A rare, primary form of mineralocorticoid resistance characterized by mild to profound salt wasting either restricted to the kidney (renal pseudohypoaldosteronism type 1), or generalized affecting many organs (generalized pseudohypoaldosteronism type 1). Clinical presentation is in the neonatal period with failure to thrive, vomiting and dehydration with biochemical findings of hyperkalaemia, metabolic acidosis and, elevated plasma aldosterone and renin concentration.

Summary:
Epidemiology
The overall prevalence at birth in the United Kingdom is estimated at 1/47,000, with prevalence at birth for renal pseudohypoaldosteronism type 1 (renal PHA1) and generalized pseudohypoaldosteronism type 1 (generalized PHA1), estimated at of 1/66,000 and 1/166,000, respectively. Epidemiological data is limited elsewhere.
Clinical description
The two different forms can be distinguished at the clinical and genetic level: i) renal PHA1 is the most frequent form and presents with mild mineralocorticoid resistance that is restricted to the kidneys and that usually improves in early childhood; ii) generalized PHA1 is a more severe form with salt wasting from multiple organs (including lung, kidney, colon, sweat and salivary glands) and persistence into adulthood. In both forms, presentation is in the neonatal period with a salt-losing syndrome, failure to thrive, vomiting and dehydration. Biological findings include hyponatremia, hyperkaliemia, metabolic acidosis and inappropriately high urinary sodium excretion. The generalized form may present with respiratory involvement (including persistent rhinorrhea, infections, tachypnea, recurrent coughing and wheezing, and, less frequently, respiratory distress syndrome), and cutaneous lesions (caused by inflammation of eccrine structures). The clinical course may be complicated by cardiac dysrhythmias and cardiac arrest in generalized PHA1.
Etiology
Renal PHA1 is caused by mutations or exon deletions in the gene encoding the mineralocorticoid receptor, NR3C2 (4q31.23). Generalized PHA1 is caused by mutations in the genes coding for one of the subunits of the amiloride-sensitive sodium channel including SCNN1A (12p13.31), SCNN1B (16p12.2) and SCNN1G (16p12.2).
Diagnostic methods
Diagnosis is confirmed by the presence of high plasma and urinary aldosterone and high plasma renin levels. Neonatal genetic diagnosis on cord blood may allow rapid diagnosis and management of the condition in affected offspring from families with identified mutations of PHA1.
Differential diagnosis
The main differential diagnoses include congenital adrenal hyperplasia (21-hydroxylase deficiency, 3b-hydroxysteroid dehydrogenase deficiency), aldosterone synthase deficiency (familial hyperreninemic hypoaldosteronism type I and II) and transient pseudohypoaldosteronism (in infants with urinary tract malformations). Occasionally, antenatal or early postnatal hyperkalemia may complicate antenatal Bartter syndrome and erroneously suggest the diagnosis of PHA1.
Antenatal diagnosis
In families with a history of generalized PHA1 (autosomal recessive), prenatal genetic testing may be requested.
Genetic counseling
Renal PHA1 is transmitted in an autosomal dominant manner or occurs sporadically. Generalized PHA1 is transmitted in an autosomal recessive manner. Genetic counselling should be offered to affected families, corresponding to the form of PHA1.
Management and treatment
Treatment consists in salt supplementation and rehydration and, where indicated, correction of hyperkalemia and acidosis. Salt supplementation is administered in accordance with disease severity. Mineralocorticoid replacement therapy with fludrocortisone and hydrocortisone may be undertaken while proceeding through differential diagnosis. Symptomatic treatment is necessary for the respiratory tract illness and to correct the skin phenotype.
Prognosis
Renal PHA1 improves with age and treatment can be discontinued after a variable period of time in most patients, generally around age 18-24 months. With age, patients compensate for the distal salt loss by up-regulating the mineralocorticoid receptor axis. Early diagnosis within the first week of life is critical to survival in patients with generalized PHA1. In this form, no remission has been reported and patients are prone to life-threatening episodes of salt loss into adulthood.

                            Last update:
                            September 2021

                            - Expert reviewer(s):
                            Dr Maria-Christina ZENNARO


A rare genetic form of hypertension characterized by hyperkalemia, mild hyperchloremic metabolic acidosis, normal or elevated aldosterone, low renin, with normal renal glomerular filtration rate (GFR).

Summary:
Epidemiology
The prevalence of the disorder is unknown. To date, more than 180 affected individuals and families have been reported.
Clinical description
Patients generally develop hypertension in adulthood. Hyperkalemia, mild hyperchloremic acidosis and low renin are present from a young age and are constant findings. Aldosterone levels may be normal to high. Hypervolemia is frequently observed. Growth failure has been described in some cases. Patients do not present renal failure. Spitzer-Weinstein syndrome is believed to be the early presentation of Pseudohypoaldosteronism type 2 (PHA2) with hypertension associated with other clinical findings such as short stature, muscle weakness, periodic paralysis and dental abnormalities.
Etiology
There are five etiological subtypes: PHA type 2A has been mapped to chromosome 1q31-q42, but no specific gene has so far been identified. PHA type 2B is due to mutations in WNK4 (17q21.2), PHA type 2C due to mutations in WNK1 (12p13.33), PHA type 2D due to mutations in KLHL3 (5q31.2), and PHA type 2E due to mutations in CUL3 (2q36.2). WNK1 and WNK4 encode serine/threonine-protein kinase WNK1 and WNK4, respectively, which regulate sodium and potassium reabsorption in the distal renal tubule. Disease-causing mutations in these genes lead to increased sodium reabsorption and decreased potassium secretion. The protein products of CUL3 and KLHL3 function together as part of the cullin-RING-based E3 ubiquitin ligase complex, which has a role in ubiquitin-mediated degradation of the proteins produced by WNK1 and WNK4.
Diagnostic methods
Diagnosis is established by the typical constellation of clinical and biochemical findings including hypertension, hyperkalemia (in the setting of normal GFR) with inappropriately low urinary potassium excretion, hyperchloremia, metabolic acidosis, low or suppressed plasma renin activity, hypercalciuria and family history. The diagnosis can be confirmed by genetic testing.
Differential diagnosis
Differential diagnosis includes other causes of hyperkalemia, notably chronic kidney disease. If GFR is normal, differential diagnoses include hyperkalemic renal tubular acidosis, as seen with PHA1, hypoaldosteronism, primary adrenal insufficiency, and hyperkalemia secondary to medication (e.g. potassium-sparing diuretics, nonsteroidal anti-inflammatory drugs, angiotensin inhibitors, trimethoprim, these forms of hyperkalemic RTA are typically associated with hypovolemia and low blood pressure. An acquired form of PHA2 can be seen with calcineurin inhibitors, especially tacrolimus.
Antenatal diagnosis
Prenatal diagnosis is possible where the genetic mutation has previously been identified in an affected family member.
Genetic counseling
The pattern of inheritance for PHA2 is typically autosomal dominant; however, PHA2 due to KLHL3 mutations can be inherited in an autosomal recessive or dominant manner. The risk to offspring of inheriting the mutation from an affected parent is 50% for the autosomal dominant forms. Offspring of an individual with autosomal recessive PHA2 are obligate carriers, and typically asymptomatic. Pathogenic variants arising de novo are possible. PHA2 due to CUL3 gene is typically the most severe form. The phenotype of PHA type II due to the WNK1 is typically less severe than PHA2 due to WNK4 or dominant or recessive mutation in the KLHL3 gene.
Management and treatment
Treatment is based on low-dose thiazide diuretics that are very effective in the correction of hypertension (important to prevent secondary complications), hyperkalemia, and hypercalciuria. Exogenous mineralocorticoids do not improve the biochemical abnormalities and likely worsen the hypertension.
Prognosis
Prognosis is good with lifelong therapy. Nephrolithiasis can be a complication of the disease if untreated and hypercalciuria persists.

                            Last update:
                            May 2019

                            - Expert reviewer(s):
                            Pr Detlef BÖCKENHAUER | ERKNet*

                                * European Reference Network


Pseudohypoparathyroidism type 1A (PHP1a) is a type of pseudohypoparathyroidism (PHP; see this term) characterized by renal resistance to parathyroid hormone (PTH), resulting in hypocalcemia, hyperphosphatemia, and elevated PTH; resistance to other hormones including thydroid stimulating hormone (TSH), gonadotropins and growth-hormone-releasing hormone (GHRH); and a constellation of clinical features known as Albright hereditary osteodystrophy (AHO; see this term).

Summary:
Epidemiology
Prevalence of PHP (1a and 1b) has been estimated at 1/295,000 in a Japanese study. The prevalence of PHP (1a, 1b and pseudopseudohypoparathyroidism (PPHP); see these terms) has been estimated at 1/150,000in Italy.
Clinical description
Onset of endocrine symptoms occurs during childhood, although cases with severe hypothyroidism at neonatal screening have been reported. Patients present with varying degrees of AHO features (including obesity). Ectopic ossifications may range from absent to extensive and generate severe pain. Developmental delay is highly variable, even in families with the same mutation. PTH resistance is not typically present at birth but develops over time, in some patients from a few months of age. Other symptoms related to hypocalcemia include: numbness, seizures, tetany, cataract or dental problems. Mild TSH resistance is often present at birth and may be diagnosed through neonatal screening of congenital hypothyroidism (see this term). It is usually asymptomatic. Gonadal dysfunction with delayed or incomplete sexual maturation, amenorrhea or oligomenorrhea and/or infertility is very frequent. Growth hormone (GH) deficiency is present in around 60% of patients, while resistance to calcitonin and to epinephrine is rare. Hormone resistance may develop over time, up until late adulthood. Rheumatologic complications have also been reported. The evolution of bone mineralization remains unclear.
Etiology
In about 70-80% of cases, PHP-Ia is caused by haploinsufficiency due to maternally-inherited heterozygous inactivating mutations in the GNAS gene (20q13). In a subset of patients negative for these mutations, methylation defects at the same locus have been reported.
Diagnostic methods
Diagnosis of PTH resistance is based on measurement of serum calcium, phosphate and PTH. After infusion of biosynthetic PTH (which may be useful in difficult cases), nephrogenic cAMP and urinary excretion of phosphate do not increase. AHO is diagnosed both clinically and on X-ray, showing typical shortening of the 4th metacarpal. Diagnosis is confirmed by genetic testing.
Differential diagnosis
Differential diagnoses include primary hypothyroidism, secondary hyperparathyroidism due to vitamin D deficiency, and other types of PHP.
Antenatal diagnosis
Antenatal diagnosis is possible when a disease causing mutation in the family is known.
Genetic counseling
Transmission is autosomal dominant with parental imprinting. Resistance to hormones develops only after maternal inheritance. In de novo mutations (25% of cases), hormone resistance is associated with a mutation on the maternal allele of the gene. In cases where methylation defects are found, genetic counseling may be difficult or impossible.
Management and treatment
Treatment is based on maintaining normocalcemia and, when possible, normalizing serum levels of PTH, with an active form of vitamin D (alfacalcidol or calcitriol) and calcium supplementation. Associated endocrinopathies should be treated when present (particularly hypothyroidism, growth hormone deficiency and hypogonadism) with levothyroxine and sex hormones. GH replacement therapy should be started as soon as possible. There is no treatment for AHO. Subcutaneous ossifications may be surgically removed when particularly large or causing pain/discomfort.
Prognosis
With proper treatment, prognosis is good, but quality of life may be affected by subcutaneous ossifications and the presence of severe short stature and obesity. Life expectancy is normal provided that endocrine disorders are correctly treated.

