A rare soft tissue tumor characterized by distinctive perivascular epitheloid cells, often arranged radially around a vascular lumen, as well as spindled cells in variable proportion. Melanocytic and muscle markers are typically positive. The tumors have been reported in the uterus, falciform ligament, and large and small intestine, among others. Depending on their location, they may present as a painful or painless mass, or with vaginal bleeding. Tumors displaying infiltrative growth, marked hypercellularity, nuclear enlargement and hyperchromasia, high mitotic activity, atypical mitotic figures, and/or coagulative necrosis should be regarded as malignant.


Periventricular nodular heterotopia (PNH) is a brain malformation, due to abnormal neuronal migration, in which a subset of neurons fails to migrate into the developing cerebral cortex and remains as nodules that line the ventricular surface. Classical PNH is a rare X-linked dominant disorder far more frequent in females who present normal intelligence to borderline intellectual deficit, epilepsy of variable severity and extra-central nervous system signs, especially cardiovascular defects or coagulopathy. The disorder is generally associated with prenatal lethality in males.


Perlman syndrome is characterized principally by polyhydramnios, neonatal macrosomia, bilateral renal tumours (hamartomas with or without nephroblastomatosis), hypertrophy of the islets of Langerhans and facial dysmorphism.

Summary:
Epidemiology
So far, about 30 patients have been reported in the literature.
Clinical description
The facial dysmorphism is considered as characteristic with upsweeping anterior scalp hair, a depressed nasal bridge, hypotonic appearance with an open mouth, a prominent everted upper lip, and mild micrognathia. Agenesis of the corpus callosum, choroid plexus haemangiomas, cleft palate, dextroposition of the heart, interrupted aortic arch, diaphragmatic hernia, visceromegaly including nephromegaly, hepatomegaly, cardiomegaly, thymus hyperplasia, hepatic fibrosis with porto-portal bridging, abdominal muscular hypoplasia, distal ileal atresia, and cryptorchidism were also described in some patients and maybe components of this syndrome. Hyperinsulinism appears to be an important feature of this disease and may be a preventable cause of death.
Differential diagnosis
The principle differential diagnoses are the Beckwith-Wiedemann (BWS) and Simpson-Golabi-Behmel syndromes (see these terms): mutations the GPC3 gene were excluded as being causative anomalies in several publications and genetic or epigenetic alterations of the 11p15 region (involved in BWS) have never been reported in patients with Perlman syndrome, despite the strong phenotypic similarities between the two syndromes.
Antenatal diagnosis
Prenatal diagnosis may be oriented by ultrasonography searching for macroglossia and renal anomalies (cysts or hypertrophy).
Genetic counseling
The syndrome appears to be inherited in an autosomal recessive manner.
Management and treatment
Management is supportive and should be multidisciplinary.
Prognosis
The prognosis for Perlman syndrome is poor with a high mortality rate, especially in the neonatal period, due to sepsis or progressive respiratory insufficiency. Among the infants who survived beyond the neonatal period, two thirds developed a Wilms' tumor and most had some degree of developmental delay. However, one girl was reported to be alive at the age of 9 and displayed normal psychomotor development.

                            Last update:
                            May 2008

                            - Expert reviewer(s):
                            Pr Alain VERLOES


Permanent congenital hypothyroidism is a type of congenital hypothyroidism (CH; see this term), a thyroid hormone deficiency present from birth.

Summary:
Epidemiology
Incidence of permanent CH varies widely with geographic location with reported incidences between 1/800 and 1/10,000 live births and an average incidence of 1/3,000 live births.
Clinical description
The clinical manifestations are often subtle, probably as a result of trans-placental passage of some maternal thyroid hormone or due to the fact that many infants have some thyroid production of their own.More specific symptoms and signs often do not develop until several months of age. Common clinical features and signs include decreased activity and increased sleep, feeding difficulty and constipation, prolonged jaundice, myxedematous facies, large fontanels (especially posterior), macroglossia, a distended abdomen with umbilical hernia, and hypotonia. Slow linear growth and developmental delay are usually apparent by 4-6 months of age. Without treatment CH results in severe intellectual deficit and short stature.
Etiology
Permanent CH has a variety of primary, secondary and peripheral causes and may occur as part of a syndrome (primary, secondary, peripheral or syndromic hypothyroidism; see these terms). Primary causes include defects in thyroid gland development (thyroid dysgenesis; see this term), deficiencies in thyroid hormone production (thyroid dyshormonogenesis; see this term), or defects of thyroid-stimulating hormone (TSH) binding or signal transduction (due to TSH receptor mutations; see this term). Secondary or central CH is most commonly due to a pituitary defect. Other causes include isolated TSH deficiency (see this term), which is transmitted in an autosomal recessive manner and is caused by mutations in the TSH beta subunit gene (1p13), by thyrotropin releasing hormone (TRH) resistance (see this term), which results from mutations in the TRH receptor gene (TRHR; 8q23), or by mutations in genes regulating pituitary gland development (see this term) including HESX1, LHX3, LHX4, POU1F1 and PROP1 (3p21.2-p21.1, 9q34.3, 1q25, 3p11 and 5q). Peripheral CH (see this term) may be caused by peripheral resistance to the action of thyroid hormone (see this term), of which 90% of cases are due to dominantly inherited mutations in genes encoding for thyroid hormone receptor beta. The majority of these individuals have normal thyroid function but some hypothyroid individuals have been described. Peripheral hypothyroidism may also be caused by defects in thyroid hormone transport, such as in Allan-Herndon-Dudley syndrome (see this term) where X-linked peripheral hypothyroidism is associated with intellectual deficiency and neurologic abnormalities including quadriplegia. Permanent CH may also be associated with a syndrome such as Pendred or Bamforth syndromes among others (see these terms).
Management and treatment
Recombinant human TSH (rhTSH) may be of use in the future confirmation of permanent CH. If at any time after the first 6 months of age, the serum TSH rises above 20mU/L due to undertreatment, permanent CH is assumed. If permanent CH has not been established by 2-3 years of age a 30 day trial off l-thyroxine therapy is recommended. If serum or free T4 is low and TSH elevated, permanent CH is confirmed and the patient is restarted on therapy.

                            Last update:
                            August 2010

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


Permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome

A rare neurologic disease characterized by neonatal diabetes mellitus associated with cerebellar and/or pancreatic agenesis. Absence or hypoplasia of the cerebellum and severe intra-uterine growth retardation can be detected prenatally. Patients also present with facial dysmorphism (a triangular face, small chin, low set ears), flexion contractures of the arms and legs, very little subcutaneous fat, and optic nerve hypoplasia. The disease is lethal in the neonatal period.


Peroxisomal acyl-CoA oxidase deficiency is a rare neurodegenerative disorder that belongs to the group of inherited peroxisomal disorders and is characterized by hypotonia and seizures in the neonatal period and neurological regression in early infancy.

Summary:
Epidemiology
Acyl-CoA oxidase deficiency is a rare disease with only 30-40 patients identified world-wide so far.
Clinical description
The disease manifests in the neonatal period with hypotonia (92%) and seizures (91%) as dominant features. Facial dysmorphism (50%) with hypertelorism, epicanthus, low nasal bridge, and low-set ears may be present. Some children have polydactyly and hepatomegaly. Psychomotor development is delayed, but children are usually able to walk and say a few words. However, neurological regression occurs usually at the age of 1-3 years (mean age: 28 months). Hypotonia is replaced by hypertonia with hyperreflexia. Epilepsy may become more severe and sensorineural hearing loss may appear. Strabismus, nystagmus, and optic atrophy can also occur.
Etiology
Peroxisomal acyl-CoA oxidase deficiency is caused by mutations in the ACOX1 gene (17q25.1) encoding peroxisomal straight-chain acyl-CoA oxidase.
Diagnostic methods
Diagnosis is based on laboratory studies revealing increased serum very-long chain fatty acids (VLCFA) and markedly reduced acyl-CoA oxidase activity in fibroblasts. MRI examination of the brain shows abnormal white matter signals. Diagnosis can be confirmed by the presence of mutations in the ACOX1 gene.
Differential diagnosis
Differential diagnoses include Usher syndrome (see this term) and all causes of neonatal hypotonia. The other peroxisomal disorders should also be discarded, especially neonatal adrenoleukodystrophy (see this term), which presents similar clinical manifestations.
Antenatal diagnosis
Antenatal diagnosis is possible through biochemical and/or molecular analysis of amniocytes or chorionic villus cells.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to the families of patients.
Management and treatment
No specific treatment is available. Multidisciplinary supportive care should be offered.
Prognosis
Prognosis is unfavorable; death usually occurs at around 5 years from respiratory issues.

                            Last update:
                            February 2010

                            - Expert reviewer(s):
                            Pr R.J.A. [Ronald] WANDERS


Peroxisome biogenesis disorders, Zellweger syndrome spectrum (PBD-ZSS) is a group of autosomal recessive disorders affecting the formation of functional peroxisomes, characterized by sensorineural hearing loss, pigmentary retinal degeneration, multiple organ dysfunction and psychomotor impairment, and is comprised of the phenotypic variants Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD) (see these terms).

Summary:
Epidemiology
The estimated incidence for PBD-ZSS is 1/50,000 births in the United States and 1/500,000 births in Japan.
Clinical description
The term PBD-ZSS reflects the disease spectrum seen in the severe, mild and intermediate variants that were described before their peroxisome etiology was known. The three subtypes have overlapping clinical phenotypes of varying degrees of severity, with ZS being the most, and IRD the least severe. Their distinction is not always clear in individual cases as patients with NALD and IRD display phenotypes that often overlap while ZS patients tend to have a more uniform presentation. Onset of manifestations is usually soon after birth or in childhood and includes neonatal seizures, hypotonia, distinctive craniofacial features (flattened facies, broad nasal bridge, widely split sutures, large anterior fontanelle), liver dysfunction, and in older children progressive sensorineural hearing loss, retinal dystrophy and developmental delays. Additional complications that can develop include adrenal insufficiency, calcium oxalate renal stones and episodes of hemorrhage and intracranial bleeding, the latter secondary to liver dysfunction and coagulopathy. The craniofacial features are most prominent in ZS, although they can still be recognizable in NALD and IRD. Atypical presentations of PBD-ZSS have recently been recognized.
Etiology
The mutations found in 90% of PBD-ZSS patients are in the PEX1, PEX6, PEX10, PEX12 or PEX26 genes. Genetic defects in the PEX1 gene (seen in approximately 70% of cases), and subsequent alteration of the metabolic function of the peroxisome organelle is the most common cause of PBD-ZSS. The other less common disease causing mutations are found in the PEX13, PEX14, PEX16, PEX19, PEX2, PEX3, PEX5, and PEX11B genes. Two PEX genes, PEX11G and PEX11A remain thus far unassociated with disease. Impaired metabolism results in the accumulation of very-long-chain fatty acids (VLCFAs), which damage developing neural cells. Accumulation of toxic bile acid intermediates damages the liver. The decreased synthesis of docosahexanoic acid (DHA) and ether phospholipids (plasmalogens) impairs cell membranes. In the 13 PEX genes associated with PBD-ZSS, there are no correlations between disease severity and the causative PEX gene. Rather, there is a general correlation between the predicted effects of the PEX gene mutation on the function of the encoded PEX protein (peroxin). Thus, mutations that encode nonfunctional peroxins are associated with ZS, and mutations that encode peroxins with residual functions are associated with less severe phenotypes.

