noninflammatory form of generalized PSS characterized by white scaling and superficial painless peeling of the skin.

Summary:
Epidemiology
The prevalence is unknown. To date, few cases have been reported in the literature.
Clinical description
Onset of symptoms can be at birth or later in life. Individuals may present with erythroderma accompanied by dry skin and superficial peeling of the skin upon minor trauma leaving red, denuded areas. The lesions heal with hyperpigmentation without scarring. Warm and humid environments aggravate the peeling tendency. Hyperkeratosis and scaling may also be present over the knees and elbows. Pruritus is variably observed. Hair is normal. There is no history of erythema or atopy and patients are in good general health.
Etiology
There are three different causal genes reported to date: CHST8, SERPINB8 and FLG2. These genes are involved in skin homeostasis and barrier function but their specific role in the epidermis remains elusive, except for FLG2 which is known to be involved in skin moisturization.
Diagnostic methods
Diagnosis is based on clinical features. Histological examination of skin lesion biopsies reveals a slight hyperkeratosis, thinning of the granular layer and a separation of the stratum corneum from the underlying stratum granulosum or an intracorneal split. Molecular analysis, if performed, may reveal mutations in one of the three causal genes.
Differential diagnosis
Differential diagnosis includes other forms of PSS, PLACK syndrome and staphylococcal scalded skin syndrome.
Antenatal diagnosis
The disease does not seem to be severe enough to justify prenatal screening.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to affected families informing them of the risk of 25% for a healthy carrier parent to have an affected child.
Management and treatment
No effective treatment has been reported. Emollients are often used to reduce skin peeling.
Prognosis
Noninflammatory skin peeling has a good prognosis and is mainly a cosmetic problem. In young patients, the condition may improve during childhood.

                            Last update:
                            January 2023

                            - Expert reviewer(s):
                            Dr Nathalie JONCA  - Pr Juliette MAZEREEUW-HAUTIER | ERN-Skin*

                                * European Reference Network


A form of generalized peeling skin syndrome (PSS) characterized by superficial patchy peeling of the entire skin with underlying erythroderma, pruritus, and atopy.

Summary:
Epidemiology
The prevalence is unknown; the disease is rare.
Clinical description
Skin anomalies manifest at birth or shortly thereafter. Patients show painless widespread, superficial asymptomatic and spontaneous peeling. Peeling of the skin consists of exfoliative white flakes of variable shape and size that evolves into mildly erythematous denuded areas with a peeling border. Palms and soles are spared or may show redness and mild skin thickening or hyperlinearity. Underlying erythroderma is present. Seasonal variations are generally observed. Pruritus is frequent and often severe, and is exacerbated with warm temperatures. In most cases, hair can be easily plucked (hair-anchoring deficiency). Mild to moderate nail changes are sometimes reported (koilonychia, onycholysis, thickness, yellowish appearance). Atopic manifestations are frequent (e.g. food allergies, episodes of angioedema, urticaria and asthma) and Staphylococcus aureus skin infections are reported. Patients are usually in good general health but may present with mild failure to thrive.
Etiology
PSS type B is an autosomal recessive monogenic disease caused by mutations in the CDSN gene (6p21.3). CDSN encodes corneodesmosin, an adhesive protein specific to corneodesmosomes, the cell-junction structures responsible for the cohesion of the stratum corneum. Most of these mutations (single nucleotide substitutions or deletions) result in total absence of the mutated protein in the epidermis which leads to impaired cell-cell adhesion, detachment of the epidermal corneal layers and disruption of the epidermal barrier that leads to increased penetration of allergens into the epidermis and an abnormal inflammatory response.
Diagnostic methods
Clinical presentation is highly suggestive of the disease. Total IgE levels can be markedly elevated. Histological examination of skin lesion biopsies reveals acanthosis, hyperkeratosis, parakeratosis and extensive detachment of the stratum corneum from the subjacent stratum granulosum. A moderate mononuclear infiltrate can be seen in the superficial dermis. Immunohistochemistry is a rapid and easy diagnostic test that shows an absence of corneodesmosin. Molecular analysis, confirms the diagnosis and reveals CDSN mutations.
Differential diagnosis
Differential diagnosis includes other forms of PSS (acral peeling skin syndrome, peeling skin syndrome type A), epidermolytic ichthyosis, autosomal recessive congenital ichthyosis, staphylococcal scalded skin syndrome, Netherton syndrome, severe dermatitis-multiple allergies-metabolic wasting (SAM) syndrome, atopic dermatitis and peeling skin induced by retinoid therapy.
Antenatal diagnosis
Genetic prenatal diagnosis is available for inherited ichthyoses and can be proposed for PSS type B because of the potential severity of the disease.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to affected families informing them of the risk of 25% for a healthy carrier parent to have an affected child.
Management and treatment
No effective treatment has been reported, especially for pruritus. Emollients are often used to reduce skin peeling. Topical and oral steroids, retinoids, methotrexate, dupilumab and UVB phototherapy have been tested but without any success. Antibiotic therapy is required to treat secondary infection.
Prognosis
The severity of PSS type B is variable. Life expectancy is normal but the disease may severely impair the quality of life because of pruritus, lack of effective treatment and complications due to associated manifestations.

                            Last update:
                            January 2023

                            - Expert reviewer(s):
                            Dr Nathalie JONCA  - Pr Juliette MAZEREEUW-HAUTIER | ERN-Skin*

                                * European Reference Network


A group of rare autosomal recessive forms of ichthyosis clinically characterized by superficial, asymptomatic, spontaneous peeling of the skin and histologically by a shedding of the outer layers of the epidermis. PSS presents with either an acral (acral PSS) or a generalized distribution for generalized PSS type A (noninflammatory) or B (inflammatory).


Peeling skin-leukonychia-acral punctate keratoses-cheilitis-knuckle pads syndrome

A rare genetic skin disease characterized by generalized skin peeling or superficial blisters without scarring, leukonychia, acral punctate keratoses coalescing into focal keratoderma on the weight-bearing areas, painful angular cheilitis, and knuckle pads with multiple hyperkeratotic micropapules. The skin appears dry and scaly with superficial exfoliation and underlying erythema. Histopathologic examination of affected skin areas is not specific and shows hyperkeratosis, acanthosis, and occasional intraepidermal clefting with irregular acantholysis.


A rare early childhood onset progressive encephalopathy characterized by extreme cerebellar atrophy, infantile-onset hypotonia, infantile spasms with hypsarrhythmia, profound intellectual disability, and optic atrophy. PEHO stands for the main features of the syndrome: Progressive encephalopathy with Edema, Hypsarrhythmia and Optic atrophy.