                            Last update:
                            October 2014

                            - Expert reviewer(s):
                            Pr Giovanna MANTOVANI


Pseudohypoparathyroidism type 1B (PHP-1b) is a type of pseudohypoparathyroidism (PHP; see this term) characterized by localized resistance to parathyroid hormone (PTH) mainly in the renal tissues which manifests with hypocalcemia, hyperphosphatemia and elevated PTH levels. About 60-70% of patients also present with elevated TSH levels due to TSH resistance.

Summary:
Epidemiology
The prevalence is unknown. The estimated prevalence of PHP (1a, 1b and PPHP) in Italy is 1/150,000.
Clinical description
PHP1b usually presents in childhood with symptoms of hypocalcemia, including numbness, seizures, tetany, cataracts, and dental problems. Patients may present with skeletal abnormalities, similar to those that occur in patients with hyperparathyroidism, such as reduced bone mineral density and osteitis fibrosa. TSH resistance is usually asymptomatic in PHP1b. Severity of symptoms can vary greatly between patients and even among kindreds.
Etiology
The majority of cases of PHP1b are sporadic, but an autosomal dominant transmission has also been described. About 70% of PHP-Ib patients display methylation defects, sporadic or genetic-based, at GNAS (20q13.2-q13.3) differentially methylated regions (DMRs). PHP-Ib familial form is typically characterized by an isolated loss of methylation at the A/B DMR, secondary to genetic deletions disrupting the upstream imprinting control region in the STX16 gene (20q13.32). Hormonal resistance seen in PHP-1b develops after maternal inheritance of the disease, while paternal inheritance is not associated with any endocrine abnormalities. In sporadic cases, broad methylation alterations at all GNAS DMRs are usually detected and in a subset of such patients, paternal uniparental disomy of chromosome 20 (see this term) may explain this pattern of alteration.
Diagnostic methods
Diagnosis of PTH resistance is based on measurement of serum calcium, phosphate and PTH. After infusion of biosynthetic PTH (which may be useful in difficult cases), nephrogenic cAMP and urinary excretion of phosphate do not increase. Gs-alpha activity in erythrocytes and fibroblasts is usually normal. Mild TSH resistance is often present at birth and may be diagnosed through neonatal screening of congenital hypothyroidism (see this term). Genetic testing can confirm diagnosis.
Differential diagnosis
Differential diagnoses include primary hypoparathyroidism (which can be ruled out by the absence of hypercalciuria), secondary hyperparathyroidism, autoimmune polyendocrinopathy (see this term), and vitamin D deficiency. It should also be excluded from other forms of PHP (see this term) based on the absence of Albright hereditary osteodystrophy (AHO; see this term) and normal expression of Gs protein.
Antenatal diagnosis
Antenatal diagnosis is possible only in those families with known deletions within GNAS or upstream of this locus.
Genetic counseling
The majority of cases of PHP1b are sporadic but familial transmission, following an autosomal dominant pattern of inheritance, has also been described and genetic counseling is possible in these cases.
Management and treatment
Treatment is based on maintaining normocalcemia and normalizing serum levels of PTH with active vitamin D metabolites (alfacalcidol or calcitriol) and calcium supplementation. Patients should be treated for other associated endocrinopathies when present, particularly hypothyroidism, with levothyroxine. Blood biochemistries and urinary calcium excretion should be monitored annually. Treatment is lifelong but calcium and calcitriol dosages can usually be progressively lowered over time.
Prognosis
With treatment the prognosis is good and life expectancy is predicted to be comparable with the normal population, provided that endocrine disorders are correctly treated.

                            Last update:
                            October 2014

                            - Expert reviewer(s):
                            Pr Giovanna MANTOVANI


Pseudohypoparathyroidism type 1c (PHP1c) is a rare type of pseudohypoparathyroidism (PHP; see this term) characterized by resistance to parathyroid hormone (PTH) and other hormones, which manifests with hypocalcemia, hyperphosphatemia and elevated PTH levels, a constellation of clinical features collectively termed Albright's hereditary osteodystrophy (AHO; see this term), but normal activity of the stimulatory protein G (Gs alpha).

Summary:
Epidemiology
The prevalence is unknown.
Clinical description
Clinical manifestations of PHP1c are similar to those seen in pseudohypoparathyroidism type 1a (PHP1a; see this term). They display the symptoms and signs of AHO (brachydactyly (most often the shortening of the 3, 4 and 5th metacarpals), rounded face, short stature, central obesity, subcutaneous ossifications and variable development delay) as well as PTH-resistance leading to hypocalcemia and hyperphosphatemia, and resistance towards TSH and, sometimes, other hormones.
Etiology
The exact etiology is unknown as mutations in the GNAS gene (20q13) are only rarely found. Other components of the cAMP-dependent signaling pathway, such as adenylyl cyclase, inhibitory G proteins, or phosphodiesterases might be impaired.
Genetic counseling
In familial cases the disease is inherited autosomal dominantly and genetic counseling is possible.

                            Last update:
                            October 2014

                            - Expert reviewer(s):
                            Pr Giovanna MANTOVANI


Pseudohypoparathyroidism type 2 (PHP2) is a type of pseudohypoparathyroidism (PHP; see this term) characterized by resistance to parathyroid hormone (PTH), which manifests with hypocalcemia, hyperphosphatemia and elevated PTH levels, absence of Albright's hereditary osteodystrophy (AHO; see this term), and normal expression of the Gs protein with a normal urinary cAMP response.

Summary:
Epidemiology
The prevalence is unknown.
Clinical description
The clinical manifestations of PHP-2 have been poorly characterized but are similar to those seen in pseudohypoparathyroidism type1b (PHP-1b; see this term). Patients present with symptoms related to low levels of calcium including: seizures, tetany (including muscle twitches and hand and foot spasms), numbness cataracts, and dental problems. Unlike PHP-1b, those with PHP-2 demonstrate a normal urinary cAMP response.
Etiology
To date, no specific genetic alteration responsible for this disorder has been detected. It has been hypothesized that in most cases it may be an acquired defect secondary to vitamin D deficiency such as in misdiagnosed secondary renal hyperparathyroidism.

                            Last update:
                            October 2014

                            - Expert reviewer(s):
                            Pr Giovanna MANTOVANI


Pseudohypoparathyroidism (PHP) is a heterogeneous group of endocrine disorders characterized by normal renal function and resistance to the action of parathyroid hormone (PTH), manifesting with hypocalcemia, hyperphosphatemia and elevated PTH levels and that includes the subtypes PHP type 1a (PHP-1a) , PHP type 1b (PHP-1b), PHP type 1c (PHP-1c), PHP type 2 (PHP-2) and pseudopseudohypoparathyroidism (PPHP) (see these terms).

Summary:
Epidemiology
The exact prevalence is unknown. PHP occurs twice as frequently in females as in males. The estimated prevalence (of PHP-1a, 1b and PPHP) in Italy is 1/150,000. The estimated prevalence in Japan (of PHP-1a and 1b) is 1/295,000.
Clinical description
All forms of PHP can present in infancy, especially if significant hypocalcemia occurs. Symptoms related to low levels of calcium can include: paresthesias, numbness, seizures and tetany (including muscle twitches and hand and foot spasms).Some forms of PHP may remain unnoticed if patients do not have hypocalcemia (or if hypocalcemia is misdiagnosed and treated as ''seizures'') and/or characteristic physical features, which include short stature, rounded face, short neck, centripetal obesity, brachydactyly and soft-tissue and calcifications/ossifications, and are collectively termed Albright hereditary osteodystrophy (AHO; see this term). AHO is observed in patients with PHP-1a, PHP-1c and PPHP but is absent in patients with PHP-1b and PHP-2. Intellectual disability is sometimes observed in patients with AHO features while it is almost always present in PHP-1A and PHP -1C. There have also been reports that olfaction is impaired in PHP-1a but not in PPHP or PHP-1b. Patients with PHP can also present with symptoms of resistance to hormones other than PTH including thyroid-stimulating hormone (TSH) (in PHP1a, PHP1c and sometimes PHP1b), gonadotropins (in PHP1a, PHP1c) and growth-hormone-releasing hormone (GHRH) (in PHP1a). Cataracts, dental problems and intracranial calcifications (bilateral striopallidodentate calcinosis; see this term) represent the long-term complications.
Etiology
PHP-1a, PPHP, and PHP-1b are all due to molecular defects in the same locus of the GNAS (20q13.2-q13.3) gene coding the alpha sub-unit of the stimulatory G protein. Patients inheriting PHP from the mother display all the signs of AHO with multi-hormone resistance, while patients inheriting the disease from the father have AHO without any resistance to hormone action (PPHP). This pattern of inheritance is consistent with a tissue-specific paternal imprinting of the gene causing the disease. Those with the autosomal dominant form of PHP-Ib display an isolated loss of methylationat exon A/B associated with a recurrent 3-kb deletion in the STX16 gene (20q13.32). To date, the genetic anomaly responsible for PHP2 and PHP1c has not yet been identified, although in a few PHP1c patients, GNAS heterozygous mutations have been detected. It has been hypothesized that in most cases, PHP2 may be an acquired defect secondary to vitamin D deficiency.
Genetic counseling
PHP can be sporadic or inherited autosomal dominantly with parental imprinting. In inherited cases, genetic counseling is possible.

                            Last update:
                            October 2014

                            - Expert reviewer(s):
                            Pr Giovanna MANTOVANI


Pseudoleprechaunism syndrome, Patterson type is a rare, genetic, adrenal disorder characterized by congenital bronzed hyperpigmentation, cutis laxa of the hands and feet, body disproportion (comprising large hands, feet, nose and ears), hirsutism and severe intellectual disability. Patients additionally present hyperadrenocorticism, cushingoid features, premature adrenarche and diabetes mellitus, as well as skeletal deformities (not present at birth and which progress with age). There have been no further descriptions in the literature since 1981.