                            Last update:
                            December 2012

                            - Expert reviewer(s):
                            Dr Nancy BRAVERMAN


A rare genetic disease characterized by a clinical picture of variable severity associating sensorineural hearing impairment with ovarian dysgenesis in females, sometimes progressive neurologic disorder, and exceptionally renal disease. The disease affects both sexes, but hypogonadism is not a feature in males.

Summary:
Epidemiology
Prevalence of Perrault syndrome (PS) is unknown but over 100 patients whose diagnosis has been confirmed by molecular analysis have been reported so far, with an approximately 2:1 female to male ratio. The disease is most likely underdiagnosed, especially in the male population where it remains undetected in the absence of an affected sister.
Clinical description
Perrault syndrome is subdivided in two types. Type 1, static, presents with deafness and ovarian dysgenesis in females. Type 2 presents with additional neurological, and rarely, muscular or renal manifestations. Mean age at diagnosis is 26 years old, and based on presentation with delayed puberty in females with sensorineural deafness. Hearing defects (mean age at diagnosis of 7 years) were noted in all but one of the reported cases. The hearing loss is sensorineural and generally bilateral, prelingual, and asymmetric, with a variable severity (mild to profound) even in affected patients from the same family. It is classically an auditory neuropathy (with presence of otoacoustic emissions initially). Ovarian dysgenesis has been reported in all female cases, but no gonadal dysgenesis has been reported in males. Amenorrhea is generally primary, but can also be secondary. Neurological features are inconstant, progressive, and of variable severity; they include cerebellar dysfunction with ataxia, sensitive or sensitive-motor neuropathy, and less frequently, developmental delay.
Etiology
PS is a heterogeneous disease. Biallelic, homozygotous, or compound heterozygous mutations in 8 genes have been identified, but molecular analysis remains inconclusive in half of the patients. PS is due to alterations of mitochondrial (CLPP, ERAL1, HARS2, LARS2, RMND1, TWNK genes) or metabolic functions (HSD17B4, GGSP1 genes). Outside of disease forms presenting with constant neurologic disorders (which sometimes precede hearing loss) associated with mutations in TWNK, or exceptional renal symptoms associated with RMND1 mutations, there is no correlation between genotype and phenotype.
Diagnostic methods
Hearing loss is evaluated by otoacoustic emissions (OAE) and auditory evoked potentials (AEP). CT scans reveal that the hearing loss is not associated with temporal bone malformations. Hormonal tests (LH, FSH, AMH levels), which are required in deaf females with no signs of puberty at 11 years old, reveal hypergonadotropic hypogonadism. Pelvic examinations reveal absent ovaries or streak gonads, and a very hypoplasic uterus. Neurologic investigations reveal reduced nerve conduction velocities, and cerebral MRI may show a nonspecific white matter hypersignal or cerebellar atrophy. Genetic analysis can reveal causal mutations in half of patients.
Differential diagnosis
Turner syndrome is the main differential diagnosis.
Antenatal diagnosis
Prenatal diagnosis is possible when the pathogenic variants have previously been identified in a family member.
Management and treatment
Treatment and follow-up should be multidisciplinary, including audiologists, endocrinologists, neurologists and psychologists. Hearing aids or cochlear implants may help for the hearing defect. Puberty induction and ovarian preservation should be discussed with the family.
Prognosis
Life expectancy is normal for patients with Perrault syndrome type 1. Outcome is variable in patients with Perrault syndrome type 2 who present with progressive neurological disease.

                            Last update:
                            March 2023

                            - Expert reviewer(s):
                            Dr Catherine VINCENT-DELORME | ERN CRANIO*

                                * European Reference Network


A rare inherited neurodegenerative disorder characterized by rapidly progressive early-onset parkinsonism, central hypoventilation, weight loss, insomnia and depression.

Summary:
Epidemiology
The prevalence is unknown. It has been described in 53 cases from 11 families to date in Canada, U.S., U.K., France, Turkey and Japan.
Clinical description
Perry syndrome has a mean age of onset of 48 years (range 35-61) and presents with parkinsonism (akinetic-rigid and rather symmetric), psychiatric changes manifesting as depression, lethargy, withdrawal, apathy, and changes in character, as well as sleep difficulties. The usual duration of Perry syndrome is about 5 years, with severe weight loss and central hypoventilation being seen late in the disease course. Marked autonomic dysfunction was reported in one family from Japan. Patients are often bedridden or wheelchair bound as motor impairment may be severe at a later stage of the disease.
Etiology
Perry syndrome is caused by mutations (five identified to date) in exon 2 of the dynactin DCTN1 gene coding for p150glued, the major subunit of the dynactin protein complex. Mutations in this gene alter the binding affinity of dynactin for microtubules and consequently this leads to the impairment of this important transport protein. Nigral neurons seem to be more affected by the dysfunction of this protein, explaining their increased cell death and the distinct pathology seen in Perry syndrome.
Diagnostic methods
Diagnosis is based on clinical findings of early-onset parkinsonism combined with depression, weight loss and hypoventilation and is confirmed by a molecular genetic test finding a mutation in the DCTN1 gene. Major histological findings consist of neuronal loss and TAR DNA-binding protein (TDP-43)-positive pathology in the substantia nigra and locus coeruleus, without Lewy bodies. Sleep studies should be performed to detect hypoventilation.
Differential diagnosis
The main differential diagnoses are other forms of familial early-onset parkinsonism (in particular those associated with mutations in the PARK2, PINK1, PARK7 and LRRK2 genes) as well as frontotemporal dementia (see these terms).
Antenatal diagnosis
Antenatal diagnosis is possible in laboratories that offer custom prenatal testing for families with a known DCTN1 mutation.
Genetic counseling
Perry syndrome is inherited in an autosomal dominant manner with full penetrance and children of a parent with the disease have a 50% risk of also having the mutation and developing the disease. Pre-symptomatic diagnosis can be offered to at-risk individuals.
Management and treatment
There is no cure for Perry syndrome. Symptomatic treatment requires a multidisciplinary team. Dopaminergic therapy is given to patients to help with parkinsonism, usually using levodopa / carbidopa. Response to levodopa can be erratic or absent but large doses (>2g) have been successful in reducing symptoms in several patients. Patients with hypoventilation require ventilator support (invasive or non-invasive), particularly at night. Respiratory function should be monitored continuously. Psychiatric follow-up along with antidepressant drugs are needed to manage depression and prevent suicide. Weight should be monitored and a high caloric diet should be implemented when weight loss is present. With worsening symptoms hospitalization and major medical assistance is often required.
Prognosis
Perry syndrome progresses rapidly and the prognosis is poor. Death is due to respiratory insufficiency or suicide or, in some cases, can be sudden and unexplained. Ventilation assistance may prolong survival with an acceptable quality of life.

                            Last update:
                            October 2012

                            - Expert reviewer(s):
                            Dr Christian WIDER


A rare congenital anomaly of the inferior vena cava characterized by the postnatal presence of an eustachian valve remnant, which may be asymptomatic and considered a normal variant or prominent and clinically significant. Clinical presentation is variable and includes obstruction of the inferior vena cava, cyanosis, thrombosis, pulmonary embolism, infective endocarditis, and when combined with persistent foramen ovale, it may generate permanent right-to-left shunt.


A rare, congenital anomaly of the great arteries characterized by an extrapericardial vessel arising from the ascending aorta proximal to the brachiocephalic artery and terminating either in the dorsal aorta or in pulmonary arteries via a persistently patent arterial duct. The resulting connection is a systemic-to-systemic or systemic-to-pulmonary. Clinical manifestation include exercise intolerance, reduced femoral pulses, cyanosis with or without pulmonary hypertension and heart failure. Other congenital cardiovascular anomalies are often present and influence the clinical presentation.


Persistent hyperplastic primary vitreous

A rare ophthalmic disorder characterized by mostly unilateral failure of the regression of a fetal ocular vessel component, the tunica vasculosa lentis and/or the hyaloid system, resulting in an anterior (presenting with microphthalmia, leukocoria, cataract, glaucoma, elongated ciliary processes, shallow anterior chamber, and retrolental fibrovascular membranes, among others) or posterior disease subtype (with microphthalmia, leukocoria, presence of a retinal fold or detachment, hypo- or dysplastic optic nerve, and vitreous membranes and stalk), respectively. Most patients present with a combination of the two subtypes.


A rare neurological disease characterized by a generally deep, poorly localized, persistent facial pain that does not present characteristics of a cranial neuralgia and which cannot be attributed to another disorder.


Persistent left superior vena cava connecting through coronary sinus to left-sided atrium

A rare, congenital vascular malformation of the major vessels characterized by a persitent left superior vena cava which drains through the left coronary sinus to the left atrium. Patients are usually asymptomatic and discovered incidentally, however hypoxia, cyanosis, murmurs, palpitations, cardiac structural anomalies (e.g. atrial septal defect, bicuspid aortic valve, cor triatriatum) and risk of paradoxical embolism may be associated.


Persistent left superior vena cava connecting to the roof of left-sided atrium

A rare congenital anomaly of superior vena cava characterized by a persistent left superior vena cava that drains into the left atrium through a direct connection to its roof, creating a right-to-left shunt. Patients are at risk of developing chronic hypoxia, decreased exercise tolerance, cyanosis, embolic cerebrovascular events, and heart failure.


Persistent Müllerian duct syndrome (PMDS) is a rare disorder of sex development (DSD) characterized by the persistence of Müllerian derivatives, the uterus and/or fallopian tubes, in otherwise normally virilized boys.