Summary:
Epidemiology
PEHO syndrome is enriched in the Finnish population, where the minimum incidence is estimated at 1 in 74,000. A few patients have been described from other countries including Estonia, The Netherlands, and Spain, but mainly before the molecular genetic analysis or neuroimaging techniques were available.
Clinical description
Onset occurs during the first few weeks or months of life with hypotonia, poor feeding, drowsiness and abnormal movements. Infantile spasms, hypsarrhythmia and seizures appear during the first year of life. Visual loss, abnormal eye movements and optic atrophy also occur during infancy. Other features include early arrest of psychomotor development, severe intellectual deficit, microcephaly, edema (particularly of the extremities), tapered fingers and facial dysmorphism (including a 'Pear-shaped' face with a narrow forehead and full cheeks, receding chin, epicanthic folds, an open mouth with a curved upper lip, protruding ear lobes and a short nose with anteverted nostrils).
Etiology
PEHO syndrome is an autosomal recessive disorder caused by mutations in the ZNHIT3 gene. ZNHIT3 encodes an evolutionarily conserved nuclear protein implicated in transcription regulation and chromatin remodeling.
Diagnostic methods
Diagnosis is based on molecular genetic testing. The clinical diagnostic criteria include: early-onset severe hypotonia; the occurrence of seizures, infantile spasms and hypsarrhythmia after the first two weeks of life; onset of optic atrophy before two years of age; and failure to obtain any of the milestones for motor, visual and language development. An additional criterion is demonstration of cerebellar and brainstem atrophy by MRI.
Differential diagnosis
A significant number of patients have been described as displaying most of the diagnostic criteria and features of PEHO syndrome, but without the typical changes in neuroimaging studies, or without ophthalmologic signs. This group of patients was diagnosed with PEHO-like syndrome. NESCAV syndrome also presents with PEHO-like features. The differential diagnosis should also include Aicardi syndrome, mevalonic aciduria, the carbohydrate-deficient glycoprotein (CDG) syndromes, autosomal recessive cerebellar hypoplasia, Joubert syndrome and olivo-pontine cerebellar atrophies.
Antenatal diagnosis
Prenatal diagnosis is available for the families with identified pathogenic variants.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Treatment is symptomatic only. The infantile spasms are refractory to antiepileptic drugs or adrenocorticotropic hormone (ACTH) therapy.
Prognosis
The prognosis is poor and most patients die before 15 years of age, mainly as a result of pneumonia or aspiration.

                            Last update:
                            April 2024

                            - Expert reviewer(s):
                            Dr Anna-Kaisa ANTTONEN | ITHACA*

                                * European Reference Network


PEHO-like syndrome is a rare, genetic neurological disease characterized by progressive encephalopathy, early-onset seizures with a hypsarrhythmic pattern, facial and limb edema, severe hypotonia, early arrest of psychomotor development and craniofacial dysmorphism (evolving microcephaly, narrow forehead, short nose, prominent auricles, open mouth, micrognathia), in the absence of neuro-ophthalmic or neuroradiologic findings. Poor visual responsiveness, growth failure and tapering fingers are also associated.


Pelizaeus-Merzbacher disease in female carriers

Pelizaeus-Merzbacher disease (PMD) in female carriers is the presentation of PMD (see this term) in some women carrying mutations in the PLP1 gene (Xq22).

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
Heterozygous females are not usually affected in families with the more severe PMD forms, including classical, transitional and connatal forms (see these terms), but are more likely to develop symptoms, possibly during adulthood, in families with more mildly affected males, such as in the null syndrome and SPG2 kindreds (see these terms). In some of the families with more severe male phenotypes, heterozygous females may manifest transient neurologic signs similar to those of boys with PMD, but from which they recover as they reach late childhood or adolescence.
Etiology
PMD is due to mutations or dosage alterations of the PLP1 gene (on Xq22) that cause hypomyelination of the central nervous system. PLP1 encodes the proteolipid protein (PLP), the most abundant protein of the myelin sheath in the central nervous system, and its alternatively spliced isoform (DM20). PMD is inherited as an X-linked disorder, usually with only males being affected. With the severe forms of the disease, oligodendrocytes undergo apoptosis. In heterozygous females, the degenerating oligodendrocytes are replaced by oligodendrocytes that have inactivated the mutated PLP1 allele. Therefore, unless there is severely unfavourably skewed X-inactivation, such females will be unaffected, and the disorder will have an X-linked recessive inheritance pattern. In contrast, in families where the PLP1 mutation causes little or no oligodendrocyte apoptosis, such as in the null syndrome, the defective oligodendrocytes survive in heterozygous females, who are more likely to have neurologic signs, typically later in adult life. In such cases, the disorder can be argued to have an X-linked dominant transmission pattern with variable penetrance.

                            Last update:
                            October 2011

                            - Expert reviewer(s):
                            Dr James GARBERN


Pelizaeus-Merzbacher disease, classic form

The classic form of Pelizaeus-Merzbacher disease (PMD) is the infantile form of PMD.

Summary:
Epidemiology
PMD has an estimated prevalence of 1/400,000. The classic form accounts for approximately 70% of all cases of PMD. It predominantly affects males.
Clinical description
The classic form of PMD manifests during the first months of life with nystagmus and hypotonia, which is progressively replaced by spasticity. Later signs include ataxia, sometimes associated with dystonia of the axis and limbs, weakness, dysarthria, impaired motor development and intellectual deficit. Patients may learn to walk with assistance and their speech is understandable but slow.
Etiology
The classic form of PMD is due most often to duplications but can also result from missense mutations of the PLP1 gene (on Xq22) that cause hypomyelination of the central nervous system. PLP1 encodes the proteolipid protein (PLP), the most abundant protein of the myelin sheath in the central nervous system, and its alternatively spliced isoform (DM20).
Genetic counseling
The disease has an X-linked inheritance pattern.

                            Last update:
                            October 2011

                            - Expert reviewer(s):
                            Dr James GARBERN


Pelizaeus-Merzbacher disease, connatal form

The connatal form of Pelizaeus-Merzbacher disease (PMD) is the most severe form of PMD (see this term).

Summary:
Epidemiology
PMD has an estimated prevalence of 1/400,000. The connatal form accounts for approximately 10 to 15 % of all cases of PMD. It predominantly affects males.
Clinical description
Connatal PMD presents, from birth, with hypotonia, nystagmus, respiratory distress, stridor, feeding difficulties and sometimes seizures. Subsequently, there is profound motor and cognitive delay and spastic quadriparesis. Patients never learn to walk, have limited language skills and usually die from respiratory complications by the second decade.
Etiology
The connatal form of PMD is due to missense mutations of the PLP1 gene (on Xq22) that cause hypomyelination of the central nervous system with profound myelin loss. PLP1 encodes the proteolipid protein (PLP), the most abundant protein of the myelin sheath in the central nervous system, and its alternatively spliced isoform (DM20).
Genetic counseling
The disease has an X-linked inheritance pattern.