Pseudomyxoma peritonei is characterized by disseminated intra-peritoneal mucinous tumors and mucinous ascites in the abdomen and pelvis.

Summary:
Epidemiology
Annual incidence is estimated at 1/1,000,000 with female predominance.
Clinical description
The disease is usually diagnosed after the age of 40. In 30 to 50% of cases, patients present with progressive abdominal distension (so-called ``jelly belly''). Diagnosis may follow discovery of an ovarian mass in women or recent development of inguinal hernia, appendicitis or intestinal occlusion. Other less common signs include abdominal pain, weight loss, urinary symptoms, constipation, vomiting, and dyspnea.
Etiology
In 90% of cases, the primary lesion is an appendiceal mucinous tumor, but ovarian mucinous tumors have been reported (7%) and, more rarely, mucinous tumors of the colon, stomach, pancreas, and urachus.
Diagnostic methods
The diagnosis is based on chest-abdominal-pelvic computed tomography (CAP-CT) findings (revealing the characteristic compartmentalized distribution pattern of mucinous ascites) and on pathology (performed by two experts), while tumor markers (carcinoembryonic antigen and CA19-9) are relatively non-specific.
Differential diagnosis
The differential diagnosis includes secondary peritoneal carcinomatoses and other rare peritoneal tumors.
Management and treatment
Treatment strategies require a multidisciplinary approach and must be discussed by a panel of physicians in a specialized center. There are currently no validated recommendations on clinical management and no cytotoxic agents have been granted a European Marketing Authorization (MA) in this indication. Nonetheless, the best curative option appears to be complete cytoreductive surgery (visceral resections and peritonectomy procedures) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) (off-label use), sometimes followed by intravenous chemotherapy (off-label use) which can only be considered in young patients with good general status.
Prognosis
Pseudomyxoma peritonei is slowly progressive but recurrence after complete tumor removal may occur. Following combined treatment (complete cytoreductive surgery and HIPEC), the 5-year survival rate reaches 70% for non-aggressive peritoneal pseudomyxoma in patients treated in a specialized center.

                            Last update:
                            March 2011

                            - Expert reviewer(s):
                            Pr François-Noël GILLY  - Pr Olivier GLEHEN


Pseudo-pelade of Brocq is a rare hair abnormality characterized by onset in adulthood of soft, irregular, flesh-toned patches of alopecia primarily in the parietal and vertex portions of the scalp, without follicular hyperkeratosis or perifollicular inflammation.


A rare syndromic intellectual deficiency characterized by psychomotor delay, severe progressive spastic quadriplegia, microcephaly, and a Hallerman-Streiff-like phenotype including absence of eyebrows and eyelashes, glaucoma, and small, beaked nose. Structural central nervous system abnormalities (cervical spinal cyst, occipital cranium bifidum occulatum) were additional findings. There have been no further descriptions in the literature since 1974.


Pseudopseudohypoparathyroidism (pseudo-PHP) is a disease characterized by a constellation of clinical features collectively termed Albright hereditary osteodystrophy (AHO; see this term) but no evidence of resistance to parathyroid hormone (PTH), which is seen in other forms of pseudohypoparathyroidism (PHP; see this term).

Summary:
Epidemiology
Prevalence is unknown but series of patients usually include one patient with pseudo-PHP for every two patients with PHP 1a (see this term).
Clinical description
Due to the absence of hormone resistance, the age at diagnosis varies from birth to late adulthood. Patients display various features of AHO including short stature which develops over time, absence of pubertal growth spurt (mean final height is between -2 and -3 SD), rounded face, brachydactyly, absence of widening of the lumbar spine, and ectopic ossifications of soft-tissues, which may develop spontaneously or after trauma. The spectrum of the ectopic ossifications ranges from absent to extensive and may generate severe pain. Patients with extensive ectopic ossifications may also be considered as having progressive osseous heteroplasia (POH; see this term). Cognitive impairment is present in only 10% of the patients. Unlike in PHP 1a, obesity is not constant and, when present, is only moderate.
Etiology
The disease is caused by paternally inherited heterozygous molecular defects in the GNAS gene (20q13) encoding the alpha sub-unit of the stimulatory G protein (Gs alpha), which results in a reduction in the expressioctivity of Gs alpha. In families in which PHP 1a and pseudo-PHP co-exist, mutations in the gene can be detected in all affected members.
Diagnostic methods
Diagnosis is based on the presence of features of AHO and the exclusion of other forms of PHP (by measuring serum calcium, phosphate and PTH). X-rays show typical shortening of the fourth metacarpal and advanced bone age. All metacarpals and metatarsals may be affected. Molecular genetic testing identifying a mutation in the GNAS gene confirms diagnosis.
Differential diagnosis
The differential diagnosis includes PHP 1a, PHP 1c and 2q37 microdeletion syndrome (see these terms).
Antenatal diagnosis
Antenatal diagnosis is possible when a disease causing mutation in the family is known.
Genetic counseling
Transmission is autosomal dominant with parental imprinting. Pseudo-PHP most frequently occurs in relatives of patients with PHP 1a, but may present in families without PHP as an isolated defect. Paternal inheritance of the mutation is responsible for pseudo-PHP. Genetic counseling is possible.
Management and treatment
There are no specific treatments for the various manifestations of AHO, although subcutaneous ossifications may be surgically removed when particularly large or causing pain/discomfort.
Prognosis
Pseudo-PHP is not life threatening but quality of life can be affected in those with severe ectopic ossification.

                            Last update:
                            October 2014

                            - Expert reviewer(s):
                            Pr Giovanna MANTOVANI


Pseudotyphus of California is a rare, flea-borne Rickettsial disease caused by a Rickettsia felis  infection. Patients can be asymptomatic or can present with unspecific symptoms (such as fever, headache, generalized maculopapular rash, myalgia, arthralgia and, ocasionally, eschar, lymphadenopathy, nausea, vomiting, loss of appetite and abdominal pain). Rarely, serious manifestations may occur and include neurological dysfunction (photophobia, hearing loss, and signs of meningitis) and pulmonary compromise.


A rare, non-syndromic uterovaginal malformation characterized by a crescent-shaped, small-sized uterus containing a single horn and fallopian tube associated with a rudimentary second horn (which can be solid or contain a cavity with functioning endometrium and be communicating or non-communicating). Urinary tract anomalies are frequently associated.


Pseudoxanthoma elasticum-like papillary dermal elastolysis (PXE-PDE) is a rare, acquired, idiopathic dermal tissue disorder characterized by numerous, asymptomatic, 2-3 mm, yellowish, non-follicular papules that tend to converge into cobblestone-like plaques which are distributed symmetrically over the posterior neck, supraclavicular region, axillae, and sometimes abdomen. Unlike PXE, these skin lesions show select elimination (absence or marked loss) of elastic fibers in the papillary dermis and there is no systemic involvement.


Pseudoxanthoma elasticum-like skin manifestations with retinitis pigmentosa

A rare, genetic, dermis elastic tissue disorder characterized by yellowish skin papules (resembling pseudoxanthoma elasticum) located on the neck, chest and/or flexural areas associated with loose, redundant, sagging skin on trunk and upper limbs, and retinitis pigmentosa, in the absence of clotting abnormalities. Patients present reduced night and peripheral vision, as well as optic nerve pallor, retinal pigment epithelium loss, attenuated retinal vessels and/or black pigment intra-retinal clumps.


A rare, genetic, metabolic disease with connective tissue and eye involvement, characterized by progressive ectopic mineralization and fragmented elastic fibers in the skin, retina and vascular walls.

Summary:
Epidemiology
Prevalence is estimated at between 1/40,000 and 1/100,000 in the general population, with, for unknown reason, female predominance (female to male ratio 4:1).
Clinical description
Disease onset is typically in adolescence or young adulthood but may appear at any age. The first clinical sign is almost always small yellow papules on the nape and sides of the neck and in flexural areas. The papules subsequently coalesce, and the skin becomes loose and wrinkled. Dystrophic calcification of Bruch's membrane of the retina, revealed by angioid streaks at fundus examination, may trigger choroidal neovascularization and, ultimately, loss of central vision and blindness in late-stage disease. Lesions in small and medium-sized artery walls may result in intermittent claudication and peripheral artery disease. The disease may be limited to one organ (skin, eye, or blood vessels) in some patients or affect two or all three organs. Cardiac complications (angina pectoris, myocardial infarction) are relatively rare but, when present, deserve thorough investigation. Transient ischemic attacks and, more rarely, ischemic strokes have been reported. Gastrointestinal hemorrhage occurs in about 5% of cases. Calcification of other organs, such as the kidneys, breasts, pancreas, testicles, liver and spleen may be observed.
Etiology
The vast majority of cases are caused by biallelic pathogenic variants in the ABCC6 gene (16p13.11). Rarely, patients with pseudoxanthoma elasticum (PXE)-like clinical features harbor pathogenic variants in the ENPP1 gene (6q23.2), which is usually associated with generalized arterial calcification of infancy (GACI). Both genes are presumably part of one metabolic way, and the pathogenic variants are thought to lead to decreased circulating pyrophosphate (PPi), a major anti-mineralization factor.
Diagnostic methods
Diagnosis is suspected on clinical presentation of characteristic yellow cobblestone skin lesions at the predilection sites. Biopsy of the affected skin using elastin and calcium-specific staining reveals abundant morphological alterations with fragmented, clustered and calcified elastin fibers in the middle and lower dermis. Fundus examination reveals characteristic retinopathy with angioid streaks, drusen or maculopathy. Genetic testing for ABCC6 can confirm diagnosis or rule it out in clinically ambiguous cases.
Differential diagnosis
Differential diagnosis of angioid streaks includes hemoglobinopathies (sickle cell disease, Beta-thalassemia, spherocytosis), dermal elastic tissue disorders (solar elastosis, perforating calcific elastosis, PXE-like late-onset focal dermal elastosis, PXE-like papillary dermal elastolysis) and other multisystem disorders (cutis laxa) as well as combined vitamin K-dependent clotting factors deficiency.
Genetic counseling
The pattern of transmission is autosomal recessive, with a 25% risk of recurrence in siblings. Pseudo-dominant pattern of inheritance due to high frequency of ABCC6 heterozygotes (around 1/200), has been occasionally observed. Genetic counseling for affected families is recommended.
Management and treatment
There is no specific therapy; the main symptomatic treatments include direct injection of vascular endothelial growth factor inhibitor in the eyes (for choroidal neovascularization), lifestyle, lipid-lowering and dietary measures (for reducing vascular risk factors), vascular surgery (for severe arteriosclerosis), and plastic surgery (for excess skin folds).
Prognosis
It is a life-long progressive disease with high debilitating potential, but the life-span is normal in most patients.