Summary:
Epidemiology
The exact prevalence in the general population is unknown.
Clinical description
All affected subjects are, by definition, genotypically (46, XY) and phenotypically (normally virilized external genitalia) male. Index symptoms are cryptorchidism or inguinal hernia. Testes are normally differentiated and, in the absence of long-standing cryptorchidism, usually contain germ cells. However, affected males may be infertile as the testes are frequently not properly connected to male excretory ducts due to aplasia of the epididymis and the upper part of the vas deferens. Testosterone levels are usually normal, unless testicular degeneration has occurred.
Etiology
Genetic analysis of more than 100 families has shown that around 45% of cases are caused by mutations in the anti-Müllerian hormone gene (AMH; 19p13.3). Mutations in the gene encoding the AMH receptor (anti-Müllerian hormone receptor, type II, AMHR2; 12q13) are responsible for a further 40% of cases, with around half of these patients carrying the same mutation (a 27-base pair deletion in exon 10). Ovarian function appears to be normal in female relatives of affected males, however, further studies are required to determine whether female homozygous carriers of AMH or AMHR2 mutations are subject to early menopause.
Diagnostic methods
PMDS is usually discovered incidentally during surgery for undescended testes or inguinal hernia in boys with normal external genitalia. A specific ELISA test can be used to determine AMH levels in the serum and is a useful screening method to guide the molecular diagnosis.
Genetic counseling
PMDS is transmitted in an autosomal recessive manner.
Management and treatment
Treatment is surgical and consists of replacement of the gonads within the scrotum, requiring careful dissection of the Müllerian derivatives. Total hysterectomy is not recommended because of the risk to the vas deferens.
Prognosis
Early diagnosis and treatment may decrease the risks of degeneration and malignancy of the testes associated with longstanding cryptorchidism. Sexual function is normal, but fertility is compromised, even in treated patients. Hemospermia has been observed in older patients, but otherwise the presence of Müllerian derivatives is not harmful.

                            Last update:
                            January 2009

                            - Expert reviewer(s):
                            Dr Jean-Yves PICARD


Persistent placoid maculopathy is characterised by white plaque-like lesions involving the macula but sparing the peripapillary areas of both eyes. It has been described in five patients. In contrast to patients with macular serpiginous choroiditis presenting with similar lesions, the five patients reported so far with persistent placoid maculopathy had good visual acuity until the onset of choroidal neovascularization (CNV) or pigmentary mottling. The macular lesions fade after several months or years, but the vascular anomalies persist leading to a loss of central vision.


Persistent polyclonal B-cell lymphocytosis (PPBL) is a rare, generally benign, lymphoproliferative hematological disease characterized by: chronic, stable, persistent, polyclonal lymphocytosis of memory B-cell origin, the presence of binucleated lymphocytes in the peripheral blood, and a polyclonal increase in serum immunoglobulin M (IgM). Patients are most frequently asymptomatic or may present with mild splenomegaly.


Peters anomaly (PA) is a congenital corneal opacity disorder characterized by a central corneal leukoma that obstructs the pupil leading to visual loss as well as absence of the posterior corneal stroma and Descemet membrane.


Peters plus syndrome is an autosomal recessively inherited syndromic developmental defect of the eye (see this term) characterized by a variable phenotype including Peters anomaly (see this term) and other anterior chamber eye anomalies, short limbs, limb abnormalities (i.e. rhizomelia and brachydactyly), characteristic facial features (upper lip with cupid bow, short palpebral fissures), cleft lip/palate, and mild to severe developmental delay/intellectual disability. Other associated abnormalities reported in some patients include congenital heart defects (i.e. hypoplastic left heart, absence of right pulmonary vein, bicuspid pulmonary valve), genitourinary anomalies (hydronephrosis, renal hypoplasia, renal and ureteral duplication, multicystic dysplastic kidneys, glomerulocystic kidneys) and congenital hypothyroidism.


A genetic intestinal polyposis syndrome characterized by development of characteristic hamartomatous polyps throughout the gastrointestinal (GI) tract, and by mucocutaneous pigmentation. This disorder carries a considerably increased risk of GI and extra-GI malignancies.

Summary:
Epidemiology
Peutz-Jeghers syndrome (PJS) prevalence estimates range from 1/25,000 to 1/300,000 births.
Clinical description
Despite high variability between families, characteristic PJS polyps generally occur in childhood and early adulthood, with onset often during the first 10 years of life. Hamartomatous polyps can occur at any site in the GI (gastrointestinal tract) tract, but are most frequent in the small intestine. Other sites include the stomach, large intestine, nares, and rarely the renal pelvis, urinary bladder, and lungs. Although benign, polyps can lead to complications including bowel obstruction, rectal prolapse, and severe GI bleeding with secondary anemia, and intussusception. Adenomas and hyperplastic polyps may also occur. During infancy or childhood, patients may develop dark blue to dark brown macules around the mouth, eyes, nares, and in the perianal area and buccal mucosa. Hyperpigmentation may also be found on the fingers and toes. The lesions may fade in adolescence and adulthood but tend to persist in the buccal mucosa. They can cause psychological stress. GI and extra-GI malignancies mainly concern adult patients and include colorectal and gastric cancer (estimated lifetime risk (LTR) of 15% by 50 years of age, and 57% by 70 years), pancreatic cancer (LTR 5% by 50 years of age, and 17% by 70 years), and breast and ovarian cancer in females (LTR 8% by 40 years of age, and 32% by 60 years of age). Female patients may also develop adenoma malignum of the cervix, and typically benign bilateral multifocal sex cord tumors with annular tubules (SCTAT).
Etiology
The disorder is usually caused by germline mutations in the STK11 gene (19p13.3). Mutations in this tumor suppressor gene are found in more than 80% of affected families. There are no clear genotype-phenotype correlations. One study showed that individuals with missense mutations had a significantly later time to onset of first polypectomy and of other symptoms compared with those either with truncating mutations or no detectable mutation.
Diagnostic methods
Diagnosis is based on clinical findings and can be made in a patient presenting one of the following signs: two or more histologically confirmed PJ polyps, any number of PJ polyps and a family history of PJS, characteristic mucocutaneous pigmentation and a family history, or any number of PJ polyps associated with characteristic mucocutaneous pigmentation. Molecular genetic testing of the STK11 gene confirms the diagnosis and is available clinically. Aside from mutations affecting the STK11 protein, large deletions of STK11 have also been reported to cause PJS and should be considered when sequencing fails to identify a protein coding or splice variant.
Differential diagnosis
Differential diagnoses include juvenile polyposis syndrome, hereditary mixed polyposis syndrome, the PTEN hamartoma tumor syndromes, and Carney complex.
Antenatal diagnosis
Prenatal diagnosis for increased risk pregnancies is available provided that the disease-causing mutation has been identified in the family.
Genetic counseling
The syndrome is inherited in an autosomal dominant manner. The number of cases related to de novo gene mutations is not known. A recent report found that 9 of 14 sporadic cases presenting in children were caused by de novo mutations and the cause of the other 5 cases could not be determined. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.
Management and treatment
Routine treatment methods should be used for polyp resection, intussusception and malignancies. Some evidence indicates routine endoscopy and intraoperative eneteroscopy with polypectomy decreases the requirement for laparotomy and bowel loss. Newer technologies such as video capsule endoscopy, magenetic resonance enterography and balloon-assisted enteroscopy are being suggested to reduce the management burden. Although generally recommended, there is no control data on the value of surveillance strategies for cancer management in PJS patients. The aim of surveillance is to reduce polyp related complications in younger patients and for early detection of malignancies in older patients.
Prognosis
The prognosis depends on the severity of polyp complications and on the development of malignancies. Routine surveillance of polyp growth will lead to better management.

                            Last update:
                            February 2020

                            - Expert reviewer(s):
                            Pr Christopher AMOS


PFAPA (Periodic fever - aphthous stomatitis- pharyngitis - adenopathy) syndrome is an auto inflammatory syndrome characterized by recurrent febrile episodes associated with aphthous stomatitis, pharyngitis and cervical adenitis.

Summary:
Epidemiology
Prevalence of PFAPA is unknown, over 500 cases have been reported and patients are predominantly male (>60%).
Clinical description
PFAPA usually presents during early childhood (<5 years old) with recurrent episodes of fever (>39°C) lasting 3-7 days, during which children appear very ill. Aphthous stomatitis is characterized by relatively painless small, round and shallow lesions on the tongue and oral mucosa (70% of cases) that recover completely in 10-14 days. Most patients present with tonsillitis, occasionally with white exudates (mimicking streptococci infection), and a general pharyngitis (75% of cases) with diffuse hyperemia of the entire palate. Swelling of upper cervical lymph nodes appears in >75% of cases. Abdominal pain has also been reported in many cases (65%) and generally correlates with mesenteric adenopathy. Other reported features include chills, headache, vomiting, diarrhea, hepatosplenomegaly and joint pain. Episodes recur every 3-5 weeks, often in a predictable fashion with patients describing a mild malaise the day before recurrence. Patients are in good health between episodes and generally develop normally, but leg pain and chronic fatigue are often reported.
Etiology
PFAPA is an idiopathic inflammatory condition. Elevated levels of IL-2, TNF-alpha, decreased levels of IL-10 and a significant over expression of IL-1-related (IL-1B, IL-1RN, CASP1, IL18RAP), and IFN-induced (AIM2, IP-10/CXCL10) genes are noted during the episodes.
Diagnostic methods
PFAPA is a diagnosis of exclusion based on clinical manifestations. The regularity of acute episodes during the active phase of the disease is an important clue. Marked leukocytosis and elevated CRP levels are observed in blood samples collected during acute episodes. Oral culture swabs are negative for infection, and patients fail to respond to antipyretic or antibiotic treatment.
Differential diagnosis
Differential diagnosis includes other diseases characterized by periodic fever such as recurrent tonsillitis, streptococcal infection, juvenile idiopathic arthritis, Behçet's disease, cyclic neutropenia, familial Mediterranean fever, TRAPS syndrome, and mevalonate kinase deficiency (see these terms).
Management and treatment
PFAPA has no specific treatment. Fever does not respond to non-steroidal anti-inflammatory medications. A dose of corticosteroid (prednisone, 1-2 mg/kg, or betametasone, 0.1-0.2 mg/kg) given upon the first signs of an episode can shorten or even end the episode within hours. This treatment has, however, been reported to reduce the interval between episodes. Cimetidine and colchicine have had some success in preventing relapse through regular administration. Tonsillectomy may be considered in more severe cases with very frequent flare ups.
Prognosis
Episodes usually decrease in frequency and resolve during the patient's second decade. Tonsillectomy may cure the disease in most cases.

                            Last update:
                            July 2014

                            - Expert reviewer(s):
                            Pr Isabelle KONE-PAUT


An acrocephalosyndactyly associated with craniosynostosis, midfacial hypoplasia, hand and foot malformation with a wide range of clinical expression and severity. Most of the affected patients show various other associated manifestations.