                            Last update:
                            October 2011

                            - Expert reviewer(s):
                            Dr James GARBERN


Pelizaeus-Merzbacher disease, transitional form

The transitional form of Pelizaeus-Merzbacher disease (PMD) is the intermediate form of PMD (see this term).

Summary:
Epidemiology
PMD has an estimated prevalence of 1/400,000. The transitional form accounts for about 15% of all cases of PMD. It predominantly affects males.
Clinical description
The predominant clinical findings are early-onset nystagmus, initial hypotonia that is replaced by spasticity later in life, moderate cognitive impairment and inability to ambulate.
Etiology
The transitional form of PMD is most often due to missense mutations of the PLP1 gene (on Xq22) that cause hypomyelination of the central nervous system. Some duplications or triplications of the gene can also cause the transitional form. PLP1 encodes the proteolipid protein (PLP), the most abundant protein of the myelin sheath in the central nervous system, and its alternatively spliced isoform (DM20).
Genetic counseling
The disease has an X-linked inheritance pattern.

                            Last update:
                            October 2011

                            - Expert reviewer(s):
                            Dr James GARBERN


Pelizaeus-Merzbacher disease (PMD) is an X-linked leukodystrophy characterized by developmental delay, nystagmus, hypotonia, spasticity, and variable intellectual deficit. It is classified into three sub-forms based on the age of onset and severity: connatal, transitional, and classic PMD (see these terms).

Summary:
Epidemiology
The estimated prevalence is 1/400,000. PMD affects males but some female heterozygotes presenting with a milder phenotype have also been reported (PMD in female carriers; see this term).
Clinical description
The disease has a broad clinical spectrum. The connatal form is the most severe form presenting, since birth, with hypotonia, nystagmus, respiratory distress, and stridor, with subsequent motor and cognitive delay and spastic quadriparesis. The classic form manifests during the first 2 months of life with nystagmus and hypotonia which is progressively replaced by spasticity. Later signs include ataxia, impaired motor development and intellectual deficit. The transitional form is of intermediate severity between the connatal and classic forms. The mildest presentation of PMD (mild developmental and motor delay beginning at 2-3 years old, later associated with spastic paraplegia, ataxia, and/or mild intellectual deficit) is not clearly distinguishable from PLP1 null syndrome (see this term), which consists on mild PMD features associated with peripheral neuropathy, and complicated spastic paraplegia 2 (SPG2; see this term), a disorder primarily characterized by spastic gait in its pure form.
Etiology
PMD is an X-linked disorder due to mutations or dosage alterations of the PLP1 gene (Xq22) that cause hypomyelination of the central nervous system (CNS). PMD is allelic to SPG2 which is also due to PLP1 mutations. PLP1 encodes the proteolipid protein PLP1, the most abundant protein of the myelin sheath in the CNS, and its alternatively spliced isoform DM20. PLP1 duplications lead to the classic form, missense substitutions from connatal to pure SPG2 forms, and PLP1 null mutations to the null syndrome. Patients without PLP1 mutations but with similar clinical and nearly identical neuroradiologic features as PMD are referred to as having PMD-like disease (PMLD; see this term).
Diagnostic methods
Diagnosis is based on clinical, electrophysiologic, and neuroradiological findings. Magnetic resonance imaging (MRI) reveals complete (connatal, some transitional forms), partial (mild PMD) or diffuse (null syndrome) hypomyelination. Brainstem auditory evoked potentials (BAEP) may be helpful to differentiate PMD (lack of waves II-V) from PMLD (recordable II-V waves). Genetic testing confirms the diagnosis.
Differential diagnosis
Differential diagnosis includes Krabbe disease, Canavan disease, metachromatic leukodystrophy, Alexander disease, familial SPG, PMLD (see these terms), and cerebral palsy.
Antenatal diagnosis
Prenatal and preimplantation genetic testing are possible when a family's underlying PLP1 mutation has been identified.
Management and treatment
Management is multidisciplinary and involves neurologists, physical therapists, orthopedic doctors, pneumologists, and gastroenterologists. Treatment may include gastrostomy for dysphagia, antiepileptic drugs for seizures, physical therapy with antispasticity drugs (baclofen, diazepam, tizanidine) for spasticity, or corrective surgery for pulmonary compromise in case of severe scoliosis. Regular surveillance is necessary.
Prognosis
PMD has a progressive course that varies depending on the phenotype. In the most moderate forms, life expectancy is quite long and the disease progresses slowly after adolescence. In the most severe forms, death usually occurs by the second decade.

                            Last update:
                            October 2011

                            - Expert reviewer(s):
                            Dr James GARBERN


Pelizaeus-Merzbacher like disease (PMLD) is an autosomal recessive leukodystrophy sharing identical clinical and radiological features as X-linked Pelizaeus-Merzbacher disease (PMD; see this term).

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
It is characterized by early-onset nystagmus, delayed motor milestones, progressive spasticity, ataxia, and diffuse leukodystrophy on MRI.
Etiology
One PMLD form is due to mutations in the GJC2 gene encoding the gap junction protein C2. There are very likely other PMLD forms that have not been defined but that are caused by mutations affecting other genes involved in myelination. Other syndromes have also been referred to as PMLD but their inclusion as PMLD has been debated because of their severity and of the evidence of neuronal, besides white matter, involvement on MRI. These syndromes include an autosomal recessive syndrome due to mutations in the HSPD1 gene, encoding the heat shock protein 1, that resembles severe PMD (nystagmus, developmental delay, spasticity, feeding and breathing problems, early-onset lethality) and that is associated with acquired microcephaly, as well as a syndrome due to mutations in the AIMP1 gene, encoding the aminoacyl tRNA synthetase complex-interacting multifunctional protein 1, and characterized by nystagmus, axial hypotonia, spastic paraparesis, severe developmental delay, kyphoscoliosis, microcephaly, intellectual deficit, and absence of speech. An X-linked syndrome, allelic to Allan-Herndon-Dudley syndrome (see this term), has also been referred to as a PMLD. This syndrome is characterized by neonatal hypotonia, nystagmus, progressive spastic paraplegia, ataxia and developmental delay, and is due to mutations in the SLC16A2 gene encoding the monocarboxylate transporter 8 involved in thyroid hormone transport. However, MRI findings are not as severe as those of PMD (diffuse hypomyelination), and tend to improve over time, making this more of a delayed myelination disorder that is probably secondary to a neuronal dysfunction related to impaired thyroid hormone transport.