                            Last update:
                            November 2020

                            - Expert reviewer(s):
                            Pr Dominique GERMAIN


Pseudoxanthomatous diffuse cutaneous mastocytosis (PDCM) is a rare form of diffuse cutaneous mastocytosis (DCM; see this term) characterized by yellow-orange infiltrated and xanthogranuloma-like lesions with only limited blistering.

Summary:
Epidemiology
Only a small number of cases (around 10) of PDCM have been reported in the literature to date.
Clinical description
Onset most commonly occurs in early infancy with small vesicles and pseudoxanthomatous lesions developing after puberty.
Etiology
Mutations in the KIT gene (4q11-q12) have been detected in patients with DCM.

                            Last update:
                            June 2013

                            - Expert reviewer(s):
                            Pr A.P. [Arnold] ORANJE


Psoriasis-related juvenile idiopathic arthritis

A rare pediatric inflammatory rheumatic disease characterized by the presence of arthritis accompanied by either psoriasis or at least two of the following supporting features; presence of nail pitting, onycholysis, dactylitis, or a family history of psoriasis in a first degree relative. Patients are younger than 16 years of age and the disease lasts longer than 6 weeks.

Summary:
Epidemiology
The incidence of juvenile idiopathic arthritis (JIA) in Caucasian is 8.3/100,000. Psoriatic juvenile idiopathic arthritis represents up to 10% of all JIA subtypes. Incidence and prevalence vary among populations, depending on race, immunogenetic susceptibility, and environmental influences.
Clinical description
Juvenile idiopathic arthritis is considered an autoimmune disease, which may arise from an abnormal immunologic response triggered by environmental factors such as infection or trauma in a genetically predisposed subject. The onset of arthritis precedes the psoriatic cutaneous manifestations in more than 60% of cases, sometimes several years earlier, and it usually presents in an asymmetric oligoarthritis pattern. Monoarthritis (inflammation at one joint at a time) is relatively common at the onset, with isolated involvement of knee and small joints of hands and feet.
Etiology
The etiology of psoriasis-related juvenile idiopathic arthritis is not currently known, although all juvenile idiopathic arthritis subtypes are most likely complex genetic traits as they lack single-gene, Mendelian patterns of inheritance. Inherited risk factors for both disease susceptibility and disease severity have been reported; the highly polymorphic HLA genes confer the strongest genetic effects.
Diagnostic methods
Diagnosis relies on observation of the clinical manifestations and ruling out other potential causes or illnesses. The disease is characterized either by the presence of a form of arthritis and psoriasis, or by the presence of arthritis associated with two or more of the following signs: dactylitis, nail pitting or onycholysis, or a family history of psoriasis in a first-degree relative. Exclusion criteria include the presence of systemic arthritis, HLA B27-positivity in males with onset of arthritis after 6 years of age, detection of rheumatoid Factor IgM in two test samples taken three months apart, the presence, or family history in a first degree relative, of ankylosing spondylarthritis, enthesitis and arthritis, sacroiliitis with an inflammatory bowel disease, or acute anterior uveitis.
Differential diagnosis
The differential diagnosis of arthritis associated with psoriasis is extensive. It includes other diseases associated with arthritis, including infectious, inflammatory and hemato-oncologic diseases. Specific examples include ankylosing spondylitis, reactive arthritis, inﬂamatory bowel disease, Behçet disease, Kawasaki disease, sarcoidosis, Blau syndrome, systemic lupus erythematosus, Sweet syndrome, and some infections such as Lyme or Whipple disease.
Management and treatment
Treatment of psoriasis-related JIA usually involves treatment with non-steroidal anti-inflammatory drugs (NSAIDs) and, when insufficient, disease modifying anti-rheumatic drugs (DMARDs; methotrexate) and then biological DMARDs (TNF inhibitor agents: etanercept or adalimumab).
Prognosis
Juvenile idiopathic arthritis has been considered (before the use of biological DMARDs) an important cause of short- and long-term acquired disability in children, impaired physical health, reduced quality of life and higher unemployment later on in life. Effective therapy helps avoid progression to the polyarticular form from the monarticular form. Furthermore, chronic uveitis may occur in 10 to 15% of children with psoriatic juvenile idiopathic arthritis. Therefore, early detection and intervention is extremely important.

                            Last update:
                            August 2020

                            - Expert reviewer(s):
                            Dr Chantal DESLANDRE


A rare neurologic disease characterized by the manifestation of an underlying psychiatric illness or malingering, and that cannot be attributed to any known structural or neurochemical diseases. Most cases fall in the psychiatric diagnostic category of conversion disorder, also referred to as functional neurological symptom disorder.

Summary:
Epidemiology
The exact prevalence of psychogenic movement disorders (PMD) is unknown. At tertiary care centers, 2-4% of movement disorders patients are diagnosed with PMD.
Clinical description
PMD present typically during adolescence or adulthood. Childhood cases and new onset in the elderly are rare, but do occur. Symptoms may include one or several types of abnormal movements seen in organic movement disorders (tremor, dystonia, chorea, bradykinesia, myoclonus, tics, athetosis, ballism, cerebellar incoordination), and also affect speech and gait. Typically, PMD present with complex movements of multiple different phenomenologies, usually incongruent with an organic movement disorder and affecting several body regions. Tremor appears to be the most commonly observed phenomenon, followed by dystonia, bradykinesia, myoclonus, and other unclassifiable abnormal movements. Symptoms often occur abruptly, and maximal symptom severity and disability are reached quickly. Other typical features are: deliberate slowness of movement, distractibility, variability, suggestibility, paroxysmal symptoms, and resolution with placebo administration or when the patient is unaware of being observed. Frequently, PMD are accompanied by other psychogenic symptoms such as false weakness, sensory findings, or excessive pain. Depression and anxiety are common comorbidities.
Etiology
Underlying causes for PMD fall into three categories: Conversion disorder (also referred to as functional neurological symptom disorder), somatic symptom disorders, or, in rare cases, factitious disorder, and malingering. Risk factors include female gender, history of childhood trauma or sexual abuse, previous injury, surgery, and major stressful life events.
Diagnostic methods
The diagnosis is usually made on clinical grounds, but certain ancillary tests may be helpful. Electromyography-based tremor and myoclonus analysis can be used to distinguish psychogenic tremor and myoclonus from their organic counterparts. Neuroimaging in the form of [123 I]-beta-CIT SPECT and [18F]-DOPA-PET is sometimes used in difficult to diagnose cases of psychogenic parkinsonism to exclude an organic etiology.
Differential diagnosis
The differential diagnosis of PMD lies in the organic counterparts of each individual presenting abnormal movement. In cases of tremor as the presenting symptom for example, Parkinson's disease and essential tremor will be considered. Some patients with PMD have movements that resemble seizures, and epilepsy should be ruled out.
Antenatal diagnosis
Prenatal diagnosis does not exist for this disorder.
Management and treatment
Avoidance of iatrogenic damage by unnecessary invasive tests or inappropriate medications, early and precise diagnosis, and the facilitation of the appropriate psychiatric and physical rehabilitation treatment are important. Clinical trials are sparse, but the available literature suggests that a combination of psychotherapy with individualized psychiatric medication (aimed at treating coexisting conditions such as depression or anxiety) may be beneficial. Some centers also offer interdisciplinary inpatient programs, combing intense physiotherapy with psychotherapy.
Prognosis
The prognosis of PMD is variable, but is better than that for patients with other somatoform complaints such as sensory symptoms, weakness or pain. The presence of psychiatric comorbidity (depression or an anxiety disorder) is a positive prognostic factor. Long-standing symptoms, insidious onset of movements and primary psychiatric diagnosis of hypochondriasis, a factitious disorder, or malingering are negative prognostic factors. If left untreated, PMD tend to be chronic, and follow-up data in several series show persistent symptoms in 65-95% of patients.

                            Last update:
                            November 2019

                            - Expert reviewer(s):
                            Dr Vanessa HINSON


Psychomotor regression-oculomotor apraxia-movement disorder-nephropathy syndrome

A rare genetic disease characterized by onset of neurological deterioration in the first two years of life, progressing to severe intellectual disability, profound ataxia, mild dyskinesia, axial hypotonia, camptocormia, and oculomotor apraxia. Some patients also develop nephropathy with features of tubulointerstitial nephritis, hypertension, and a tendency for hyperkalemia.


A group rare skin tumor or hamartoma diseases characterized by a germline PTEN mutation and clinical manifestations of hamartomas, overgrowth, and increased risk of neoplasia, notably breast carcinomas, epithelial thyroid carcinomas, endometrial carcinomas, renal cell carcinomas, and colorectal carcinoma. Non-malignant manifestations include macrocephaly, benign thyroid pathology (especially Hashimoto thyroiditis), mucocutaneous hamartomas, colonic polyps, and vascular malformations. Diseases in this group include Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus-like syndrome, Lhermitte-Duclos disease, and Segmental outgrowth-lipomatosis-arteriovenous malformation-epidermal nevus syndrome.


Pterin-4 alpha-carbinolamine dehydratase deficiency

A rare genetic, transient and benign form of hyperphenylalaninemia due to tetrahydrobiopterin deficiency and characterized by muscular hypotonia, irritability (detected by EEG), slow acquisition of psychomotor skills, age-dependent movement disorders, including dystonia and an accompanying excretion of 7-substituted pterins. Neurological developement is normal with dietary control of blood phenyalanine.


Pterygium colli-intellectual disability-digital anomalies syndrome

A rare disorder characterized by pterygium colli, digital anomalies (abnormal small thumbs, widened interphalangeal joints, and broad terminal phalanges), and craniofacial abnormalities (brachycephaly, epicanthic folds, angulated eyebrows, upward slanting of the palpebral fissures, ptosis, hypertelorism, and prominent low-set, posteriorly rotated ears). It has been described in a woman and her son, but the manifestations were much less severe in the mother. The son also had intellectual deficit. The inheritance is either X-linked dominant or autosomal dominant.


A rare disorder characterized by the association of ptosis, strabismus and ectopic pupils. It has been described in one family (in a mother and three of her children). Transmission is autosomal dominant.


Ptosis-upper ocular movement limitation-absence of lacrimal punctum syndrome

A rare opthalmic disorder characterized by bilateral ptosis, upper ocular movement limitation, absence of the lacrimal punctum and facial dysmorphism including, narrow and squared forehead, bilateral thick and arched eyebrows, absence of bilateral lower medial eyelashes, telechantus, mild anteverted nostrils, a relatively long philtrum and maxillary hypoplasia. Some patients may have low set and dysplastic ears.


Ptosis-vocal cord paralysis syndrome is a rare, hereditary disorder with ptosis characterized by the combination of congenital bilateral recurrent laryngeal nerve paralysis and congenital bilateral ptosis. There have been no further descriptions in the literature since 1983.