Summary:
Epidemiology
Pfeiffer syndrome (PS) birth prevalence is 1/100,000. The disorder affects males and females equally.
Clinical description
Abnormal skull shape is usually detected in the neonatal period (possibly on prenatal ultrasound). Characteristic cranial features include a wide cranial vault, a flat occiput, broad forehead, a small nose with depressed nasal bridge, orbital hypertelorism and proptosis. The clinical picture depends on the extent of craniosynostosis (mostly bicoronal) and the associated functional disorders (respiratory, otological, ocular, neurological). Three forms of PS have been described (PS type 1, type 2, and type 3). Type 1 described as the "classic PS", is the less severe form of PS and is characterized by mild-to-moderate midface hypoplasia, minimal hand and foot abnormalities, little to no ocular proptosis and usually normal intellectual development. In contrast, types 2 and 3 are associated with more severe manifestations such as extreme proptosis and choanal stenosis or atresia, finger and toes abnormalities, elbow ankylosis or synostosis, and complications (hydrocephalus and seizures) resulting in a poorer prognosis. Other complications include brain development disorders, exposure keratopathy, exorbitism, bilateral and symmetrical hearing loss, airway obstruction, and obstructive sleep apnea. Type 2, the most severe form, is distinguished from type 3 by the presence of a cloverleaf skull. Types 2 and 3 have occurred only in sporadic cases and have increased risk of early death due to severe neurological compromise and respiratory problems.
Etiology
The majority of cases are caused by  de novo mutations in the FGFR2 gene (10q25.3-q26), and very rarely in type 1 cases, by mutations in the FGFR1 (8p11.23-p11.22) gene. Patients meeting criteria for a clinical diagnosis of Pfeiffer syndrome without a mutation in FGFR1 or FGFR2 are estimated to be as high as 21%. Spontaneous mutations have been associated with advanced paternal age.
Diagnostic methods
The diagnosis is based on the presence of the characteristic clinical findings including craniosynostosis or cloverleaf skull, facial features, and variable hand and foot malformations. Diagnosis can be confirmed by molecular genetic testing.
Differential diagnosis
Differential diagnoses include other acrocephalosyndactyly syndromes (Apert, Crouzon, Carpenter, Saethre-Chotzen, Waardenburg) and other syndromic forms of craniosynostosis such as Jackson-Weiss, Muenke and Antley-Bixler syndromes and Cutis gyrata-acanthosis nigricans-craniosynostosis.
Antenatal diagnosis
Prenatal molecular genetic testing is possible. Results of genetic testing for low-risk pregnancies are of little prognostic value. Prenatal imaging may also be used for diagnosis if physical findings are apparent. Some ultrasound findings could pose the suspicion of the disease.
Genetic counseling
Genetic counseling should be provided to affected families. Inheritance from an affected parent in an autosomal dominant manner is reported in less severe cases of Pfeiffer syndrome. PS shows complete penetrance, although the expressivity is variable. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring. When prenatal features are evocative for PS, gene molecular testing for mutation, after standard and molecular karyotyping should be suggested.
Management and treatment
Treatment is symptomatic and corrective, depending on the extent of disease manifestations. A multidisciplinary approach should be adopted to plan multiple-stage surgical interventions and other treatments with the aim of improving cosmetics, function and quality of life. The psychosocial aspects of the disease should also be addressed.
Prognosis
The success of timely treatment is the main prognostic factor. Favorable outcomes can be achieved but the prognosis remains poor in severe cases with a high risk of early demise due to respiratory and neurological complications.

                            Last update:
                            August 2019

                            - Expert reviewer(s):
                            Dr Chiara BOCCHERINI  - Dr Valentina D'AMBROSIO  -  Antonella GIANCOTTI  - Dr Antonio PIZZUTI


Pfeiffer-Palm-Teller syndrome is a very rare dysmorphic syndrome described in two sibs and characterized by a short stature, unique facies, enamel hypoplasia, progressive joint stiffness, high-pitched voice, cup-shaped ears, and narrow palpebral fissures with epicanthal folds, and intellectual deficit.


A rare, genetic, congenital disorder of glycosylation and glycogen storage disease characterized by a wide range of clinical manifestations, most commonly presenting with bifid uvula with or without cleft palate at birth, associated with growth delay, hepatopathy with elevated aminotransferase serum levels, myopathy (including exercise-related fatigue, exercise intolerance, muscle weakness), intermittent hypoglycemia, and dilated cardiomyopathy and/or cardiac arrest, due to decreased phosphoglucomutase 1 enzyme activity. Less common manifestations include malignant hyperthermia, rhabdomyolysis, and hypogonadotropic hypogonadism with delayed puberty.


A rare congenital disorder of glycosylation caused by mutations in the PGM3 gene and characterized by neonatal to childhood onset of recurrent bacterial and viral infections, inflammatory skin diseases, atopic dermatitis and atopic diatheses, and marked serum IgE elevation. Early neurologic impairment is evident including developmental delay, intellectual disability, ataxia, dysarthria, sensorineural hearing loss, myoclonus and seizures.


PHACE is an acronym used to describe a syndrome characterised by the association of Posterior fossa brain malformations, large facial Haemangiomas, anatomical anomalies of the cerebral Arteries, aortic coarctation and other Cardiac anomalies, and Eye abnormalities. Sternal anomalies are also sometimes present, and in these cases the syndrome is referred to as PHACES. Two additional manifestations have recently been added to the clinical spectrum of PHACE syndrome: stenosis of the vessels at the base of the skull and segmental longitudinal dilations of the internal carotid artery.

Summary:
Epidemiology
This association of manifestations is rare and less than 100 cases have been reported in the literature so far. The syndrome is much more common in females than in males (8:1).
Clinical description
Newborns and infants are affected. Expression of the complete clinical picture of PHACE syndrome is extremely rare and most patients display only a partial phenotype (or incomplete clinical spectrum). The posterior fossa malformations include cerebellar hypoplasia, arachnoid cysts, cortical dysgenesis and Dandy-Walker malformation. The capillary haemangiomas have the same morphological, clinical and evolutive characteristics as those of sporadic benign haemangiomas. Intracranial and subarachnoid lesions may occur concurrently, with the intracranial lesions evolving in the same manner as the maxillofacial or cervical haemangiomas. Two types of arterial anomalies have been described: persistence of embryological arteries and agenesis of the carotid or vertebral artery. These anatomical arrangements allow normal cerebral function but limit the capacity for collateral circulation in case of an associated occlusive or stenotic lesion. The ophthalmological anomalies include glaucoma, coloboma, microphthalmia, cryptophthalmia and optic nerve hypoplasia. In most cases, the vascular lesions are uni- and homolateral, indicating that PHACE syndrome is a member of the group of cerebrofacial syndromes with involvement of several adjacent segments of the neural crest. Sternal anomalies resulting from ventral developmental defects are rare and include sternal clefts and/or malformations of the supraumbilical raphe. Progressive stenotic lesions of the intracerebral arteries (which are usually unilateral) are localised to the anterior or posterior divisions of the internal carotid artery. They result from concentric proliferation of the vascular wall causing a progressive reduction in the size of the lumen. Thickening of the vascular wall is also responsible for elongation of the internal carotid artery segments. The resulting neurological symptoms are variable, depending on the size and associated territory of the occluded vessels. Other manifestations such as headaches or delayed psychomotor development may also be caused by the same ischemic aetiology.
Etiology
The aetiology of the syndrome is unknown.
Diagnostic methods
Diagnosis can be confirmed by CT scan, MRI and cardiopulmonary investigations. Angiography is not performed systematically. Early diagnosis and treatment decreases the number and lessens the severity of complications.
Genetic counseling
The female predominance indicates male-lethal X-linked dominant transmission.
Management and treatment
Management should be multidisciplinary with the aim of stabilising the cardiac and neurological manifestations and preventing angioma growth. Depending on the volume and location of the lesions, drug treatment or surgical management may be proposed for the capillary haemangiomas. Treatment with aspirin is often recommended to prevent ischemic accidents and cerebral revascularisation, a surgical intervention often indicated for a patients with Moya-moya, may be also be proposed for PHACE.
Prognosis
The prognosis depends on the severity of the clinical signs associated with the cerebral and arterial anomalies. Neurological sequelae are frequent.

                            Last update:
                            March 2007

                            - Expert reviewer(s):
                            Dr Hortensia ALVAREZ  - Pr Pierre LASJAUNIAS


A rare ophthalmic disorder characterized by a zonal granulomatous inflammatory reaction centered around the lens secondary to its traumatic rupture. Signs and symptoms include photophobia, ocular irritation or pain, blurred vision, redness, mutton-fat keratic precipitates, posterior synechiae, and sometimes hypopyon. Intraocular pressure may be elevated due to blockage of the trabecular meshwork by inflammatory cells or lens material.


A rare epidermal nevus disorder characterized by the association of speckled lentiginous nevi with epidermal sebaceous nevi, and extracutaneous anomalies.


A rare skin disease characterized by the co-occurrence of a widespread vascular nevus (typically nevus flammeus) and a pigmentary nevus, potentially associated with a variety of other cutaneous nevi, and with or without extracutaneous (most commonly central nervous system, ocular, or musculoskeletal) involvement. Several subtypes are distinguished based on phenotypic characteristics.


A rare primary osteolysis disorder characterized by multiple small osteolytic areas and sclerosis in the phalanges of one or both hands associated with swelling and redness of the phalanges. Condition is benign, self-limited and may be associated with cold exposure.


Pharyngeal-cervical-brachial variant of Guillain-Barré syndrome is a rare, acquired peripheral neuropathy disease characterized by rapidly progressive oropharyngeal (facial palsy, dysarthria) and cervicobrachial weakness, associated with upper limb weakness and hypo/areflexia, in the absence of ophthalmoplegia, ataxia, altered consciousness, and prominent lower limb weakness. The presence of monospecific IgG anti-GT1a antibodies is associated.


A rare multiple congenital anomalies syndrome characterized by the association of limb pterygia, heart anomalies, autosomal recessive inheritance, vertebral defects, ear anomalies and radial defects.