                            Last update:
                            October 2011

                            - Expert reviewer(s):
                            Dr James GARBERN


Pellagra is a nutritional disorder caused by a deficiency in niacin (vitamin B3) or its precursor (tryptophan) that is mainly observed in Asia and Africa where it is generally due to poor nutrition. It is characterized by dermatitis (symmetrical photodistributed erythema that may be accompanied by vesicles and bullae, and that develops into hyperkeratotic and hyperpigmented skin), gastrointestinal symptoms (diarrhea), and neuropsychiatric disorders (dementia). It can be life-threatening without a correct management.


A rare disorder of the anterior segment of the eye characterized by slowly progressive, bilateral, non-ulcerative, non-inflammatory, clear thinning of the inferior portion of the peripheral cornea (extending from the 4 o'clock to the 8 o'clock position), with an area of corneal protrusion above the point of maximal thinning, resulting in against-the-rule astigmatism with decreased visual acuity. The central cornea is of normal thickness.


Pelvic dysplasia-arthrogryposis of lower limbs syndrome is a rare, genetic, dysostosis syndrome characterized by intrauterine growth restriction, short stature (with short lower segment), lower limb joint contractures and muscular hypotrophy, narrow, small pelvis, lumbar hyperlordosis with scoliosis, and foot deformity (short, overlapping toes). Imaging reveals ovoid/wedge-shaped vertebral bodies, pelvic and skeletal hypoplasia with metatarsal fusion in the lower limbs, and normal skull and upper limbs.


Pelvis-shoulder dysplasia is a rare focal skeletal dysostosis characterized by symmetrical hypoplasia of the scapulae and the iliac wings of the pelvis.

Summary:
Epidemiology
Approximately 10 patients have been reported so far.
Clinical description
Additional skeletal abnormalities may include hypoplasia of the clavicles, ribs, femora and fibula, together with spina bifida and prominent lumbar lordosis. Eye anomalies (coloboma of iris and retina) have occasionally been reported. Intelligence is described as normal.
Etiology
Pelvis-shoulder dysplasia seems to be a genetically heterogeneous disorder but no causative genes have been identified so far.
Differential diagnosis
Pelvis-shoulder dysplasia is phenotypically similar to pelvis-scapular dysplasia (Cousin syndrome, which also presents with craniocervical abnormalities; see this term), and, according to some authors, the two entities represent different manifestations of the same disease.
Genetic counseling
Autosomal dominant inheritance has been described in some cases.

                            Last update:
                            December 2008

                            - Expert reviewer(s):
                            Pr Raoul HENNEKAM


Pelviscapular dysplasia (Cousin syndrome) is characterized by the association of pelviscapular dysplasia with epiphyseal abnormalities, congenital dwarfism and facial dysmorphism.

Summary:
Epidemiology
Pelviscapular dysplasia was initially described in a North African brother and sister. Two other unrelated patients (a German and a Turkish girl) from consanguineous families have recently been reported.
Clinical description
The facial dysmorphism is characterized by frontal bossing, hypertelorism, narrow palpebral fissures, deep-set eyes, strabismus, low-set posteriorly rotated and malformed ears, dysplasia of conchae, a small chin, a short neck with redundant skin folds, and a low hairline. Intelligence may vary from normal to moderately impaired. Pelviscapular dysplasia is phenotypically similar to pelvis-shoulder dysplasia (Kosenow syndrome, scapuloiliac dysostosis; see this term), and the two entities may represent different manifestations of the same disease. However, Kosenow syndrome is not associated with craniocervical abnormalities and seems to be inherited as an autosomal dominant trait.
Etiology
Mutations in the TBX15 gene have been identified as potentially causative.
Diagnostic methods
Radiographic features comprise aplasia of the body of the scapula, hypoplasia of the iliac bone, humeroradial synostosis, dislocation of the femoral heads, and moderate brachydactyly.
Genetic counseling
An autosomal recessive mode of transmission has been suggested.

                            Last update:
                            December 2008

                            - Expert reviewer(s):
                            Pr Raoul HENNEKAM


A rare autoimmune bullous skin disease characterized by pruritus with or without polymorphic skin eruption, affecting pregnant women typically during the second and third trimester.

Summary:
Epidemiology
The estimated incidence ranges between 1/3,000-60,000 pregnancies.
Clinical description
Pemphigoid gestationis (PG) typically presents during the second or third trimesters, although onset during the first trimester and postpartum is possible. Pruritus may remain the only symptom. Clinical presentation typically include urticarial papules and annular plaques, erythema multiform-like changes, eczematous lesions, or papulovesicles that in some cases may develop into large tense blisters. Lesions first erupt around the umbilicus and subsequently spread to the abdomen and the extremities. The mucous membranes and the face are typically spared. The clinical course is fairly benign and PG typically resolves with an average duration of 4-6 months. A flare may occur immediately after delivery but typically resolves within 4 weeks. There is an increased risk of small-for-gestational-age baby, premature birth, and development of mild, self-limiting skin lesions in the neonate (10-11% of cases). PG can be associated with the autoimmune Graves disease in the mother.
Etiology
PG is caused by production of anti-BP180 IgG antibodies that result from antigen presentation by MHC class II molecules aberrantly expressed on amniochorionic stromal cells and on the trophoblast. PG is strongly associated with maternal MHC class II antigens haplotypes HLA-DR3 and HLA-DR4.
Diagnostic methods
Clinical and histological features are not specific to PG; therefore, additional tests are required for diagnosis. Direct immunofluorescence demonstrates a linear deposition of C3 and IgG autoantibodies at the dermal-epidermal junction as in bullous pemphigoid. Indirect immunofluroescence detects serum IgG autoantibodies targeting the basement membrane of the skin in 30%-100% of cases. ELISA (enzyme-linked immunosorbent assay) can reveal circulating IgG antibodies against BP180.
Differential diagnosis
Differential diagnosis includes atopic eruption of pregnancy, polymorphic eruption of pregnancy, and intrahepatic cholestasis of pregnancy, herpes virus infection, urticaria, drug hypersensitivity reactions, contact dermatitis and other eczemas, pityriasis rosea, pityriasis versicolor, yeast folliculitis as well as other types of folliculitis, miliaria, and scabies.
Management and treatment
Most patients are controlled with potent or super-potent topical corticosteroids in combination with H1-receptor antagonists such as cetirizine. In more severe cases, oral corticosteroids are necessary. Preferred corticosteroids are prednisone and prednisolone. Minimum effective doses should be used to reduce the risk of side effects, and gradually tapered to a lower maintenance dose. If exacerbation in the peripartum period occurs, the maintenance dose can be increased. Ultraviolet light therapy is relatively contraindicated. In unresponsive cases, patients may benefit from systemic immunoadsorption, or intravenous immunoglobulin. In cases of persisting (postnatal) symptoms, systemic immunosuppressants might be beneficial.
Prognosis
The disease is typically self-limiting; however, onset in the first or second trimester and presence of blisters is associated with adverse pregnancy outcomes. Recurrence in subsequent pregnancies is common (35-50%), and is typically more severe with earlier onset. The disease can persist and converts to bullous pemphigoid (in less than 5% of patients).