A rare, acquired peripheral neuropathy characterized by chronic neuropathic pain involving the sensory territory of the pudendal nerve (from clitoris to anus or from penis to anus) aggravated by sitting. It is often associated with pelvic dysfunction.

Summary:
Epidemiology
The prevalence of Pudendal neuralgia (PN) is unknown. A female predominance is reported, with a female/male ratio of 6:4.
Clinical description
PN usually presents between the ages of 50-70 years. and manifests with neuropathic pain of varying intensity in the perineal region. The pain is described as an intense, sharp, burning sensation, and sometimes as numbness. Rectal or vaginal foreign body sensations (sympathalgia) are commonly reported. Pain is unilateral or often medial, and is more intense during the day, when sitting or when wearing tight clothing. The pain is often associated with pelvic sensitization, which explains the urinary (pollakiuria, dysuria), anorectal (dyschezia, increased pain after bowl movement) and sexual (dyspareunia, intolerance of vulval contact, post-coital exacerbation of pain, persistent genital arousal, erectile dysfunction) problems as well as myofascial pain in the buttocks. The co-occurrence of truncal sciatica is common. Several forms of PN exist: benign, regressive, evolutive with flares, stable, and very debilitating forms with progressive symptom aggravation.
Etiology
The pudendal nerve can be compressed or entrapped by posterior pelvis ligaments (comprised of the sacrotuberous and sacrospinalis ligaments), or in the Alcock's canal (due to splitting of the obturator muscle aponeurosis). There is also the possibility of proximal entrapment at the level of the sub-piriformis canal and distal entrapment of the dorsal nerve of the clitoris/penis at the level of the sub-pubic canal. Other causes of pudendal neuralgia may include birth-related difficulties (due to excessive stretching), trauma, surgical, radiation sequalae, intense bicycling, spinal deviation, pelvic skeletal fractures or a tumor. In these cases, the pain is likely to be permanent and sitting position has little or no effect on it.
Diagnostic methods
The diagnostic criteria (Nantes criteria) for PN includes the presence of pain in the distribution of the pudendal nerve that is worsened by sitting, with no objective sensory impairment, which does not provoke awakening in the night, and that is relieved with anesthesia by pudendal nerve block. The diagnosis is strictly clinical and no additional examination can validate the diagnosis with certainty. Imaging tests may be necessary to rule out other diagnoses (pelvic and lumbosacral MRI, endoscopy, infection check-up, etc.). Normal imaging findings do not exclude a diagnosis of PN.
Differential diagnosis
Differential diagnoses include neuropathies of the neighboring nerves (ilio-inguinal, genitofemoral, lower cluneal), coccygodynia (given the location of pain projecting into the anus and rectum, aggravated by sitting position) and myofascial syndromes of the deep gluteus muscles (piriformes, obturator internus muscle, levator ani). Dermatological inflammatory pathologies (psoriasis, vulvar sclerotrophic lichen) should be systematically eliminated. When the pain is not triggered by sitting position, but rather by sexual intercourse, vestibulodynia should be considered. Isolated chronic urethralgia or bladder pain syndrome may be considered when perineal pain varies with urination.
Management and treatment
Management includes the treatment of neuropathic pain with antidepressant therapy (amitriptyline at low dose or duloxetine) or antiepileptic (pregabalin, gabapentin) and percutaneous posterior tibial nerve stimulation. Physiotherapy, osteopathy and short-term psychotherapy are also proposed as first-line solutions. The effect of anesthetic infiltration of the pudendal nerve is limited and its therapeutic effects in the medium and long term have not been demonstrated. In refractory forms, surgical decompression of the pudendal nerve has been effective (the trans-gluteal pathway being the only surgery whose efficacy has been proved). In those where surgery has been ineffective, an implanted neurostimulator can be proposed at the conus medullaris level or on sacral roots and pudendal nerve level.
Prognosis
PN greatly affects quality of life, but has no effect on life expectancy.

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Dr Amélie LEVESQUE


A rare, non-syndromic respiratory or mediastinal malformation characterized by unilateral complete absence of lung tissue, bronchi, and pulmonary vessels. It may be isolated or associated with congenital malformations, most commonly with heart anomalies. Presentation is highly variable including airway narrowing, stridor, respiratory distress, recurrent respiratory tract infections, and pulmonary hypertension.


A rare genetic respiratory disease characterized by widespread intra-alveolar accumulation of minute calcium phosphate microliths, leading to pulmonary fibrosis, pulmonary hypertension, and chronic respiratory failure. Age of onset is highly variable, and most patients are asymptomatic for years or decades, before signs and symptoms like dyspnea on exertion, dry cough, chest pain, hemoptysis, or finger clubbing develop. The disease takes a long-term progressive course. Routine chest radiographs typically show a fine, ''sandstorm-like'' micronodular pattern that is more pronounced in the bases than in the apices.


Pulmonary arterial hypertension associated with another disease is a group of conditions that lead to PAH (see this term); connective tissue diseases (lupus erythematosus, systemic sclerosis and mixed connective tissues disease), congenital heart disease (Eisenmenger syndrome), HIV infection, portal hypertension, schistosomiasis and chronic hemolytic anemia (see these terms),which is characterized by elevated pulmonary arterial resistance leading to right heart failure that is progressive and potentially fatal.


Pulmonary arterial hypertension associated with chronic hemolytic anemia (PAH-CHA) is a form of PAH (see this term) characterized by an elevated pulmonary arterial resistance leading to right heart failure observed as a complication of chronic hemolytic anemia.


Pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) is a form of pulmonary arterial hypertension (PAH, see this term), characterized by elevated pulmonary arterial resistance leading to right heart failure occurring as a common complication of congenital heart malformations (see this term) with left to right cardiac shunts. Eisenmenger syndrome (see this term) is the most advanced form of PAH-CHD and is defined as the complete or partial reversal of an initial left-to-right shunt to a right-to-left shunt, causing cyanosis and limited exercise capacity. PAH-CHD also includes mild to moderate systemic-to-pulmonary shunts with no cyanosis at rest, patients with small defects, and those with residual PAH following corrective cardiac surgery.


Pulmonary arterial hypertension associated with connective tissue disease

A form of pulmonary arterial hypertension (PAH) characterized by an elevated pulmonary arterial resistance leading to right heart failure observed as a complication of a connective tissue disease.


Pulmonary arterial hypertension associated with HIV infection

A form of pulmonary arterial hypertension characterized by elevated pulmonary arterial resistance leading to right heart failure observed as a complication of HIV infection.


Pulmonary arterial hypertension associated with portal hypertension (PAH-PH) is a form of pulmonary arterial hypertension (PAH), characterized by an elevated pulmonary arterial resistance leading to right heart failure observed as a complication of portal hypertension.


Pulmonary arterial hypertension associated with schistosomiasis (PAHS) is a form of pulmonary arterial hypertension (see this term) characterized by an elevated pulmonary arterial resistance leading to right heart failure, observed as a complication of a chronic schistosomiasis (see this term).


Pulmonary arterial hypertension (PAH) is a group of diseases characterized by elevated pulmonary arterial resistance leading to right heart failure. PAH is progressive and potentially fatal. PAH may be idiopathic and/ or familial, or induced by drug or toxin (drug-or toxin-induced PAH, see these terms) or associated with other diseases like congenital heart disease, connective tissue disease, HIV, schistosomiasis, portal hypertension (PAH associated with other disease, see this term).

Summary:
Epidemiology
Prevalence of PAH, in all of its forms, is estimated around 5/1,000,000.
Clinical description
Most forms of PAH develop in adults, and in rare cases in children; women are twice as likely as men to be affected. Initial symptoms include dyspnea, syncope, chest pain, palpitations and pedal edema. Precordial signs include loud and palpable second heart sound, pulmonary ejection click and murmurs of pulmonary and tricuspid regurgitation. 70% of patients present with severe heart failure. More rarely, abdominal distension, clubbing of digits and Raynaud phenomenon (predominantly in females) are observed. Hemoptysis has also been reported.
Etiology
PAH is caused by vascular remodeling of pulmonary arteries leading to widespread obliteration of the smallest arteries; sufficient occlusion of these vessels increases the resistance to pulmonary blood flow and a compensating increased pressure in the right ventricle. Mutations in BMPR2 gene (2q33) and also in ACVRL1(12q13), Endoglin(9q34), CAV1 (7q31), KCNK3(2p23),Smad9 (13q12) and TBX4 (17q21)have been described in heritable PAH. Mutations in PAH predisposing genes were identified in patients with idiopathic and/or familial form of PAH and in PAH associated with intake of drugs or toxins. Patients carrying a mutation in PAH predisposing gene, and those displaying a familial form of the disease (with or without mutations identified), are grouped under the term heritable PAH (see this term).
Diagnostic methods
Chest X-ray reveals an enlarged pulmonary artery and lung hyper perfusion and ECG shows right ventricular strain and hypertrophy. Echocardiography allows an estimate of pulmonary artery systolic pressure and detects cardiac disease. Right-heart catheterization is essential to establish the diagnosis:. PAH is diagnosed when resting mean pulmonary artery pressure is >25mmHg and a normal Pulmonary capillary wedge pressure.
Differential diagnosis
Rarer forms of pulmonary hypertension include pulmonary veno-occlusive disease /pulmonary capillary hemangiotosis (PVOD /PCH, see these terms).Differential diagnoses include asthma, chronic obstructive pulmonary disease, hypoplastic left heart syndrome, chronic thromboembolic pulmonary hypertension and complete atrio-ventricular canal - left heart obstruction (see these terms).
Antenatal diagnosis
Pregnancy is considered to be associated with a high rate of mortality (30-50%) in PAH patients. Prenatal genetic testing could be considered in cases of heritable PAH (see this term).
Genetic counseling
Genetic counseling and testing have to be proposed to patients with idiopathic or heritable form of PAH (transmitted as an autosomal dominant disease with an incomplete penetrance) and to patients displaying drug-or toxin-induced PAH.
Management and treatment
Management includes general measures (aggressive management of respiratory tract infections, annual influenza vaccination, family planning) and medical therapy (oxygen, anticoagulants, diuretics, digoxin. Calcium channel blockers are indicated only in patients with acute vasodilator response to Nitric oxide during right heart catheterization. Endothelin receptor agonists (ambrisentan,), prostanoids (epoprostenol) and phosphodiestrease inhibitors (sildenafill) have been used. Lung transplantation is the last option for resistant patients.
Prognosis
Prognosis varies between different forms, but is generally poor; the mean survival rate after diagnosis is <3 years. However, early therapeutic intervention may lead to better survival.

                            Last update:
                            January 2015

                            - Expert reviewer(s):
                            Dr Barbara GIRERD  - Pr David MONTANI


An aberrant communication between one or more pulmonary arteries and one or more pulmonary veins leading to an anatomic intrapulmonary right-to-left shunt.