Summary:
Epidemiology
A rare genetic neurodevelopmental disorder characterized by neonatal hypotonia, global developmental delay, normal to accelerated growth, absent to severely delayed speech, and minor dysmorphic features.
Clinical description
The severity of the developmental delay tends to vary with deletion size, with most individual functioning in the severe to profound range. Behavior is autistic-like with decreased perception of pain and habitual chewing or mouthing. Major milestones are delayed, receptive language skills typically exceed expressive skills, and many individuals are nonverbal. Other neurological features include seizures, ataxic gait, sleep disturbance, abnormal brain imaging, and regression or loss of skills. Common physical traits include long eye lashes, large or unusual ears, relatively large hands, dysplastic toenails, full brow, dolicocephaly, full cheeks, bulbous nose, and pointed chin. Between 10 to 25% of individuals have gastrointestinal reflux, cardiac abnormalities renal anomalies, lymphedema, or visual defects.
Etiology
The majority of cases result from the loss of 22q13.3 due to a simple deletion, translocation, ring chromosome or other structural chromosome changes involving the SHANK3 gene (PMS-SHANK3 related). About 15% of people have a heterozygous pathogenic variant in the SHANK3 gene. Less frequently, an individual may have an interstitial deletion of 22q13 that does not involve the SHANK3 gene (PMS-SHANK3 unrelated).
Diagnostic methods
The diagnosis of monosomy 22q13.3 syndrome should be considered in all cases of hypotonia of unknown etiology and in individuals with absent speech. Chromosomal microarray is recommended as the first tier of testing. Detection of pathogenic variants of SHANK3 requires gene testing (genome sequencing, exome sequencing).
Differential diagnosis
Differential diagnosis includes syndromes associated with hypotonia, developmental delay, speech delay and/or autistic-like behavior (Prader-Willi, Angelman, Williams, Smith-Magenis, fragile X, Sotos, FG, and velocardiofacial syndromes, autism spectrum disorders and cerebral palsy).
Antenatal diagnosis
Antenatal diagnosis is possible where a parental chromosome rearrangement or pathogenic variant has previously been identified. Because of the difficulty detected parental mosaicism, antenatal diagnosis may also be offered to parents of children with apparently de novo deletions or pathogenic variants.
Genetic counseling
Transmission is autosomal dominant; while most cases occur sporadically, genetic counseling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy. The risk of affected offspring is also increased for parents who carry balanced structural abnormalities of chromosome 22. The risk to a translocation carrier depends on the type of chromosome abnormality, the size of the chromosome segments involved, the mode of ascertainment, the sex of the transmitting parent, and other factors. Most risk estimates will fall below 30%.
Management and treatment
Individuals with monosomy 22q13.3 should have routine examinations by the primary care physician, as well as genetic evaluations with referral to specialists if neurological, gastrointestinal, renal, or other systemic problems are suspected. Affected individuals benefit from early intervention programs, intense occupational and communication therapies, adaptive exercise and sport programs, and other therapies to strengthen their muscles and increase their communication skills. Because ring chromosome 22 is associated with a specific risk of neurofibromatosis type 2 (NF2), individuals ring 22 must undergo increased surveillance for symptoms of NF2.
Prognosis
No apparent life-threatening organic abnormalities accompany the diagnosis of monosomy 22q13.3.

                            Last update:
                            July 2024

                            - Expert reviewer(s):
                            Dr Katy PHELAN


A teratologic disorder associated with intrauterine exposure of phenobarbital during the first trimester of pregnancy. Infants are usually asymptomatic but an increased risk of intellectual disability, tetralogy of Fallot, unilateral cleft lip, hypoplasia of the mitral valve and some other mild abnormalities such as hypertelorism, epicanthus, hypoplasia and low insertion of the nose, low insertion of the ears, prognathism, ﬁnger hypoplasia, brachydactyly and hypospadias have been reported in rare cases.


A rare inborn error of amino acid metabolism characterized by elevated blood phenylalanine and low levels or absence of phenylalanine hydroxylase enzyme. If not detected early or left untreated, the disorder manifests with mild to severe mental disability.

Summary:
Epidemiology
The prevalence of phenylketonuria (PKU) shows considerable geographic variation. It is estimated to be 1/10,000 live births in Europe with a higher rate in some countries (Ireland, Italy). Prevalence is particularly high in Turkey: 1/4,000 live births. PKU is far rarer in the Finnish, African and Japanese populations.
Clinical description
In the absence of neonatal diagnosis, symptoms develop within a few months of birth, may be very mild to severe and include gradual developmental delay, stunted growth, microcephaly, seizures, tremors, eczema, vomiting, and musty odor. Untreated patients subsequently develop intellectual disability, behavioral disorders (hyperactivity) and motor disorders. Patients often have fair coloring as a result of tyrosine deficiency. The most common form of the condition is known as classical phenylketonuria and is characterized by severe symptoms. A mild form has also been described (mild PKU), and an even milder form known as mild hyperphenylalaninemia (mild HPA or non-PKU HPA). A subset of patients with milder phenotypes has been found to be responsive to tetrahydrobiopterin (BH4), the cofactor of phenylalanine hydroxylase (BH4-responsive HPA).
Etiology
PKU is caused by a wide range of variants in the PAH gene (12q22-q24.2) coding for phenylalanine hydroxylase. Non-PAH variants have been reported to cause a disorder known as hyperphenylalaninemia due to BH4 deficiency. Variant frequency varies among different ethnic groups. Lower levels or absence of the phenylalanine hydroxylase enzyme underlie the clinical manifestations, as a result of toxic accumulation of phenylalanine in the blood and brain.
Diagnostic methods
The disorder is usually diagnosed through neonatal screening programs.
Differential diagnosis
PKU should be distinguished from BH4 deficiency.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.
Management and treatment
The mainstay of treatment is a low-phenylalanine diet and amino acids mixture for the forms that require treatment. According to the European guidelines for the management of PKU, the recommended maintenance level is usually between 120 and 360 micromol/L in newborns, with treatment considered essential in older patients with levels above 600 micromol/L.
Prognosis
Prognosis is variable, but favorable if diagnosed early and treated properly.

                            Last update:
                            December 2020

                            - Expert reviewer(s):
                            Pr Nenad BLAU


A rare neuroendocrine tumor arising from chromaffin cells of the adrenal medulla (pheochromocytoma) or from sympathetic and parasympathetic ganglia (paraganglioma). These tumors are most often benign and may produce catecholamines in excess causing hypertension and sometimes severe acute cardiovascular complications.

Summary:
Epidemiology
Pheochromocytomas and paragangliomas (PPGL) are rare, occurring in 0.1 to 0.6% of patients with hypertension and 5% with adrenal incidentaloma. The incidence is approximately 0.57 per 100,000 person-years (0.46 for pheochromocytomas and 0.11 for paragangliomas).
Clinical description
The symptomatology may be related to hypersecretion of catecholamines. It is variable, fluctuating, non-specific and even sometimes completely non-existent. Hypertension is the most common sign and can be permanent (50-60%) or paroxysmal (35%) and associated with orthostatic hypotension. Blood pressure can also be normal, especially in patients with low or no hypersecretion. A sudden discharge of catecholamines can cause paroxysmal symptoms that may or not occur concomitantly: headache (60-90%), sweating (55-75%), and palpitations (50-70%). The specificity and sensitivity of this triad for the diagnosis of pheochromoctyoma and/or catecholamines-producing paraganglioma are 94% and 91% respectively. Ten to 15% of PPGL are diagnosed after an acute cardiomyopathy, the most frequent being the Takotsubo cardiomyopathy. The others symptoms, less frequent, are general impairment, weight loss, constipation, anxiety, hyperglycemia and nausea. Head and neck paraganglioma are classically non-secreting tumors: the discovery could be made because of the palpation of a cervical mass or a swelling sometimes pulsatile, tinnitus, hypoacousia or even paralysis of the cranial nerves (dysphonia, dysphagia...). In genetically determined forms, others tumors or signs may be associated. For instance, gastrointestinal stromal tumors in patients with Carney-Stratakis syndrome.
Etiology
About 40% of PPGL occur in the context of an autosomal inherited syndrome. More than 15 predisposing genes have been identified (SDHA, SDHB, SDHC, SDHD, RET, VHL, NF1, TMEM127, MAX, FH...). About 60% are sporadic but up to 30% of sporadic tumors actually carry somatic mutations in these known susceptibility genes.
Diagnostic methods
The diagnosis of secreting PPGL is based on plasma free metanephrines or 24-hour urinary fractionated metanephrines measurements. A radiological evaluation is necessary to locate the tumor with conventional and nuclear medicine imaging. Biopsy should not be performed due to the high risk of acute catecholamines-induced hypertensive crisis and of hematoma. An early onset and/or the presence of multiple, extra-adrenal PPGL, bilateral pheochromocytoma or of metastases suggest a genetic form.
Differential diagnosis
In patients with paroxysmal symptoms, main differential diagnoses are panic disorder, hot flashes, carcinoid syndrome.
Antenatal diagnosis
Prenatal diagnosis is not performed except for patients with VHL disease. Genetic testing may be offered to children at risk over 6 years old.
Genetic counseling
Genetic testing is recommended for all patients diagnosed with PPGL because 40% of cases occur in the context of an autosomal inherited syndrome. Moreover, patient follow-up is adapted according to the mutated gene (for example, intensive follow-up for SDHB mutation because the risk of malignancy is increased). It is also important to offer screening to first-degree relatives of mutation-carriers.
Management and treatment
For catecholamines-producing PPGL, referral treatment is surgical excision. Patients need to undergo preoperative alpha-adrenergic blockade and rehydration for preventing hypertensive crisis during surgery. In case of tachycardia, a cardioselective beta-blocker can be added in a second step. Radiotherapy can be proposed for non-functioning paragangliomas of the skull base and neck. Indeed, the risk of neurovascular damage is important with surgery. For metastatic PPGL, there is no consensus. The therapeutic decision requires a multidisciplinary discussion by an expert team (surgery, metabolic or conventional radiotherapy, embolization, chemotherapy, targeted therapy...). Patients management should be organized in a referral center.
Prognosis
The acute cardiovascular complications (sudden death, acute stress cardiomyopathy, myocardial infarction, heart failure...) represent the most frequent causes of morbi-mortality. Moreover, a metastatic evolution or a recurrence can be observed in about 15% of the cases, especially in cases of genetic predisposition.

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Pr Laurence AMAR  - Dr Alexandre BUFFET  - Dr Nelly BURNICHON  - Dr Erika CORNU  - Pr Anne-Paule GIMENEZ-ROQUEPLO


PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by variable developmental delay and intellectual disability, overweight or obesity, behavioral abnormalities (including hyperactivity, aggressive behavior, anxiety, mood disorder, or autistic features), and facial dysmorphism (such as high forehead, full eyebrows and/or synophrys, upturned nose, and fleshy ears, among others). Additional reported manifestations are hypotonia, ocular anomalies, anomalies of the fingers and toes, joint hypermobility, or abnormal pigmentation. Brain imaging may show mild nonspecific abnormalities.