                            Last update:
                            April 2020

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

                                * European Reference Network


A rare superficial pemphigus disease characterized clinically by well-demarcated, localized, erythematous, scaly, hyperkeratotic, crusted plaques, with frequent butterfly distribution over the malar area of the face (but also commonly involving trunk and scalp, and less frequently the extremities, with a photoexposed distribution). Histologically, granular deposits along the dermal-epidermal junction, in addition to intercellular deposition in the upper epidermis, are observed.


A rare superficial pemphigus disease characterized by multiple, pruritic, scaly, crusted cutaneous erosions, with flaky circumscribed patches, localized mostly on the face, scalp, trunk and extremities, often presenting an erythematous base. Mucosal involvement is rarely observed.


A rare autoimmune bullous skin disease characterized by mucocutaneous bullae with subsequent erosion and formation of vegetative plaques, predominantly affecting intertriginous areas and the oral mucosa. Two clinical forms of the disease are recognized: the Hallopeau type, which presents an indolent course with pustules healing as vegetative plaques and frequent lack of involvement of the oral mucosa, and the Neumann type, which takes a more severe, refractory course with vegetations developing during an eruption of vesiculobullous lesions and involvement of the oral mucosa. Serum analysis reveals antibodies against desmoglein 1 and 3.


A rare autoimmune bullous skin diseases characterized by painful, flaccid blisters and erosions of the oral mucosa, predominantly involving the buccal area, and with or without extension to the epidermis. Mucosa of the larynx, oesophagus, conjunctiva, nose, genitalia and anus, are less frequently affected.

Summary:
Epidemiology
Annual incidence worldwide ranges from 1/143,000 to 1,430,000.
Clinical description
Onset occurs on average at 50-60 years, although childhood onset forms have been described. The disease begins with blisters (bullae) in the mouth, which are often mistaken for aphthae. The blisters are flaccid and are easily broken, often leading to painful lesions or erosions. The disease is classified into three subtypes: mucosal dominant type with blisters in the deep layers of the oral mucosa and limited cutaneous involvement, the mucocutaneous type involving both the mucosa and epidermis, and the cutaneous type with blisters in the deep layers of the epidermis only. Blistering can also affect the oesophagus, rectum, nose or the lining of the eyelids. Skin lesions appear several weeks or several months after the onset of mucosal erosions. Nikolsky's sign can appear on perilesional skin or, in some cases, even on healthy skin. Pemphigus vegetans is a clinical variant characterized by intertriginous lesions developing into vegetating plaques.
Etiology
The exact etiology of the disease is unknown. Autoantibodies directed against desmosome components cause acantholysis and intraepidermal cleft. In pemphigus vulgaris, autoantibodies bind to desmogleine 1 and 3 (keratinocyte membrane molecules).
Diagnostic methods
Diagnosis should be considered in the presence of bullae on chest or scalp. It can be confirmed by standard histopathological analysis and direct immunofluorescence (DIF) test. Intraepidermal blisters due to suprabasal acantholysis and IgG (mostly IgG1 and IgG4) and/or C3 complement deposits can be detected at the cell surface of keratinocytes. The disease grade is correlated with the level of circulating antibodies.
Differential diagnosis
Differential diagnosis includes the full range of subepidermal diseases, mainly mucous membrane pemphigoid and epidermolysis bullosa acquisita. Oral erosive lichen planus and recurrent buccal aphtosis are characterized by a negative DIF pattern.
Management and treatment
Systemic steroid therapy, given as a 12-month course in absence of relapse, is the treatment of choice. Rituximab can be proposed at first line therapy in association with systemic steroids. Immunosuppressant drugs can be administered in case of relapse or non-responsive disease
Prognosis
The prognosis of pemphigus has markedly improved over the last decades with steroid therapy. Nevertheless, mortality remains an issue (5% of cases). In these cases, death occurs during the first years of disease progression, mostly as a consequence of treatment-related systemic infections and in a smaller proportion, as a consequence of superinfected lesions. Prognosis can be improved by early use of rituximab allowing a rapid tapering of steroids.

                            Last update:
                            June 2020

                            - Expert reviewer(s):
                            Pr Christophe BEDANE


A syndromic genetic deafness clinically variable characterized by bilateral sensorineural hearing loss and euthyroid goiter.

Summary:
Epidemiology
Pendred syndrome (PDS) is one of the most frequent forms of syndromic genetic deafness. Although precise prevalence is unknown, PDS may account for up to 7.5% of cases of congenital hearing loss.
Clinical description
Considerable phenotypic variability is found even within families. The main presenting clinical sign is prelingual sensorineural deafness, although occasionally the hearing loss develops later in childhood. The degree of hearing loss is variable: it can be mild-to-moderate and progressive in some patients, and severe-to-profound in others. Fluctuations in hearing are also common and may be associated with or preceded by vertigo. The onset and presentation of euthyroid goiter (75%) is highly variable within and between families, with thyroid enlargement usually developing in late childhood or early adulthood. The thyromegaly reflects a defect in iodide transport from the thyrocyte to the colloid, although organification itself is not impaired. Hypothyroidism may develop if nutritional iodide intake is low. Genetic deafness at the DFNB4 locus is part of the phenotypic spectrum that includes PDS at one extreme and autosomal recessive non-syndromic sensorineural deafness type DFNB4 at the other. In patients with the latter disease, thyroid function is normal.
Etiology
Biallelic or double heterozygous genetic mutations are identified in about half of patients: biallelic mutations in SLC26A4 (7q31), or double heterozygous mutations in SLC26A4 and FOXI1 (5q34), or in SLC26A4and KCNJ10 (1q23.2). Nearly all mutations identified in SLC26A4 are biallelic and affect the encoded protein, pendrin, a 780-amino acid multifunctional anion exchanger. Less than 1% of affected persons present with double heterozygous mutations.
Diagnostic methods
The diagnosis of PDS is based on the presence of hearing impairment, temporal bone anomalies of the inner ear, and an abnormal perchlorate discharge test (if available) or goiter. The anomalies can be diagnosed by computed tomography (CT) and/or magnetic resonance imaging (MRI), although the former provides better resolution of bony changes. Diagnosis is confirmed by molecular genetic testing which is available clinically.
Differential diagnosis
The differential diagnosis includes congenital cytomegaloviral infection (cCMV), BOR syndrome, and deafness at the DFNX2 locus (POU3F4).
Antenatal diagnosis
Prenatal testing for at-risk pregnancies is possible when mutations in a family are known.
Genetic counseling
PDS follows an autosomal recessive pattern of inheritance. Genetic counseling should be provided to affected families.
Management and treatment
Management includes annual audiograms with suitable amplification (hearing aids) as soon as hearing impairment is diagnosed. Patients with severe-to-profound hearing loss should be evaluated for cochlear implantation, and when appropriate, specific educational programs for the hearing impaired should be considered. Abnormal thyroid function should be treated with standard therapy.
Prognosis
Patients with PDS may have progressive hearing loss, although it is not yet possible to identify these patients in advance. As a general rule, however, progression of hearing loss is more common in patients with more severe inner ear anomalies.