Summary:
Epidemiology
In Japan, prevalence estimated by screening thoracic CT scans is 1/2,600 for all causes of pulmonary arteriovenous malformations (PAVMs).
Clinical description
PAVMs differ from other thoracic vascular anomalies in that the right-to-left shunt places individuals at high risk of paradoxical embolic complications, particularly neurological, and these risks are present whether or not the individual has symptoms from the PAVM(s). In most cases, PAVMs are asymptomatic because of successful physiological compensations such as polycythemia, and higher cardiac outputs. The mean age for presentation is over 50 years of age, though lower if screening programs are utilized. If present, exercise intolerance and dyspnea usually reflect concurrent conditions such as low hemoglobinemia, mild airflow limitation, and/or other cardiorespiratory impairments. Hemoptysis is rare, but is the most frequent cause of maternal death in pregnancy. Major neurological complications such as early onset ischemic strokes, transient ischemic attacks, and cerebral abscesses affect more than 15% of adult patients in recent European studies, but are extremely rare in children. Tachyarrhythmias and angina may be present at diagnosis, although they usually reflect a more complex underlying pathology; particularly iron deficiency and/or visceral arteriovenous malformations (AVMs) due to underlying hereditary hemorrhagic telangiectasia (HHT). HHT is present in more than 70% of people with PAVMs.
Etiology
The exact pathogenesis is still unknown. As many as 20% of PAVMs are idiopathic (sporadic), although PAVMs generally occur in the context of HHT, or, less frequently, other vascular malformation syndromes. PAVMs can also result from surgical corrections of cyanotic congenital heart disease; gestational trophoblastic disease; the hepatopulmonary syndrome; telomeric disorders, or trauma.
Diagnostic methods
Diagnosis is based on imaging demonstrating one or more AVMs usually located in the lower lobes of the lungs. Although PAVMs may be clearly visible on chest X-rays, many are not, even when clinically significant. Computed tomography is generally considered the gold-standard investigation for diagnosing PAVMs. AVMs can be isolated or multiple, unilateral or bilateral. 'Simple' lesions consist of an aneurysmal venous sac communicating with a dilated feeding artery and draining vein. Complex PAVMs are supplied by more than one pulmonary artery and/or drained by more than one vein; diffuse PAVMs are multiple small PAVMs affecting one or more segments of one or more lobes. Arterial partial pressure of oxygen and oxygen saturation, are often low, and are inversely related to the size of the right-to-left shunt. Approximately one-third of patients demonstrate orthodeoxia, but platypnea is seldom observed.
Differential diagnosis
Differential diagnoses include pulmonary artery aneurysms, pulmonary varices, bronchoceles, systemic artery-pulmonary artery communications and vascular tumors.
Antenatal diagnosis
Prenatal genetic testing is possible for inherited forms of PAVM but is not necessary for proper pregnancy and delivery management.
Genetic counseling
Where PAVMs are multiple and no other precipitants can be identified, the condition is likely inherited, and genetic testing should be suggested. If negative, screening of children for PAVMs is suggested after puberty. Single PAVMs may be due to inherited conditions even in the absence of other symptoms and signs, with mosaic cases described and potentially heritable.
Management and treatment
Treatment of adult patients is recommended irrespective of respiratory symptoms. Percutaneous transcatheter embolization of the pulmonary artery/ies feeding the PAVMs is the treatment of choice, irrespective of respiratory symptoms. Additional recommendations include judicious dental hygiene; antibiotic prophylaxis prior to dental and surgical procedures; optimization of iron status; and pregnancy-specific recommendations. In highly selected cases, parenchymal sparing surgery may be considered.
Prognosis
With appropriate management and interventions, prognosis is generally very good with many patients reaching their 9th and 10th decades of life. During pregnancy, however, there is a 1% maternal death rate. Difficult management issues arise in patients who continue to experience neurological complications, or when PAVMs acquire a systemic arterial supply, increasing the risk of hemoptysis.

                            Last update:
                            May 2021

                            - Expert reviewer(s):
                            Dr Ali ALSAFI  - Pr Claire SHOVLIN


Pulmonary artery coming from patent ductus arteriosus is a rare, congenital, non-syndromic heart malformation characterized by the presence of a single (or a double) patent ductus arteriosus which associates one or both pulmonary arteries originating from it. Manifestations are variable, frequently presenting with neonatal cyanosis, severe progressive hypoxia, persistent pulmonary hypertension, increased susceptibility to pulmonary infections, and thoracic asymmetry resulting from asymmetric lung volumes.


A rare, congenital anomaly of the great arteries characterized by various clinical signs and symptoms, including shortness of breath, recurrent lower respiratory tract infections, lung hypoplasia, pulmonary hypertension, and haemoptysis. The anomaly can be isolated or associated with congenital heart disease, such as tetralogy of Fallot, atrial septal defect, coarctation of the aorta, right aortic arch, truncus arteriosus, patent ductus arteriosus and pulmonary atresia.


Pulmonary atresia with ventricular septal defect (PA-VSD) is a rare cyanotic congenital heart malformation characterized by underdevelopment of the right ventricular outflow tract and atresia of the pulmonary valve, ventricular septal defect (VSD) and pulmonary collateral vessels. Clinical features depend on the anatomic variability of the lesion and patients may be minimally symptomatic, severely cyanotic or may develop congestive heart failure. PA-VSD may represent a severe form of Tetralogy of Fallot (see this term).


Pulmonary atresia-intact ventricular septum syndrome

A rare cardiac malformation characterized by congenital either membranous or long segment muscular atresia of the right ventricular outflow tract in the absence of communication at the level of ventricles. The spectrum ranges from simple membranous pulmonary atresia with normal-appearing right ventricle (RV) to hypoplastic RV with abnormal connections between the RV and coronary arteries. Major presenting symptoms are cyanosis and desaturation.


A biphasic primary lung neoplasm, belonging to the group of sarcomatoid lung carcinomas (SLCs). The tumor contains both an epithelial well-differentiated component, showing tubular architecture resembling the normal fetal lung, and a mesenchymal undifferentiated stroma with a so-called ''blastema-like'' configuration that resembles an embryonic lung.

Summary:
Epidemiology
PB is a rare tumor, accounting for less than 0.25% of all primary malignant lung tumors, with only around 350 cases having been reported in the literature so far. PB occurs almost exclusively in adults and has a peak incidence in the fourth decade of life (earlier than other forms of SLC), with a marked female predominance (70% of cases) and frequent association with tobacco smoking.
Clinical description
Symptomatic patients present with nonspecific respiratory manifestations (cough, hemoptysis and chest pain). Other features may include dyspnea, fever, weight loss, and recurrent pneumonia. However, up to 40% of patients may be identified presymptomatically after a chest radiograph for another indication. PBs are usually well-demarcated solitary tumors (average size 10 cm) with cystic and necrotic features and are often located in the peripheral lung. Common sites of metastases include the brain, lymph nodes and liver.
Etiology
Little is known about the pathogenesis and histogenesis of PB. Molecular studies indicate that mesenchymal and epithelial components are derived from a single precursor cell. Mutations in several genes (including TP53, CTNNB1 and EGFR) may be identified in some PB tumors.
Diagnostic methods
Clinical laboratory and imaging studies are nonspecific and definitive diagnosis of PB requires identification of both the epithelial and mesenchymal components of the tumor, through histological studies on a resected specimen. Bronchoscopy and fine needle biopsy have been useful for diagnosis in some cases.
Differential diagnosis
The differential diagnosis should include other forms of SLC (pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma and adenocarcinoma (particularly fetal adenocarcinoma); see these terms). PB also has to be distinguished from the childhood tumor pleuropulmonary blastoma (see this term).
Management and treatment
In many cases, the tumor is initially thought to be a bronchogenic carcinoma. Complete surgical resection with mediastinal lymph node dissection ensures both diagnosis and therapy. Adjuvant treatment, mostly consisting of radiotherapy, has been reported in a few cases, following incomplete resection, or in patients with N2 mediastinal involvement. For unresectable tumors, chemotherapy may be based on protocols used for sarcomas, including doxorubicin and ifosfamide.
Prognosis
PB is an aggressive tumor and the prognosis has historically been reported as being poor: 5-year survival rates for patients with stage I disease were around 30%. In most recent reports, survival -adjusted by stage- is better than that for non-small cell lung cancer, especially in completely resected cases. Recurrences (occurring in 30-40% of patients) and metastases are common.

                            Last update:
                            November 2012

                            - Expert reviewer(s):
                            Pr Nicolas GIRARD


Pulmonary fibrosis-hepatic hyperplasia-bone marrow hypoplasia syndrome

A rare disease, manifesting with idiopathic pulmonary fibrosis, hepatic nodular regenerative hyperplasia leading to portal hypertension and thrombocytopenia due to bone marrow hypoplasia. The condition was associated with 100% mortality.


Pulmonary interstitial glycogenosis (PIG) is a rare non-lethal pediatric form of interstitial lung disease (ILD, see this term).

Summary:
Epidemiology
Very few cases have been described to date but there appears to be male predominance.
Clinical description
Neonates present with respiratory distress syndrome shortly after birth. The characteristic histological feature of PIG is the accumulation of monoparticulate glycogen in interstitial cells on lung biopsy.
Etiology
The disease is thought to be the result of a maturation defect of interstitial cells leading to glycogen accumulation within the cytoplasm.
Prognosis
Prognosis is dependent on the type of lung growth abnormalities associated with the infiltrative disease.

                            Last update:
                            January 2011

                            - Expert reviewer(s):
                            Pr Annick CLEMENT


Pulmonary nodular lymphoid hyperplasia (PNHL) is a reactive lymphoid proliferation manifesting as solitary or multiple nodules in the lung.


Pulmonary non-tuberculous mycobacterial infection

A rare bacterial infectious disease caused by non-tuberculous mycobacteria (including Mycobacterium avium complex, Mycobacterium kansasii, or Mycobacterium xenopi, among others), characterized by chronic pulmonary disease with symptoms like chronic cough (with or without sputum production), chest pain, and weight loss. Predisposing factors are preexisting lung conditions, neoplasms, immunosuppression, or thoracic skeletal abnormalities.


Pulmonary valve agenesis-intact ventricular septum-persistent ductus arteriosus syndrome

A rare, life-threatening, congenital, non-syndromic, conotruncal heart malformation disease characterized by absent or severely undeveloped pulmonary valve leaflets (with a restrictive ring of thickened tissue at the place of the pulmonary valve annulus), associated with an intact ventricular septum and a patent ductus arteriosus, manifesting with marked respiratory insufficiency. Additional features include dilated main pulmonary artery (with or without dilatation of pulmonary artery branches), to-and-fro flow at site of the dysplastic pulmonary valve, and systolic pressure gradient across narrowed pulmonary valve. Tricuspid atresia and variable extra-cardiac anomalies (e.g. diaphragmatic hernia or cleft lip/palate), may be present.