A rare genetic syndrome with limb reduction defects characterized by skeletal malformations comprising absent or hypoplastic pelvic bones (including sacral agenesis or hypoplasia), intercalary limb deficiencies (phocomelia potentially combined with polydactyly, oligodactyly or ectrodactyly), and skull defects (frequently a defect of the occipital bone with or without meningocele). Additional features may include thoracic dystrophy, dysmorphic facial features (dysplastic and large ears, and a high and narrow palate), and genital malformations (Mullerian aplasia, agenesis of the uterus and vagina, micropenis with cryptorchidism). Growth and mental development are not affected.


A rare gluconeogenesis disorder that results from impairment in the enzyme phosphoenolpyruvate carboxykinase, and comprised of cytosolic and mitochondrial forms of enzyme deficiency. Onset of symptoms is neonatal or a few months after birth and includes hypoglycemia associated with acute episodes of severe lactic acidosis, progressive neurological deterioration, severe liver failure, renal tubular acidosis and Fanconi syndrome. Patients also present progressive multisystem damage with failure to thrive, muscular weakness and hypotonia, developmental delay with seizures, spasticity, lethargy, microcephaly and cardiomyopathy. To date, there is no conclusive evidence of the existence of an isolated form of this disorder.


A rare X-linked disorder of purine metabolism associated with hyperuricemia and hyperuricosuria, and comprised of two forms: an early-onset severe form characterized by gout, urolithiasis, and neurodevelopmental anomalies and a mild late-onset form with no neurologic involvement.

Summary:
Epidemiology
Phosphoribosylpyrophosphate (PRPP) synthetase superactivity is is a rare disorder with 30 families described in the literature to date. Males are predominantly affected.
Clinical description
Most individuals (approximately 75%) are affected by the milder form (mild PRPP synthetase superactivity), which manifests in late adolescence or early adulthood, usually with uric acid crystalluria and (kidney and/or bladder) urinary stones, followed by the development of gouty arthritis and eventually renal failure as a result of obstructive uropathy from uric acid crystal deposition. The severe form (severe PRPP synthetase superactivity) usually starts from infancy or early childhood and shares the same clinical features with the mild form but also shows neurologic impairment, mainly sensorineural hearing loss, hypotonia, ataxia, developmental delay, and /or intellectual disability. Heterozygous carrier women are either asymptomatic or display mild metabolic and neurologic symptoms.
Etiology
The disease is due to overactivity of ribose-phosphate pyrophosphokinase 1 (PRS-I), an enzyme that catalyzes the synthesis of PRPP, a cofactor involved in the synthesis of purine and pyrimidine nucleotides. PRS-I overactivity results in the overproduction of purine nucleotides and uric acid (a waste product of purine breakdown). In the severe form, PRS-I overactivity is due to gain-of-function point mutations in the open reading frame of the PRPS1 gene (Xq22.3) encoding PRS-I, that lead to defective allosteric control of PRS-I isoform activity. The exact molecular mechanism leading to the mild form is not yet well understood as no mutations have been found in PRPS1, but it seems to be linked to increased rates of PRPS1 transcription. Loss of function mutations in PRPS1 are linked to Charcot-Marie-Tooth X type 5, X-linked non-syndromic sensorineural deafness and Arts syndrome, together these diseases form part of a spectrum of PRPS1-related disorders.
Diagnostic methods
In both forms, diagnosis is based on blood and urine analysis showing hyperuricemia, hyperuricosuria, and uric acid crystalluria. Diagnosis is confirmed by a PRS enzyme assay showing increased PRS-I activity in fibroblasts, lymphoblasts, and erythrocytes. Molecular genetic testing also confirms the diagnosis in the severe form.
Differential diagnosis
Differential diagnosis includes hypoxanthine-guanine phosphoribosyltransferase deficiency and psychomotor delay due to S-adenosylhomocysteine hydrolase deficiency.
Antenatal diagnosis
Prenatal genetic testing in male fetuses are possible if the mutation has been previously identified in the family.
Genetic counseling
PRPP synthetase superactivity is an X-linked recessive disorder with complete penetrance. An affected mother has a 50% risk of transmitting the mutation to any of her offspring; an affected father transmits the mutation only to his daughters. De novo PRSP1 mutations have also been reported. Heterozygous carrier women are either asymptomatic or display mild metabolic and neurologic symptoms.
Management and treatment
Treatment of uric acid overproduction with xanthine oxidase inhibitors like allopurinol or febuxostat successfully reverses or prevents the consequences of hyperuricemia and hyperuricosuria. A high daily fluid intake is warranted; and, as needed, potassium citrate to alkalinize the urine in order to avoid the formation of kidney stones. A low-purine and low-fructose diet along with regular surveillance of serum urate concentration is essential. For patients with the severe form, regular audiometric and neurologic evaluations are also recommended.
Prognosis
The prognosis is uncertain in the severe form of the disease. Severe gout can lead to renal impairment, if not properly treated. Of note, the interventions have no known beneficial effect on hearing loss or neurologic impairment.

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Dr Arjan DE BROUWER


Phosphoserine aminotransferase deficiency, infantile/juvenile form

A rare form of serine deficiency syndrome characterized clinically by acquired microcephaly, psychomotor retardation, intractable seizures and hypertonia.


A rare reflex epilepsy characterized by seizures and photoparoxysmal responses triggered by flashing or flickering lights, or patterns. Exact nature of the stimulus and seizure type are variable. The disorder mainly presents in childhood and adolescence and can either occur as an isolated condition, or be associated to other epilepsy syndromes.


A rare fibroepithelial tumor of the breast characterized by a painless, circumscribed, firm mass potentially arising in any part of the breast, histologically showing a prominent intracanalicular growth pattern with leaf-like stromal fronds, capped by luminal epithelial and myoepithelial cell layers, accompanied by stromal hypercellularity. The tumor may be benign, borderline, or malignant.


A rare urogenital tumor characterized by stromal and epithelial components forming cysts lined by hyperplastic epithelium in a cellular or sarcomatoid stroma. The tumors may be clinically benign or malignant and tend to recur after transurethral resection. Metastatic spread is to lungs, bone, and liver. Patients may present with obstructive voiding symptoms, dysuria, hematuria, urinary retention, or a palpable abdominal mass. The prostate is palpably enlarged but feels soft and spongy.


Piebald trait-neurologic defects syndrome is a rare, genetic, pigmentation anomaly of the skin syndrome characterized by ventral as well as dorsal leukoderma of the trunk and a congenital white forelock, in association with cerebellar ataxia, impaired motor coordination, intellectual disability of variable severity and progressive, mild to profound, uni- or bilateral sensorineural hearing loss. There have been no further descriptions in the literature since 1971.


Piebaldism is a rare congenital pigmentation skin disorder characterized by the presence of hypopigmented and depigmented skin areas (leukoderma) on various parts of the body, preferentially on the forehead, chest, abdomen, upper arms, and lower extremities, that are associated with a white forelock (poliosis), and in some cases with hypopigmented and depigmented eyebrows and eyelashes.


A rare multiple congenital anomalies/dysmorphic syndrome characterized by axial hypotonia after birth, prolonged feeding difficulties, moderate to severe global developmental delay, seizures (in particular absence seizures), fetal digital pads, distinctive plantar fat pads anteromedial to the heels, and deep palmar and plantar grooves. Over time, fat pads may become less prominent and disappear. Distinct craniofacial dysmorphic features include a broad face with high forehead, high anterior hairline, narrow palpebral fissures that take on a crescent moon shape when smiling, broad nasal bridge and tip with anteverted nostrils, mild midfacial hypoplasia, long, smooth philtrum, thin upper lip vermillion, small, widely spaced teeth, and flat occiput/microcephaly/brachycephaly.


Pierre Robin syndrome-faciodigital anomaly syndrome

A rare orofacial clefting syndrome characterized by the association of Pierre Robin sequence (retrognathia, cleft palate and glossoptosis) with facial dysmorphism (high forehead with frontal bossing) and digital anomalies (tapering fingers, hyperconvex nails, clinodactyly of the fifth fingers and short distal phalanges, finger-like thumbs and easily subluxated first metacarpophalangeal joints). Growth and mental development were normal.


A rare primary glomerular disease characterized by the association of congenital nephrotic syndrome, early onset renal failure and ocular anomalies with microcoria and severe neurodevelopment deficits.

Summary:
Epidemiology
Less than 70 cases have been described in the literature to date.
Clinical description
Presentation is typically with congenital microcoria and heavy proteinuria. Proteinuria is usually nephrotic range, at or shortly after birth and progresses rapidly to early onset renal failure. The histological finding is usually diffuse mesangial sclerosis characterized by small and condensed appearance of glomerulus in which mesangial region shows some collagenous tissue. Ocular anomalies are usually bilateral but may vary in severity which include microcoria, iris hypoplasia, posterior embryotoxon, megalo- or microcornea, cataract, lenticonus, persistent fetal vasculature, retinal detachment, glaucoma, and phthisis bulbi. Neurological manifestations include severe global development delay, marked muscle hypotonia, movement disorders, and blindness. It should be noted that some cases with this disease show mild phenotypes of late onset proteinuria without ocular or neurological abnormalities.
Etiology
Mutations in the LAMB2 gene (3p21) encoding laminin beta 2 have been identified. Laminin beta 2 is expressed in the glomerular basement membrane, at the neuromuscular junctions, as well as in the intraocular muscles, lens and retina.
Differential diagnosis
Early onset severe proteinuria accompanied by ocular anomalies are rare. Therefore, in typical cases, it is relatively easy to suspect this disease. Lowe syndrome (proteinuria, mostly low molecular weight protein, and congenital cataract) or renal-coloboma syndrome (due to PAX2 gene pathogenic variants) can be candidates for differential diagnosis.
Antenatal diagnosis
Prenatal diagnosis is difficult, but sometimes may be suspected on hyperechogenic kidneys and oligohydramnios. Only genetic testing allows early and reliable prenatal diagnosis. Prenatal diagnosis may be offered to families in which the disease-causing mutation has already been identified in affected siblings.
Genetic counseling
The disease is transmitted as an autosomal recessive trait. Where both parents are unaffected carriers of the disease, there is a 25% risk of transmission to offspring. Carrier testing of healthy family members is possible where the mutation has been identified in a family with at least one affected member.
Management and treatment
There is no specific treatment available. Since protein loss is limited, nephrectomy to prevent protein loss to urine is rarely needed. Angiotensin converting enzyme (ACE) inhibitors could help reduce urine protein loss and can delay the progression to end-stage kidney disease (ESKD) due to their renal protective effects. Renal replacement therapies including kidney transplantation are successfully employed. To date, there is no-evidence of disease-recurrence reported in the grafts after kidney transplantation. Careful ophthalmological follow up is required for the care of retinal detachment.
Prognosis
The kidney prognosis is severe with most patients progressing towards renal failure within the first year of life. Visual prognosis is generally poor: visual acuity ranges from no light perception to 20/200. Mild to severe intellectual disability is always observed. Survival into adult is reported with renal replacement therapies.