                            Last update:
                            August 2019

                            - Expert reviewer(s):
                            Pr Richard SMITH


Penile agenesis is a rare urogenital tract malformation characterized by complete congenital absence of the phallus. It is usually accompanied by a well-developed scrotum and presence of a skin tag at the anal verge (with or without a urethral meatal opening within it). Often, other genitourinary (e.g. cryptorchidism, renal agenesis and dysplasia, urinary reflux, prostate agenesis) as well as non-genitourinary abnormalities (including skeletal and neural disorders, anal stenosis, imperforate anus, cardiac defects) are associated.


A rare congenital genital anomaly in which the scrotum is positioned superior and anterior to the penis. PST may present with a broad spectrum of anomalies ranging from simple shawl scrotum (doughnut scrotum) to very complex extreme transposition with craniofacial, central nervous system, cardiac, gastrointestinal, urological, and other genital (undescended testicles, hypospadias, chordee) malformations. Growth deficiency and intellectual disability may also be noticed (60% of cases).


PENS syndrome is a rare, genetic, neurocutaneous syndrome characterized by the presence of randomly distributed, small, white to yellowish, multiple, rounded or irregular polycyclically-shaped, epidermal keratotic papules and plaques of ''gem-like'' appearance with a rough surface, typically located on the trunk and proximal limbs, associated with variable neurological abnormalities, including psychomotor delay, epilepsy, speech and language impairment and attention deficit-hyperactivity disorder. Clumsiness, dyslexia and oftalmological abnormalities have also been reported.


Pentalogy of Cantrell (POC) is a lethal multiple congenital anomalies syndrome, characterized by the presence of 5 major malformations: midline supraumbilical abdominal wall defect, lower sternal defect, diaphragmatic pericardial defect, anterior diaphragmatic defect and various intracardiac malformations. Ectopia cordis (EC) is often found in fetuses with POC.

Summary:
Epidemiology
The prevalence of POC is estimated to be 1/65,000-1/200,000 live births.
Clinical description
POC is a congenital disorder characterized by the presence of 5 major malformations: midline supraumbilical abdominal wall defect (diastasis recti, epigastric and umbilical hernia), lower sternal defect (sternal cleft (see this term), absent xiphoid process, short sternum and defective formation of lower two third), diaphragmatic pericardial defect, anterior diaphragmatic defect and heart malformations (ventricular septal defect (72%), interauricular communication (35%), cardiac diverticulum (32%), congenital pulmonary valve stenosis (PS; 31%) (isolated PS or in combination with double outlet right ventricle in fetuses with EC and univentricular heart in fetuses without EC), tetralogy of Fallot (17%), dextrocardia (15%), and transposition of the great arteries (TGA; 6%) (see these terms)). Thoraco-abdominal wall defects may lead to omphalocele (see this term) and EC, with the heart located outside the thoracic wall and sometimes covered by pigmented loose skin. The heart can be partially or completely repositioned into the thoracic cavity when the patient is in a supine position. Neonates usually present with severe respiratory distress and cyanosis. Additional features that may be observed include craniofacial and central nervous system (CNS) anomalies (cleft lip and/or palate, encephalocele, craniorachischisis (see these terms) and hydrocephalus), limb defects (club foot, absence of tibia/radius, hand and foot oligodactyly, phocomelia (see this term), and abdominal organ defects (gallbladder agenesis and polysplenia, as part of heterotaxia (see this term)). POC may occur in association with Trisomy 13, 18, Down syndrome and Turner syndrome (see these terms).
Etiology
The etiology of POC is still unknown. It has been postulated that at around 14 to 18 days post conception, a failure of the lateral mesodermal folds to migrate to the midline may cause the sternal and abdominal wall defects and abnormal development of the septum transversum result in defects in the anterior diaphragm and pericardium.
Diagnostic methods
Diagnosis of complete POC relies on the following classification: class 1, a definite diagnosis, when all 5 defects are present; class 2, a probable diagnosis with 4 defects being present, including intracardiac and ventral wall abnormalities; and class 3, an incomplete expression with various combinations of defects being present, including a sternal abnormality.
Differential diagnosis
Differential diagnosis includes limb body wall complex, omphalocele (see these terms), thoracic EC and amniotic bands (see this term).
Antenatal diagnosis
Prenatal diagnosis can be made in first-trimester ultrasonography by detection of multiple thoraco-abdominal defects, including EC and CNS anomalies.
Genetic counseling
POC usually occurs sporadically but rare cases of chromosomal anomalies, autosomal or X-linked transmission have also been reported.
Management and treatment
Management is surgical, consisting of palliative repair of the ventral hernia and diaphragmatic defect and palliative or corrective repair of the cardiovascular anomalies. Surgical repair to relocate the heart into the chest cavity is usually performed in the neonatal period or in infancy. For patients unable to tolerate a single-staged approach, an intraoperative ''heart restoring'' trial may be proposed. If heart position can be successfully restored without obvious hemodynamic changes, one-staged operation is advised; if hemodynamic changes are minor, a combined operation may be possible.
Prognosis
The prognosis of POC is poor and only few patients survive through early childhood. The main causes of death are tachyarrhythmias, bradycardia, low blood pressure, rupture of the diverticulum, and heart failure.

                            Last update:
                            January 2015

                            - Expert reviewer(s):
                            Dr Suresh CHANDRAN


Pentasomy X is a sex chromosome anomaly caused by the presence of three extra X chromosomes in females (49,XXXXX instead of 46,XX).

Summary:
Epidemiology
The prevalence is unknown but less than 40 cases have been described in the literature so far.
Clinical description
Pentasomy X is associated with developmental delays, short stature, craniofacial anomalies and musculoskeletal abnormalities. The craniofacial anomalies may include microcephaly, micrognathia, plagiocephaly, hypertelorism, upslanting palpebral fissures, a flat nasal bridge and ear malformations. The hands and feet are generally small and camptodactyly, clinodactyly, and radioulnar synostosis are common findings. Immunoglobulin anomalies and an increased susceptibility to infection have also been reported. Cardiovascular malformations may also be present. External genitalia are generally normal but gonadal dysfunction has been reported. Developmental profiles usually show global developmental delay and intellectual disability; however, receptive language skills are usually less severely affected than expressive language abilities.
Etiology
Pentasomy X is generally thought to arise as a result of successive maternal nondisjunction during meiosis.