Pulmonary valve agenesis-tetralogy of Fallot-absence of ductus arteriosus syndrome is a rare congenital heart malformation characterized by a tetralogy of Fallot (pulmonary stenosis, overriding aorta, ventricular septal defect and right ventricular hypertrophy), complete absence or rudimentary pulmonary valve that is both stenotic and regurgitant and an absence of the ductus arteriosus. It presents prenatally with cardiomegaly, polyhydramnios, fetal heart failure, hydrops fetalis and fetal demise or postnatally with cyanosis and respiratory failure due to bronchomalacia secondary to bronchial compression from dilated pulmonary arteries. It is frequently associated with 22q11 deletion.


Pulmonary valve agenesis is a rare congenital heart malformation characterized by a total or partial absence of the pulmonary valve leaflets associated with stenosis of the pulmonary artery orifice and aneurysmal dilatation of the pulmonary arteries. It usually occurs in association with additional cardiovascular malformations such as teralogy of fallot or ventricular septal defect, or can occur as part of a syndrome (e.g. 22q11.2 deletion syndrome). Clinical features depend on the presence of associated cardiac malformations and include pulmonary insufficiency, bronchial obstruction (secondary to compression by aneurysmally dilated pulmonary arteries), pulmonary stenosis, cyanosis, and cardiac failure.


Pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis

A disorder that constitutes a rare subgroup of rare pulmonary hypertension characterized by obliterative fibrosis of the small pulmonary veins and venules and/or capillary infiltration of the pulmonary interstitium leading to increased pulmonary vascular resistance and right ventricular dysfunction.

Summary:
Epidemiology
Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis (PVOD and/or PCH) annual incidence has been estimated at between 1 in 5-10 millions but this likely to be an underestimate. PVOD and/or PCH is believed to account for up to 5 to 10% of patients initially diagnosed with idiopathic pulmonary arterial hypertension (PAH).
Clinical description
Onset may occur at any age and there is no overall sex predilection in the genetic form of the disease but a male predominance in sporadic PVOD cases. Patients present with non-specific respiratory symptoms, most commonly progressive exertional dyspnea and fatigue. PVOD and/or PCH and idiopathic PAH share the same clinical presentation and clinical examination is unhelpful to distinguish them. As the disease progresses, patients may show signs of right ventricular failure and the use of PAH drugs is associated with a potential risk of life-threatening pulmonary edema.
Etiology
Several factors have been suspected to influence disease development including various chemotherapy regimens as well as bone marrow and hematopoietic blood stem cell transplantation. Occupational exposure is a frequently encountered risk factor for PVOD (mainly organic solvents, as trichloroethylene (a chlorinated solvent)). Pulmonary venous involvement may also occur in patients with connective tissue diseases (systemic sclerosis), sarcoidosis, and adult pulmonary Langerhans cell histiocytosis. Familial cases of PVOD and/or PCH have also been reported and around 10 to 20% of PVOD and/or PCH patients have a heritable form of the disease due to bi-allelic mutations in the EIF2AK4 gene (15q13.3).
Diagnostic methods
Right heart catheterisation confirms pulmonary hypertension and shows pattern of precapillary PH with normal pulmonary artery wedge pressure. Although histology is considered the gold standard for definite diagnosis, lung biopsy carries a high risk of morbidity and mortality. Hence the diagnosis is usually based on the combination of clinical findings, pulmonary function tests and blood gas measurements (resting hypoxemia and low carbon monoxide diffusion capacity), bronchoalveolar lavage (occult alveolar hemorrhage) and high resolution CT scans (septal thickening, ground-glass opacities and lymphadenopathy). Mutations in EIF2AK4 gene confirm the diagnosis.
Differential diagnosis
The main differential diagnoses are PAH (idiopathic or secondary to chronic lung diseases), and chronic thromboembolic pulmonary hypertension.
Antenatal diagnosis
Prenatal diagnosis can be considered in families with identified bi-allelic mutations in EIF2AK4 gene.
Genetic counseling
Genetic counseling and screening for the EIF2AK4 gene are offered to PVOD/PCH patients. Heritable PVOD and/or PCH is an autosomal recessive disease.
Management and treatment
The usual recommended regimens involve oxygen therapy, anticoagulants and antithrombotic agents, immunosuppressants, pneumococcal and influenza vaccinations, and limiting physical activity. The use of PAH-specific therapies (endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, prostacyclins) remains controversial due to the high risk of pulmonary edema. Importantly, PVOD patients who respond acutely to inhaled NO may develop severe pulmonary oedema rapidly after initiation of calcium channel blocker therapy. Given the above considerations, acute vasoreactivity testing is contraindicated in PVOD. At present, it is recommended that PVOD and/or PCH patients be treated in highly specialized centers for PAH and that they be fully informed of the risks if PAH-specific therapies are initiated. Because of poor prognosis, lung transplantation should be discussed early in the course of the disease.
Prognosis
The prognosis for PVOD and/or PCH patients remains poor in the absence of lung transplantation.

                            Last update:
                            June 2019

                            - Expert reviewer(s):
                            Dr Barbara GIRERD  - Pr David MONTANI


PUM1-associated developmental disability-ataxia-seizure syndrome

A rare genetic syndromic intellectual disability characterized by developmental delay, intellectual disability, ataxia, and, more variably, seizures and short stature. Behavioral abnormalities may also be observed, as well as variable facial and other dysmorphic features (such as broad nasal bridge, hypertelorism, almond-shaped eyes, high-arched palate, and anomalies of the fingers and toes). Brain imaging may reveal dilated ventricles, small corpus callosum, or posterior fossa abnormalities.


Punctate acrokeratoderma freckle-like pigmentation

A rare epidermal disease characterized by the association of punctate acrokeratoderma with a pigmentary disorder. Patients present skin-colored keratotic papules on the hands and feet and pronounced hyperkeratosis of the palms and soles. Freckle-like pigmentation on the dorsal surfaces of the hands and feet is also reported. Histological examination reveals no fragmentation of dermal elastic tissue. There have been no further descriptions in the literature since 1993.


A rare ophthalmic disorder characterized by typically bilateral, asymmetric, yellowish, punctate chorioretinal lesions of the posterior pole forming a linear branching pattern and progressing to atrophic scars. Subretinal neovascular membranes occur in many cases. Vitritis is always absent. Patients may present with blurred vision, scotoma, floaters, photopsia, and metamorphopsia. Choroidal neovascular membrane formation and subretinal fibrosis are the major causes of visual loss. The condition predominantly occurs in young myopic females.


Punctate palmoplantar keratoderma type 1

A rare hereditary skin disease characterized by irregularly distributed epidermal papular/punctate hyperkeratosis of the palms and soles with wide variation among patients.

Summary:
Epidemiology
The prevalence of PPKP1 has been estimated at 1.17/100,000 in Croatia and 3.3/100,000 in Slovenia. PPKP1 has been reported in over 400 patients worldwide to date.
Clinical description
Typical clinical characteristics are multiple hyperkeratotic papules and central indentations that are irregularly distributed on the palms and soles. The lesions usually start to develop in early adolescence but can also present earlier or later in life. Sometimes additional confluent thickening of the soles can be observed. Depending on the clinical presentation, PPKP1 can be associated with pain at pressure points, especially on the soles. The lesions may coalesce over pressure points. There can be considerable variation between affected family members.
Etiology
Mutations in the AAGAB gene (15q22.33-q23) have been identified as one of the causes of PPKP1. This gene encodes for the alpha and gamma-adaptin-binding protein p34 which is involved in the clathrin-mediated pathway and when disrupted causes an increase in the half-life of several receptor tyrosine kinases in basal keratinocytes, leading to hyperproliferation and hyperkeratosis. COL14A1 (8q24.12) is another gene that has been suggested to be implicated in the pathogenesis of PPKP1, but this association needs further confirmation, as it has only been reported once in a few cases from the same Chinese family.
Diagnostic methods
Mutational analysis of the AAGAB gene and the COL14A1 gene confirms the clinical diagnosis. Although not specific for PPKP1, histological examination of papules reveals hypergranulosis and hyperkeratosis with a well-defined central epidermal depression.
Differential diagnosis
Differential diagnosis includes verrucae vulgaris and any other form of palmoplantar keratoderma, primarily the focal types, such as porokeratosis punctata palmaris et plantaris (PPKP2) and focal acral hyperkeratosis (or PPKP3 without elastoidosis).
Genetic counseling
PPKP1 is inherited in an autosomal-dominant manner. Genetic counseling is possible.
Management and treatment
Mechanical removal of the hyperkeratosis is the most effective symptomatic treatment. Keratolytic creams can support the treatment. In some patients with a severe phenotype, oral retinoids have been shown to reduce symptoms.
Prognosis
Although the clinical appearance of lesions can worsen over time, the general prognosis is good. Depending on the clinical severity and pain sensitivity of patients, quality of life can be affected.

                            Last update:
                            December 2022

                            - Expert reviewer(s):
                            Dr M.C. [Marieke] BOLLING | ERN-Skin* - Dr P.C. [Peter] VAN DEN AKKER | ERN-Skin*

                                * European Reference Network


Punctate palmoplantar keratoderma type 2 is a type of isolated, punctate, hereditary palmoplantar keratoderma characterized by multiple, asymptomatic, 1 to 2 mm-long, firm, hyperkeratotic projections ('spiny keratosis') on the palms, soles and digits (typically confined to their volar and/or lateral aspects). Histopathologically, compact columnar parakeratosis over hypo- or agranular epidermis is observed.


PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome

A rare neurologic disease characterized by neonatal hypotonia, global developmental delay, feeding difficulties, and often seizures or seizure-like episodes. Other frequently observed signs and symptoms include variable dysmorphic features, myopathic facies, respiratory problems, and visual abnormalities, such as strabismus or esotropia. Brain imaging may show delayed myelination and other white matter abnormalities.


Pure autonomic failure (PAF) is a neurodegenerative disease that affects the sympathetic branch of the autonomous nervous system and that manifests with orthostatic hypotension.