                            Last update:
                            July 2020

                            - Expert reviewer(s):
                            Pr Iijima KAZUMOTO  - Pr Kandai NOZU  - Dr Kusuhara SENTARO


PIEZO1-related generalized lymphatic dysplasia with non-immune hydrops fetalis

A rare genetic primary lymphedema characterized by uniform, widespread lymphedema, often with systemic involvement such as intestinal and pulmonary lymphangiectasia, pleural and pericardial effusions, and chylothorax. There is a high incidence of non-immune hydrops fetalis, which may result in fetal demise or fully resolve after birth. Severe, recurrent facial cellulitis is observed in some patients. Presence of epicanthic folds or micrognathia has occasionally been reported, while intelligence is normal, and seizures are absent.


Pigeon-breeder's lung disease, also called bird fanciers lung, is a hypersensitivity pneumonitis (see this term) induced by inhalation of bird derived-proteins. Presentation can be acute with chills, cough, fever, shortness of breath, chest tightness usually resolving within 24 h after cessation of antigen exposure, sub-acute with cough and dyspnea over several days to weeks, whereas chronic form results in breathlessness, coughing, lack of appetite and weight loss.


Pigmentation defects-palmoplantar keratoderma-skin carcinoma syndrome

A rare genetic skin disease characterized by infantile onset of diffuse alopecia, abnormal skin pigmentation (hypo- and hyperpigmented macules of the trunk and face and areas of reticular hypo- and hyperpigmentation of the extremities), palmoplantar keratoderma, and nail dystrophy. Patients develop recurrent spinocellular carcinomas later in life. Brittle teeth resulting in early loss of dentition have also been described.


Pigmented paravenous retinochoroidal atrophy (PPRCA) is a rare, commonly bilateral and symmetric retinal disease characterized by non-progressive or slowly progressive chorioretinal atrophy, peripapillary pigmentary changes and accumulation of ''bone-corpuscle'' pigmentation along the retinal veins and which is usually asymptomatic or can present with mild blurred vision.


An uncommon transitory hair shaft dysplasia characterized by segmental duplication of the hair shaft: a ramification generates two parallel branches which fuse to form a single shaft again. Each branch is covered by its own cuticle.

Summary:
Epidemiology
Prevalence is unknown, only a few cases have been reported.
Clinical description
Patients generally present with diffuse alopecia which can be more apparent in some areas. Hypopigmentation can be observed. This anomaly of the hair shaft occurs in normal hair, pili canaliculi, or monilethrix (see this term) and has been associated with the mosaic trisomy 8 syndrome (see this term), pseudomonilethrix type II or protein deficiency states. It can also be secondary to ulcerative colitis (see this term) and extensive bowel resection.
Etiology
Pili bifurcati is caused by a transient duplication of the papilla's tip during the anagen phase, leading to the transitory production a two complete shafts, in the same follicular matrix, that emerge through a single pilary canal. When the two papilla tips fuse, both parallel branches form a single shaft again. When the transient duplication of the papilla tip occurs repetitively during the anagen phase, a serie of bifurcation-fusion can be observed along the shaft. This situation is called pili multi-bifurcati. As a duplicated papilla tip can split again, a doubly bifurcated shaft may be observed: pili bi-bifurcati.
Diagnostic methods
Diagnosis is based on the trichogram analysis, which could show a high prevalence of dystrophic anagen hairs presenting the characteristic bifurcation(s), reduction in the shaft caliber and pigmentation and telogen effluvium.
Management and treatment
Management could include a protein complementation diet; mechanical procedures for care of the hair must be avoided.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Pr Francisco CAMACHO-MARTÍNEZ


Pili gemini defines a situation where the papilla's tip of a hair follicle splits during the anagen phase and consequently grows two hair shafts emerging through a single pilary canal. A papilla tip that divides in several tips will produce several hair shafts, a situation named pili multigemini. Pili gemini or multigemini can occur in each type of hair.

Summary:
Epidemiology
The prevalence of this anomaly is unknown but might be very high, so much so that it could be supposed to be an evolutional trait.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Pr Francisco CAMACHO-MARTÍNEZ


Pili torti-developmental delay-neurological abnormalities syndrome is characterized by growth and developmental delay, mild to moderate neurologic abnormalities, and pili torti. It has been described in a brother and his sister born to consanguineous Puerto Rican parents.


A rare ectodermal dysplasia syndrome characterized by congenital onychodystrophy (particularly of the distal nail) and severe hypotrichosis with alopecia involving the eyebrows, eyelashes and body hair. Scalp, beard, pubic and axillary hair is brittle and shows a twisting pattern on electron microscopy. There have been no further descriptions in the literature since 1991.


Pili torti is a hair shaft abnormality characterized by flat hair that is twisted at irregular intervals. Hair is normal at birth but progressively stops growing long and becomes fragile. Pili torti can be isolated or occur in association with syndromes such as Menkes disease or Bazex syndrome (see these terms).


Pilocytic astrocytoma is a rare subtype of low-grade glioma of the central nervous system characterized by a well circumscribed, often cystic, brain tumor with a discrete mural nodule and long, hair-like projections that extend from the neoplastic astrocytes. Depending on the primary localization and the size of the tumor, patients can present with signs of raised intracranial pressure (headache, vomiting, papilledema), blurred vision, decreased visual acuity, ataxia and/or nystagmus, among others. It is most commonly located in the cerebellum, but ocurrence in the hypothalamus, brain stem, optic chiasma, and hemispheres has also been reported.


Pilodental dysplasia-refractive errors syndrome is a rare ectodermal dysplasia syndrome characterized by dysplastic abnormalities of the hair and teeth (including hypodontia, abnormally shaped teeth, scalp hypotrichosis and pili annulati), follicular hyperkeratosis on the trunk and limbs, and hyperopia. Intensified delineation, reticular hyperpigmentation of the nape and astigmatism have also been reported. There have been no further descriptions in the literature since 1985.


A rare skin tumor characterized by an asymptomatic, solitary, often ulcerated nodule most commonly located in the face, involving the deep dermis, subcutaneous tissue, and skeletal muscle and fascia. Histopathologically, the lesion is composed of aggregates of atypical basaloid cells with numerous mitoses. Typical features include shadow cells, keratin cysts, and trichohyalin and keratohyalin granules. The tumor is locally aggressive and shows a tendency to recur after incomplete excision. Regional lymph node or visceral metastasis has been reported.


Pilomatrixoma is a rare and benign hair cell-derived tumor occurring mostly in young adults (usually under the age of 20) and characterized as a 3-30 mm solitary, painless, firm, mobile, deep dermal or subcutaneous tumor, most commonly found in the head, neck or upper extremities. When superficial, the tumors tint the skin blue-red. Multiple pilomatrixomas are seen in myotonic dystrophy, Gardner syndrome, Rubinstein-Taybi syndrome, and Turner syndrome (see these terms).


Pineal parenchymal tumor of intermediate differentiation

A rare type of pineal parenchymal tumor (PPT) of intermediate-grade malignancy manifesting with visual disturbances, headaches, loss of coordination and balance, nausea and vomiting due to obstructive hydrocephalus, and that is classified as either grade II PPTID (pineal parenchymal tumor of intermediate differentiation) or grade III PPTID according to the degree of neuronal differentiation and mitotic activity.


Pineoblastoma is a rare, malignant type of supratentorial primitive neuroectodermal tumor (sPNET), found mainly in children (less than 10% of cases are reported in adults), and located in the pineal region of the brain but that can metastasize along the neuroaxis. As it is the most aggressive of the pineal parenchymal tumors, it is usually associated with a poor prognosis.


Pineocytoma is the least aggressive form of pineal parenchymal tumors, manifesting with symptoms such as Parinaud's syndrome (a group of eye movement abnormalities and pupil dysfunction, including deficiency in upward-gaze and convergence-retraction nystagmus), headaches, balance impairment, urinary incontinence, and changes in mood and that are not known to disseminate in a diffuse manner. They are usually associated with a good prognosis.


Pinnae fistula or cyst is a rare otorhinolaryngological malformation characterized by the presence of a, usually unilateral, sinus tract or cyst located in the vicinity of the auricle (most frequently identified by a small pit near the anterior margin of the first ascending portion of the helix). Typically, patients are asymptomatic and usually only present symptoms (pain, erythema, discharge from pit) in relation to infection. Renal and inner ear anomalies may be associated.


A rare multiple congenital anomalies syndrome characterized by the association of intellectual deficit, characteristic facial morphology and problems of abnormal and irregular breathing.

Summary:
Epidemiology
Reliable prevalence figures have not been published but based on the number of known affected individuals in the United Kingdom and the Netherlands prevalence is estimated between 1/225 000-300 000.
Clinical description
The facial features are recognizable by a narrow forehead, thin lateral eyebrows, wide nasal bridge and ridge, broad nasal tip, prominent midface, full cheeks, wide mouth and thickened or overfolded helices of the ears. Half of the affected individuals have marked and early onset myopia and also squint is relatively common. Psychomotor development is disturbed from early on and severe with hypotonia, late-acquired unstable walking and complete or almost complete absence of language. Malformations of internal organs are uncommon. Severe constipation and gastro-esophageal reflux are common, and in 50% fingers are slender and demonstrate a single transverse palmar crease. Microcephaly is uncommon, and various types of seizures occur in 40% of affected individuals. Breathing disorders can appear during (early) childhood or adolescence and occur only when the patient is awake. Typically, the bouts of hyperventilation come without eliciting factor, have a duration of 2-5 minutes, and are often followed by apnea. Hyperventilation and apnea may also occur independently. Frequency is extremely variable. Underdevelopment of external and internal reproductive organs (small penis, cryptorchidism, labial fusions) occurs regularly in males and females.
Etiology
The syndrome is caused by heterozygous, usually de novo mutations in the TCF4 gene (18q21), coding for a ubiquitous b-HLH transcription factor. Germline or low-grade parental mosaicism has been reported in 2-3% of published cases.
Diagnostic methods
Diagnosis is based on clinical examination, and cytogenetic and molecular studies.
Differential diagnosis
The principal differential diagnosis includes Angelman syndrome, Rett syndrome and Mowat-Wilson syndrome.
Antenatal diagnosis
Detection of the mutation by amniocentesis should be discussed with the parents of an index case during subsequent pregnancies.
Genetic counseling
Transmission is autosomal dominant; however, most cases arise de novo and thus the risk of sibling recurrence is low. The empirical recurrence risk is 2%.
Management and treatment
Management requires a lifelong multidisciplinary approach. Regular follow‐up by a pediatrician, neurologist, psychologist/psychiatrist, and speech therapist will have a major impact. Developmental assessments are needed to tailor medical services to each individual's needs. The use of syndrome‐specific information booklets is recommended for affected families and caregivers; adequate information regarding the breathing disturbances is especially important to avoid mismanagement.
Prognosis
The course of the disease is non-progressive. Longitudinal data are insufficient to determine life expectancy, although survival into adulthood is typical and, at the present, there is no reason that life expectancy is limited. Autonomy is likely to be limited and affected individuals will probably require life-long support from caregivers.