                            Last update:
                            January 2010

                            - Expert reviewer(s):
                            Dr Natalie AYARI  - Dr A BERGE  - Dr Susan HOWELL  - Dr Nicole TARTAGLIA


Pentosuria is an inborn error of metabolism which is characterized by the excretion of 1 to 4 g of the pentose L-xylulose in the urine per day.

Summary:
Epidemiology
The condition occurs essentially in Ashkenazi Jews with an estimated incidence of the heterozygote mutation of 1/79.
Clinical description
Pentosuria is benign and shows no symptoms. The sole biological feature is the constant excretion of L-xylulose in the urine that may be mistaken with glycosuria.
Etiology
It is due to mutations in the DCXR gene on chromosome 17 that codes for L-xylulose reductase (or L-xylitol dehydrogenase), an enzyme that catalyzes the conversion of 1-xylulose into xylitol.
Genetic counseling
Transmission is autosomal recessive.

                            Last update:
                            August 2011


Pericardial and diaphragmatic defect is a rare combination of absent pericardium with congenital diaphragmatic defect.

Summary:
Epidemiology
It has been reported in less than 20 patients.
Clinical description
The absence of pericardic tissue is complete or partial. The diaphragmatic hernia is most often left-sided. Some patients have additional digestive tract malformations.
Genetic counseling
The few reported cases were all sporadic except in a family in which the recurrence of these anomalies in two sibs and the parental consanguinity suggested an autosomal recessive inheritance.

                            Last update:
                            October 2010


A rare, genetic form of hypophosphatasia (HPP) characterized by markedly impaired bone mineralization in utero due to reduced activity of serum alkaline phosphatase (ALP) and causing stillbirth or respiratory failure within days of birth.

Summary:
Epidemiology
Incidence of Perinatal lethal hypophosphatasia (PL-HPP) is not known. However, the birth prevalence for severe HPP (both perinatal-lethal and infantile forms) is estimated at 1/300,000 in North and West Europe.
Clinical description
Affected infants may have characteristic skin-covered osteochondral spurs protruding from the forearms or legs and often a small thoracic cavity. They may have hypercalcemia associated with apnea or seizures, and marked shortening of the long bones. Patients rarely survive for more than a few days due to inadequate chest size, hypoplastic lungs and rachitic deformities, leading to respiratory failure.
Etiology
Loss of function mutations in the ALPL gene (1p36.12) are known to cause hypophosphatasia. The specific mechanisms underlying PL-HPP have not been elucidated.
Diagnostic methods
Diagnosis is suspected either on prenatal ultrasound findings or clinical presentation at birth, and confirmed by genetic testing (Sanger or next generation sequencing of ALPL).
Differential diagnosis
A benign form of HPP (prenatal benign HPP) has been described in which skeletal abnormalities resolve spontaneously and patients subsequently develop nonlethal HPP, often adult or childhood HPP. Osteogenesis Imperfecta is the most frequent differential diagnosis of this severe form of HPP. Other differential diagnoses include campomelic dysplasia, chondrodysplasia and Stuve Wiedemann syndrome.
Antenatal diagnosis
Suspicious ultrasound findings include short and/or bowed limbs, skeletal hypomineralization, osteochondral spurs and, sometimes, the absence of certain bones (skull, ribs, vertebrae, pubis). Confirmation by genetic testing is indispensable, although correlation between the genotype and the prognosis remains a challenge. Genetic prenatal testing is also possible in at risk families with a previous index case and where at least one mutation has been identified.
Genetic counseling
The reported pattern of inheritance in this form of HPP is autosomal recessive but is not necessarily predictive of the lethal form of HPP.
Management and treatment
Ventilation support is initiated shortly after birth. Prompt diagnosis is essential in order to start targeted therapy. Asfotase alfa is approved (Europe and USA) for enzyme replacement therapy (ERT) in patients with pediatric-onset hypophosphatasia and is associated with improvement of the skeletal manifestations as well as respiratory and motor function.
Prognosis
Perinatal HPP is of poor prognosis when not treated with ERT; however, long term prognosis with ERT is currently unknown.

                            Last update:
                            February 2020

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


Periodic fever-infantile enterocolitis-autoinflammatory syndrome

A rare genetic systemic or rheumatologic disease characterized by neonatal or infantile onset of enterocolitis (which resolves with age), periodic fever, and episodes of severe systemic inflammation, which may be precipitated by infections, stress, or fatigue. Signs and symptoms include splenomegaly, urticaria-like rashes, arthralgia, and myalgia. Associated laboratory findings are elevated inflammatory markers (such as ferritin, C-reactive protein), pancytopenia, and elevated transaminases. If left untreated, flares can progress to coagulopathy, organ failure, and death.


Periodic paralysis with later-onset distal motor neuropathy is a rare, genetic, neuromuscular disease characterized by acute episodic muscle weakness in upper and lower extremities (which responds to acetazolamide treatment) associated with later-onset, chronic, slowly progressive, distal, axonal neuropathy.


Periodic paralysis with transient compartment-like syndrome

A rare genetic neuromuscular channelopathy characterized by normokalemic episodes of painful muscle cramping followed by progressive, permanent, flaccid weakness, triggered by stress, cold and exercise, associated with myopathic myopathy and painful acute edema with neuronal compression, foot drop and muscle degeneration when located in the tibialis anterior muscle group.


A rare type of Ehlers-Danlos syndrome characterized by childhood or adolescence onset of severe, intractable periodontitis, lack of attached gingiva, and presence of pretibial plaques. Additional manifestations are easy bruising, hypermobility mainly of the distal joints, skin hyperextensibility and fragility, abnormal scarring, recurrent infections, hernias, marfanoid facial features, acrogeria, and prominent vasculature.


A rare epilepsy syndrome characterized by absence seizures with perioral myoclonia as the main seizure type, accompanied by generalized tonic-clonic seizures, appearing before or together with absences. Consciousness is usually impaired, although to variable degree. Commonly observed absence status epilepticus, poor response to antiepileptic drugs and persistence of seizures into adulthood, in the presence of normal neurological status and intelligence, are additional clinical features of this syndrome.


A rare congenital optic disc excavation characterized by deep fundus excavation of chorioretinal atrophy surrounding a relatively normal appearing optic disc. Retinal vasculature is normal, and retinochoroidal coloboma and glial anomalies are absent. Patients present with mostly unilateral markedly reduced visual acuity. Association with other congenital defects or systemic diseases is uncommon.