Summary:
Epidemiology
The exact prevalence is unknown.
Clinical description
The disease affects adults. PAF manifests initially with orthostatic hypotension, erectile dysfunction and urinary disorders. Other symptoms, including sweat disorders and Horner syndrome (see this term), indicate a deficit of the sympathetic nervous system. There are no associated neurological signs.
Etiology
PAF is sporadic and its etiology is unknown. It is a synucleinopathy with Lewy bodies and neuronal rarefaction in the intermediate-lateral tract of the medulla and in the sympathetic ganglia.
Diagnostic methods
Diagnosis of PAF is indicated in cases with clinical signs compatible with chronic sympathetic deficiency, without associated neurological signs. The diagnosis is confirmed with evidence of neurogenic orthostatic hypotension (falling >= 20/10 mm Hg of arterial pressure when standing without reactive tachycardia). Ambulatory blood pressure monitoring can reveal a disappearance or reversal of the day/night rhythm. Specific tests for PAF (Ewing test, pupillary or sudoral function, analysis of heart rate and blood pressure variability, sympathetic microneurography and MIBG scintigraphy) are carried out by some laboratories. Plasma levels of noradrenaline are low at rest and do not increase on standing. The EMG and cerebral MRI/CT are normal. Examinations to identify an immunologic, deficiency, metabolic or toxic cause are negative.
Differential diagnosis
Differential diagnoses include iatrogenic (including cardiovascular, urologic and psychotropic drugs) or curable (dehydration, venous insufficiency, anemia) causes of orthostatic hypotension, dopamine beta-hydroxylase deficiency (see this term), which is ruled out by the presence of plasma noradrenaline in patients affected by orthostatic hypotension that is considered idiopathic, primary or secondary peripheral polyneuropathy (including diabetes, amyloidosis, renal dysfunction, Guillain-Barré syndrome (see these terms), those due to deficiency or paraneoplasic syndrome) or neurodegenerative disease dysautonomias (multiple system atrophy, Parkinson's disease; see these terms), which are ruled out by normal neurological and paraclinical examinations in patients affected by PAF. The progression of PAF is slow, which distinguishes it from acute or sub-acute pandysautonomias.
Management and treatment
Management includes non medicinal measures (tight support stockings, abdominal binders, frequent meals, standing up slowly, increased liquid and salt intake, and avoiding prolonged orthostatism, alcohol, and warm environments). Standard medical treatment is with midodrine (an alpha-adrenergic agonist) and fludrocortisone (a hypokalemic mineralocorticoid). The efficacy of indirect sympathomimetics (heptaminol) and ergot derivatives (dihydroergotamine) have not been proven. Other drugs are subject to ongoing trials (pyridostigmine, droxidopa) or are designed for particular situations such as anemia (erythropoietin) or postprandial hypotension (octreotide). Decubitus arterial hypertension can be prevented by following simple rules (avoiding taking a vasoconstrictor before sleeping, resting in a semi-sitting position over night, taking an antihypertensive drug in extreme cases).
Prognosis
Progression of PAF lasts over 20 years. The appearance of neurological signs during the course of autonomic deficiency progression allows orthostatic hypotension to be a posteriori linked to multiple system atrophy or Parkinson's disease.

                            Last update:
                            January 2009

                            - Expert reviewer(s):
                            Pr Jean-Luc ELGHOZI  - Pr Jean-Michel SENARD


Pure hair and nail ectodermal dysplasia is characterised by the association of onychodystrophy and severe hypotrichosis, which is mainly limited to the scalp but may also affect the eyelashes and eyebrows. Less than 20 cases have been reported so far. The mode of transmission is autosomal dominant.


Pure mitochondrial myopathy is a rare mitochondrial disease characterized by exclusive skeletal muscle involvement, without clinical evidence of other organ involvement, manifesting with progressive limb weakness, proximal limb muscle atrophy, and eye muscle anomalies (e.g. ocular motility restriction, ptosis). Patients may present with lactic acidosis, diffuse myalgia and overall fatigability (particularly during/after physical activities), dysphagia, and diminished deep tendon reflexes.


Purine nucleoside phosphorylase deficiency

A rare immune disease characterized by progressive immunodeficiency leading to recurrent and opportunistic infections, autoimmunity and malignancy as well as neurologic manifestations.

Summary:
Epidemiology
To date, more than 70 patients have been reported with Purine nucleoside phosphorylase (PNP) deficiency in the world literature. PNP deficiency accounts for less than 4% of patients with severe combined immunodeficiency (SCID).
Clinical description
PNP deficiency typically manifests in the 1st years of life, with recurrent, opportunistic infections caused by bacterial, viral (such as varicella zoster virus), and fungal (such as Pneumocystis carinii) pathogens. The susceptibility to infections is variable ranging from classical SCID in infancy to infrequent infections during childhood and even the 2nd decade of life. Failure to thrive has also been reported. Up to 2/3 of patients have neurologic involvement including motor system dysfunction, hyper/hypotonia, spastic paresis, ataxia, hyperactivity, and behavioral problems. Cerebrovascular accidents and sensorineural deafness are less commonly observed. The neurologic involvement often precedes immune abnormalities. Autoimmune manifestations are reported in 1/3 of cases and include autoimmune hemolytic anemia, immune thrombocytopenic purpura and systemic lupus erythematosus.
Etiology
PNP deficiency is caused by loss-of-function mutations in the PNP gene (14q11.2) which encodes a key enzyme (PNP) in the purine salvage pathway. PNP is vital for removal of metabolites of DNA breakdown and promotes recycling of purine bases. Lack of PNP allows intracellular accumulation of such metabolites which are particularly toxic to immature lymphoid cells, leading to lymphopenia and impaired cell-mediated immunity. Intracellular accumulation of purine bases has also been suggested to cause neuronal cell apoptosis.
Diagnostic methods
Diagnosis is based on the clinical examination and on laboratory findings showing leukopenia, severe lymphopenia with low CD3, CD4, and CD8 counts and variable B cell function and immunoglobulin levels. Neutropenia has also been reported. Hallmark diagnostic markers of PNP deficiency include hypouricemia, complete or near complete absence of PNP activity in red blood cell lysate and increased urine or blood levels of inosine, guanosine and their deoxy forms. Diagnosis is confirmed by genetic screening of PNP.
Differential diagnosis
Differential diagnosis includes aplastic anemias, SCID, severe combined immunodeficiency due to adenosine deaminase deficiency, ataxia-telangiectasia, and viral meningoencephalitis.
Antenatal diagnosis
Measurement of T cell receptor excision circles during newborn screening for SCID can detect some patients suffering from PNP deficiency, although removal of metabolites by maternal PNP may delay the deleterious effects on PNP-deficient lymphocytes. Few newborn screening programs also measure purine metabolites in dried blood spots.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be proposed to affected families informing them of a 25% risk of transmitting the disease where both parents are unaffected carriers.
Management and treatment
Specific enzyme replacement is not available for PNP deficiency, although frequent red blood cells transfusions rich in PNP have been shown to provide temporary benefit. Hematopoietic stem cell transplantation (HSCT) is the only treatment option for the severe immune deficiency. Transplanted cells deliver the missing enzyme, thereby improving purine homeostasis. Supportive treatment, including intravenous immunoglobulin therapy, prophylaxis for Pneumocystis carinii, and physical, occupational, and speech therapy, reduces the risk of infection and may encourage optimal neurologic development for patients.
Prognosis
If left untreated, prognosis is poor and patients usually die in the first decade of life, often succumbing to infections. Few patients have reached the 2nd and even 3rd decade of life. After HSCT from family or unrelated donors, patients may achieve successful immune reconstitution and are free from infections. Nevertheless, even with HSCT, improvement of neurological deficits is not definite.

                            Last update:
                            January 2020

                            - Expert reviewer(s):
                            Pr Eyal GRUNEBAUM


A rare subtype of pyoderma gangrenosum characterized by multiple painful, sterile pustules with a surrounding erythematous halo, predominantly occurring on the trunk and extensor surfaces of the limbs, and potentially persisting for months. Histopathology shows a dermal neutrophilic infiltrate and subcorneal neutrophilic micropustules. The condition is commonly associated with inflammatory bowel disease.


A rare skin disease characterized by chronic eruption of sterile pustules on an erythematous and desquamative background. The lesions are usually painful and affect the palms and soles, sometimes also the lateral aspects of hands and feet. Nail lesions (such as nail pitting, onycholysis, subungual pustules, and nail dystrophy) are also observed. The condition takes a chronic and relapsing course. Typical associations are psoriatic arthritis, thyroid gland dysfunction, and smoking.


Pycnodysostosis is a genetic lysosomal disease characterized by osteosclerosis of the skeleton, short stature and brittle bones.

Summary:
Epidemiology
It is very rare, the exact prevalence is unknown but it is less than 1/100,000.
Clinical description
The disease is discovered at variable ages, ranging from 9 months to 50 years. The condition is most often diagnosed in childhood, but sometimes the condition is not detected until adulthood, usually as a result of a fracture or a routine examination. The most frequent clinical or radiological manifestations of the disease are osteosclerosis, short stature or dwarfism, acroosteolysis of the distal phalanges, fragile bones associated with spontaneous fractures and dysplasia of the clavicles. Patients present with characteristic cranial malformations: a voluminous skull with wormian bones present and persistence of the anterior fontanelle, and a small mandible. Dental abnormalities such as decayed, poorly located or abnormally shaped (pointed or conical) teeth and delayed tooth eruption may be observed. Nails are sometimes irregular and cracked. Very rarely, the disease is associated with anemia, hepatosplenomegaly, hematologic alterations, respiratory distress and sleep apnea. The short stature is variable but moderate (1.35m to 1.50m).
Etiology
Pycnodysostosis is due to mutations in the gene encoding cathepsin K (localized to 1q21), a lysosomal enzyme secreted by osteoclasts, which allows the division of proteins of the bone matrix (collagen type I, osteonectin or osteopontin).
Diagnostic methods
Diagnosis is clinical and should be confirmed by radiographic examination of the entire skeleton and skull.
Differential diagnosis
Differential diagnoses include osteoporosis, osteopetrosis, cleidocranial dysplasia and idiopathic acroosteolysis (see these terms).
Genetic counseling
Inheritance is autosomal recessive.
Management and treatment
Management is symptomatic and multidisciplinary. It includes orthopedic monitoring, treatment of fractures, of which consolidation is sometimes slow, and static vertebral surveillance to detect frequent spondylolisthesis.
Prognosis
The prognosis is favorable; the disease is not progressive.

                            Last update:
                            December 2008

                            - Expert reviewer(s):
                            Dr Martine LE MERRER


PYCR2-related microcephaly-progressive leukoencephalopathy is a rare, genetic, syndromic intellectual disability disorder characterized by progressive postnatal microcephaly, cerebral hypomyelination and severe psychomotor developmental delayed with absent speech, as well as axial hypotonia, appendicular hypertonia with hyperextensibility of the wrists and ankles, hyperreflexia, severe muscle wasting and failure to thrive. Associated craniofacial dysmorphism includes triangular facies with bitemporal narrowing, down- or upslanting palpebral fissures, malar hypoplasia, large malformed ears with overfolded helices, upturned bulbous nose, long smooth philtrum and thin vermilion borders.