                            Last update:
                            February 2020

                            - Expert reviewer(s):
                            Pr Raoul HENNEKAM | ITHACA*

                                * European Reference Network


A rare glial tumor originating from pituicytes, the specialized glial cells of the neurohypophysis, characterized by a sellar or suprasellar mass manifesting with clinical signs secondary to mass effect. Typical manifestations are visual disturbances, headaches, and hypopituitarism. Pituicytomas are low-grade tumors, and prognosis is good after total resection.


A rare pituitary disease characterized by hemorrhagic or non-hemorrhagic necrosis of the pituitary gland. Clinical manifestations typically comprise sudden and severe headache (often with nausea and vomiting), visual disturbances (visual-field defects, loss of visual acuity), oculomotor palsies, and variable degrees of altered consciousness, ranging from lethargy to coma. Acute endocrine dysfunction may also be present, most commonly corticotropic deficiency with severe hypotension and hyponatremia as well as secondary adrenal failure, but also thyrotropic and gonadotropic deficiency.


A rare pituitary tumor characterized by the presence of a pituitary adenoma that has metastasized either within the central nervous system, or to distant sites. The vast majority of pituitary carcinomas are hormonally active, most frequently with ACTH or prolactin production. The most common clinical symptoms are diabetes insipidus, optic nerve dysfunction, anterior pituitary dysfunction, palsy of cranial nerves III, IV, or VI, and headaches, although patients may also be asymptomatic. The tumors behave aggressively, and prognosis is poor.


Pituitary deficiency due to empty sella turcica syndrome

A rare pituitary deficiency characterized by herniation of the subarachnoid space into the sella turcica, resulting in flattening of the pituitary gland and endocrine dysfunction. Most common endocrine abnormalities are hyperprolactinemia and growth hormone deficit. Clinical symptoms are highly variable and include headaches, irregular menstruation, galactorrhea, obesity, and visual disturbances, among others.


Pituitary deficiency due to Rathke cleft cysts

A rare, acquired pituitary hormone deficiency characterized by combination of headache, visual field defects that correlate with cyst size, and pituitary dysfunction. Most frequent hormonal manifestations are hypogonadism with amenorrhea/impotence or low libido and galactorrhea.


Pituitary dermoid and epidermoid cysts is a rare, acquired pituitary hormone deficiency characterized by the presence of rare, benign tumor in the sellar region. Clinical presentation is either acute or insidious, and is variable according to the cyst location, size and potential rupture. Most commonly patients present with headache, visual disturbances, and pituitary dysfunction.


A rare endocrine disease characterized by excessively tall stature and rapid growth velocity due to growth hormone excess from a pituitary adenoma/hyperplasia occurring before closure of the epiphyseal growth plates. Additional features may include pubertal delay, visual defects, headache, excessive appetite, hyperhidrosis, menstrual irregularity, prognathism, coarse facial features and large hands/feet.

Summary:
Epidemiology
The epidemiology of pituitary gigantism is unknown. Among acromegaly populations, pediatric and adolescent onset cases are rare (<5%).
Clinical description
Disease onset is from early infancy to late adolescence as long as the epiphyseal growth plates remain open. Pituitary gigantism is associated with excessive height (>2 standard deviations over the population mean) and growth velocity. Pituitary gigantism predominantly affects males (78%), probably due to amplification by excess GH of greater pubertal height gain in males. Median age at first symptoms is approximately 14 years, but long delays in establishing a diagnosis give a median age at diagnosis of 21 years. The GH-secreting pituitary adenoma is usually a macroadenoma in pituitary gigantism. Patients develop symptoms related to tumor mass effects, deficiencies of other pituitary hormones and chronic excess of GH and insulin-like growth factor 1. Pituitary gigantism patients can have classical signs/symptoms of acromegaly (growth of hands/feet, facial changes, metabolic disease, cardiovascular effects and musculoskeletal disease).
Etiology
In nearly 50% of cases of pituitary gigantism the pituitary adenoma is caused by a known genetic abnormality such as: germline AIP mutations (29%), GPR101 duplications in X-linked acrogigantism syndrome (X-LAG; 10%), somatic mosaic activating mutations in GNAS in McCune-Albright syndrome (5%), germline mutations in MEN1 and PRKAR1A.
Diagnostic methods
Clinical assessment of overgrowth by physicians should lead to establishment of a diagnosis of elevated GH and insulin-like growth factor 1 (IGF1) by hormonal testing. MRI is also used.
Differential diagnosis
Gigantism and overgrowth can be due to an extensive range of normal and pathological conditions. Excess GH and IGF-1 from a pituitary adenoma/hyperplasia distinguishes pituitary gigantism from other forms of constitutional, familial or pathological tall stature/overgrowth.
Antenatal diagnosis
Germline mutations in AIP, MEN1, PRKAR1A can be inherited but are not usually screened for in prenatal testing strategies. In X-LAG related pituitary gigantism, chromosome Xq26.3 duplications can be passed from affected mother to affected son.
Genetic counseling
In AIP mutation carriers, 20% develop a pituitary macroadenoma in their life-time, as the disease is autosomal dominant with incomplete penetrance. Familial cases of gigantism have been described in familial isolated pituitary adenoma (FIPA) kindreds with AIP mutations, in X-LAG and in those with no known genetic cause. Pituitary gigantism is exceptionally rare in MEN1 and PRKAR1A mutation carriers. McCune Albright syndrome due to post-zygotic mosaicism for GNAS activating mutations is not inherited.
Management and treatment
The management of pituitary gigantism focuses on early and effective control of elevated GH and IGF-1 levels to limit final adult height. Patients with pituitary gigantism are usually have large and aggressive pituitary adenomas and these tumors can be relatively treatment-resistant. Multimodal therapy employs neurosurgery to resect the adenoma, usually in combination with medical therapy (somatostatin analogs, pegvisomant and dopamine agonists). Radiotherapy is reserved for individual cases. Replacement of deficient hormonal axes should be pursued. In cases where the patient has entered the pubertal growth spurt, some reduction in final height can be gained by orthopedic epiphysiodesis to destroy the growth plates at the knee joint.
Prognosis
Early diagnosis and rapid achievement of GH and IGF-1 control leads to lower final height in pituitary gigantism, which is a desirable outcome. Multimodal treatment can also lead to a high level of pituitary axis deficiencies, which require lifelong replacement. There are no formal outcome studies on life expectancy in patients with pituitary gigantism.

                            Last update:
                            January 2020

                            - Expert reviewer(s):
                            Pr Albert BECKERS  - Dr Adrian DALY


Pituitary stalk interruption syndrome (PSIS) is a congenital abnormality of the pituitary that is responsible for pituitary deficiency and is usually characterized by the triad of a very thin or interrupted pituitary stalk, an ectopic (or absent) posterior pituitary (EPP) and hypoplasia or aplasia of the anterior pituitary visible on MRI. In some patients the abnormality may be limited to EPP (also called ectopic neurohypophysis) or to an interrupted pituitary stalk.

Summary:
Epidemiology
The prevalence of PSIS is unknown but to date around 1,000 cases with and without the full triad have been reported.
Clinical description
In the neonatal period, PSIS presents with hypoglycemia, prolonged jaundice, congenital abnormalities and microphallus and/or cryptorchidism, which are all suggestive of hypothalamic-pituitary deficiency. PSIS is also associated with higher than normal frequency of breech presentation, Cesarean section and/or low Apgar score. The birth conditions are probably a consequence rather than the cause of PSIS. Later in childhood, signs suggestive of PSIS include short stature, decreased growth rate and/or a difference between the target and actual heights of greater than 1.5 SD. Patients may also present with seizures, hypotension and/or intellectual delay. PSIS can be associated with septooptic dysplasia and Fanconi anemia (see these terms).
Etiology
The exact etiology of PSIS is unknown. Mutations in the transcription factor HESX1 (3p21.2-p21.1) have been found both in patients with isolated PSIS and in those with PSIS associated with septooptic dysplasia. Mutations in the LHX4 gene (1q25) have also been associated with PSIS. In the majority of cases no genetic cause is found, however, the presence of familial forms and the association of PSIS with microphallus and congenital abnormalities, particularly of the eyes, suggest an antenatal origin.
Diagnostic methods
Diagnosis is suspected on clinical findings and on the basis of a low growth hormone (GH) peak after stimulation test and low insulin-like growthfactor 1. MRI, showing EPP as a hypterintense nodule in the region of the infundibular recess of the third ventricle, confirms the diagnosis. The diagnosis of PSIS indicates a permanent GH deficiency. It is necessary to determine if GH deficiency is isolated or associated with other anterior pituitary deficiencies (as occurs in 70% of PSIS). If PSIS is diagnosed from MRI there is no other possible diagnosis.
Genetic counseling
The risk of the familial form is less than or equal to 5%.
Management and treatment
Treatment is based on replacement of deficient hormones, particularly GH, thyroxine, hydrocortisone and, at puberty, sex steroids. It is important to diagnose PSIS at birth to avoid hypoglycemia and secondary adrenal deficiency and their associated cerebral and vital risks.
Prognosis
The prognosis is good if there is timely diagnosis and treatment. Delay in diagnosis and treatment may result in seizures due to hypoglycemia and/or hypotension due to cortisol deficiency and/or intellectual delay due to thyroid deficiency. As a result of these risks, mortality and morbidity in patients with PSIS are higher than in the general population, mainly occurring before 2 years of age.

                            Last update:
                            July 2010

                            - Expert reviewer(s):
                            Pr Raja BRAUNER


Pityriasis rubra pilaris is a rare chronic papulosquamous disorder of unknown etiology characterized by small follicular papules, scaly red-orange patches, and palmoplantar hyperkeratosis, which may progress to plaques or erythroderma. Although most of the cases are sporadic and acquired, a familial form of the disease exists.