Peripartum cardiomyopathy (PPCM) is an idiopathic, potentially fatal form of dilated cardiomyopathy that develops during the final month of pregnancy or within five months after delivery.


Peripheral demyelinating neuropathy-central dysmyelinating leukodystrophy-Waardenburg syndrome-Hirschsprung disease (PCWH) is a systemic disease characterized by the association of the features of Waardenburg-Shah syndrome (WSS) with neurological features of variable severity.

Summary:
Epidemiology
Prevalence is unknown. Less than 50 cases have been reported in the literature so far.
Clinical description
PCWH occurs in the neonatal and infancy period, and includes features of WSS (sensorineural hearing loss, iris heterochromia, skin hypopigmentation associated with Hirschsprung disease) and neurological features (neonatal hypotonia, intellectual disability of variable severity, nystagmus, progressive spasticity, ataxia and epilepsy). These signs are not fully penetrant (PCWH without Hirschsprung disease is sometimes referred as PCW), the depigmentation may not be obvious, and there is a broad range of severity for the neurologic features. Autonomic dysfunction (asialia, alacrima and hypohidrosis, bradycardia and arrhythmia) may also be present. Delayed white matter myelination is observed on brain magnetic resonance imaging (MRI), and may also be responsible for neuropathy at the peripheral level. MRI often shows defects of the semi-circular canals and agenesis of the olfactory bulbs. Kallmann syndrome can be associated.
Etiology
Most of the cases are caused by mutations involving the SOX10 gene (22q13.1, coding for the SOX10 transcription factor). Most frequently truncating mutations of the last coding exon induce escape from NMD (non-sense mediated mRNA decay), although a few gene deletions and missense mutations have also been described.
Diagnostic methods
Diagnosis is suspected on recognition of the clinical picture and should be confirmed by genetic molecular analysis.
Differential diagnosis
The disease overlaps with central or peripheral neuropathies/dysmyelination, and the diagnosis may be difficult in absence of the typical Waardenburg syndrome depigmentation.
Antenatal diagnosis
Prenatal diagnosis is possible by fetal DNA mutation analysis if a causal mutation is identified in a member of the family (either in case of an affected parent (a rare situation) or due to the risk of germline mosaicism).
Genetic counseling
The inheritance pattern of PCWH is autosomal dominant (parents of an affected individual have a probability of 50% to transmit the causal mutation to the offspring). Most cases are sporadic but a few patients with an affected sibling have been reported and are associated with germinal mosaicism in one of the parents. Genetic counseling should be offered to affected families in order to provide more information about this genetic condition, its risk of recurrence and the availability of prenatal diagnosis.
Management and treatment
Management is only symptomatic, consisting in the management of WS (protection from exposure to ultraviolet light, avoidance of sunburn, management of hearing loss), Hirschprung disease (surgical treatment) and the neurologic manifestations.
Prognosis
The prognosis and disease course may be severe with onset of deafness, intellectual disability and sometimes motor impairment. In rare cases, the disease is fatal shortly after birth. Long-term evolution in adulthood is not well established.

                            Last update:
                            March 2018

                            - Expert reviewer(s):
                            Dr Véronique PINGAULT


Peripheral motor neuropathy-dysautonomia syndrome is characterised by distal, slowly progressive muscular weakness, childhood-onset amyotrophy, autonomic dysfunction characterized by profuse sweating, distal cyanosis related to cold weather, orthostatic hypotension, and esophageal achalasia. It has been described in two sisters. Inheritance appears to be autosomal recessive.


Peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome is a rare, syndromic genetic deafness characterized by a combination of muscle weakness, chronic neuropathic and myopathic features, hoarseness and sensorineural hearing loss. A wide range of disease onset and severity has been reported even within the same family.


Peripheral primitive neuroectodermal tumor

A rare, aggressive, malignant, neoplastic disease characterized by a usually ill-defined, solid, multilobulated mass, frequently having necrosis, located on any site of the body (except the central nervous system), composed of small, round, poorly differentiated cells, with or without Homer-Wright rosettes, showing varying degrees of neuroectodermal differentiation. Manifestations are variable depending on location, with osteolytic destruction being common when arising from bone.


Peripheral pulmonary stenosis is a rare congenital anomaly of the great arteries that may occur at single or multiple sites, in isolation or in association with other congenital heart defects (valvular pulmonary stenosis, atrial, or ventricular septal defects or tetralogy of Fallot) and genetic syndromes (Williams, Alagile syndrome). Clinical presentation is variable and includes heart murmurs, dyspnea, syncope, chest pain and pulmonary hypertension-associated symptoms.


Peritoneal cystic mesothelioma is a rare benign tumor characterized by the formation of intra-abdominal multilocular cystic masses.

Summary:
Epidemiology
Fewer than 150 cases have been reported to date. It occurs more frequently in women of child-bearing age.
Clinical description
Clinical features include lower abdominal or pelvic pain, presence of a palpable mass, amenorrhea, dysuria, dyspareunia, and more rarely weight loss. In women, the masses are generally located on the peritoneal surface of the uterus and rectum, while in men they are generally located on the peritoneal surface of the bladder and rectum. The tumor can also spread into the upper portions of the peritoneal cavity.
Etiology
Peritoneal cystic mesothelioma seems to originate from the peritoneal mesothelium. However, etiology is unknown. There is no relation with asbestos exposure. Peritoneal cystic mesothelioma occurs frequently in women with previous history of surgery, pelvic inflammation or endometriosis. Chronic peritoneal irritation may be an aggravating factor.
Diagnostic methods
Diagnosis is based on abdominal and pelvic ultrasound, abdominal computerized tomography (CT) and laparoscopic examination that reveal abdominal multicystic separated grapelike structures. Biopsy shows vascularized, translucent fluid-filled, thin-walled cysts composed of loose connective tissue. Immunohistochemistry confirms the diagnosis by showing the mesothelial origin of the parietal cells (this examination must be reviewed by an expert pathologist).
Differential diagnosis
The main differential diagnoses include cystic peritoneal lymphangioma, pseudomyxoma peritonei (see this term), and other cystic neoplastic lesions.
Management and treatment
The treatment approach is multidisciplinary and must be discussed by a panel of physicians in a specialized center. There are currently no validated recommendations on clinical management and no cytotoxic agents have been granted a European Marketing Authorization (MA) in this indication. Treatment is surgical and is based on ablation of cysts. In case of recurrence or even in first-line treatment, certain teams have proposed combination of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) (off-label use) in specific patients (young patients with good general status).
Prognosis
Prognosis is usually good. 5-year survival is 100% when the combined treatment is given. With surgery alone, disease inevitably recurs or persists. Invasive or malignant progression has been described.

                            Last update:
                            March 2011

                            - Expert reviewer(s):
                            Pr Olivier GLEHEN