A rare motor neuron disease characterized by isolated lower motor neuron features, including progressive flaccid weakness, muscle atrophy, fasciculations, and reduced or absent tendon reflexes. Onset is in late adulthood, with men being affected more often than women. Upper motor neuron signs may develop later in some cases. Occurrence of respiratory insufficiency determines the prognosis. Neuropathological analysis shows intraneuronal Bunina bodies and ubiquitin-positive inclusions.


A rare progressive myoclonic epilepsy (PME) disorder characterized by action- and stimulus-sensitive myoclonus, and tonic-clonic seizures with ataxia, but with only a mild cognitive decline over time.

Summary:
Epidemiology
Progressive myoclonic epilepsy type 1 (EPM1) has the highest incidence among the progressive myoclonus epilepsies (PMEs), with prevalence reportedly higher in certain geographic areas (Finland, Italy, Tunisia, Algeria, Morocco, and Reunion Island). The prevalence in Finland is estimated at 1/50,000. Whilst the disorder is recognized worldwide, it appears to be underdiagnosed. Both genders are equally affected.
Clinical description
The first symptoms are stimulus-sensitive myoclonus, and tonic-clonic epileptic seizures appearing between 6-15 years of age. Prompt treatment of myoclonic seizures may prevent generalized tonic-clonic seizures (GTCS). Gradually, patients develop additional neurological symptoms including ataxia, dysarthria, intentional tremor, and decreased coordination. Depression is common. Cognitive performance is mostly within the normal range. However, patients may exhibit poor performance in tests dependent on motor functions. The tonic-clonic seizures are well controlled by anti-seizure medications, but the myoclonic jerks are progressive, action activated, treatment resistant and can be severely disabling.
Etiology
The majority of cases are due to a homozygous expansion of an unstable dodecamer repeat (typically 30 to 125 repeats) in the promoter region of CSTB (21q22.3), resulting in the classic phenotype. In a minority of patients, the dodecamer repeat expansion occurs as a compound heterozygous form with a mutation in the coding region of CSTB. The clinical phenotype is the result of a partial loss of function in CSTB.
Diagnostic methods
Diagnosis is suspected on electroencephalogram demonstrating photosensitivity at onset and action myoclonus detected through polygraphy. Diagnosis is confirmed on targeted molecular genetic testing for the dodecamer expansion of CSTB. When heterozygosity for the dodecamer expansion is found in an affected individual, it is appropriate to pursue molecular genetic testing for other CSTB pathogenic variants either by targeted analysis for a broader panel of pathogenic variants or by sequence analysis.
Differential diagnosis
The initial symptoms may be so mild that a diagnosis of juvenile myoclonic epilepsy is made, and the signs of EPM1 may become evident only with the progression of the disease. Differential diagnosis includes other PMEs with preserved cognition, for example PRICKLE1 and SCARB2-related PME, that have been identified in a few families with a similar clinical phenotype.
Genetic counseling
The pattern of inheritance is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy. Pre-symptomatic testing is not recommended.
Management and treatment
Anti-seizure and anti-myoclonic interventions include valproate, clonazepam, piracetam (the latter only for myoclonus), levetiracetam, brivaracetam, perampanel, topiramate and zonisamide. Phenytoin and fosphenytoin should be avoided as these trigger detrimental neurological side effects. In addition, other sodium channel blockers such as carbamazepine should be excluded as they may negatively contribute to myoclonic seizures.
Prognosis
The disease course is progressive, showing remarkable individual variation, with myoclonus usually presenting as the most disabling symptom. One third of patients become severely incapacitated, wheelchair-bound or even unable to eat on their own. On the other hand, some patients are able to live fully autonomous lives. With modern medical care, the survival rates are comparable to controls up to 40 years of age, but are poorer in the long-term. Death occurs mainly due to respiratory infections. Compound heterozygous mutations are associated with a more severe phenotype than homozygous dodecamer repeat expansions.

                            Last update:
                            September 2021

                            - Expert reviewer(s):
                            Dr Tiziana GRANATA | EpiCARE* - Pr Reetta KÄLVIÄINEN | EpiCARE* - Pr Rima NABBOUT | EpiCARE*

                                * European Reference Network


A rare, genetic, neuronal ceroid lipofuscinosis disorder characterized by infantile- to early childhood-onset of progressive myoclonic seizures (occasionally accompanied by generalized tonic-clonic seizures) and severe, progressive neurological regression, leading to psychomotor and cognitive decline, cerebellar ataxia, dementia and, frequently, early death. Vision loss may be associated. EEG typically reveals epileptiform activity with predominance in the posterior region and photosensitivity.


A rare, genetic neurological disorder characterized by early-onset progressive ataxia associated with myoclonic seizures, generalized tonic-clonic seizures (which are often sleep-related), and normal to mild intellectual disability. Dysarthria, upward gaze palsy, sensory neuropathy, developmental delay and autistic disorder have also been associated.


A rare, genetic, neurological disorder characterized by early-onset, progressive ataxia associated with myoclonic seizures (frequently associated with other seizure types such as generalized tonic-clonic, absence and drop attacks), scoliosis of variable severity, areflexia, elevated creatine kinase serum levels, and relative preservation of cognitive function until late in the disease course.


A rare, genetic, neurological disorder characterized by childhood to adolescent onset of progressive myoclonus (which becomes very severe and results in major motor impediment) associated with infrequent tonic-clonic seizures, and, occasionally, ataxia. Learning disability prior to seizure onset and mild cognitive decline may be associated.


A rare, genetic, neurological disorder characterized by childhood to adolescent-onset of action myoclonus, generalized tonic-clonic seizures, and slowly progressive, moderate to severe cognitive impairment that may lead to dementia. EEG reveals progressive slowing of background activity and epileptic abnormalities and brain MRI shows cerebellar and brainstem atrophy.


A rare, genetic, neurological disorder characterized by childhood-onset severe myoclonic and tonic-clonic seizures and early-onset ataxia leading to severe gait disturbances associated with normal to slightly diminished cognition. Scoliosis, diffuse muscle atrophy and subcutaneous fat loss, as well as developmental delay, may be associated. Brain MRI may reveal complete agenesis of the corpus callosum, ventriculomegaly, interhemispheric cysts, and simplified gyration (frontally).


Progressive myoclonic epilepsy with dystonia is a rare, genetic epilepsy syndrome characterized by neonatal or early infantile onset of severe, progressive, typically frequent and prolonged myoclonic seizures that are refractory to treatment, associated with localized and/or generalized paroxysmal dystonia (which later becomes persistent). Other features include severe hypotonia, hemiplegia, psychomotor regression (or lack of psychomotor development) and progressive cerebral and cerebellar atrophy, with affected individuals becoming progressively non-reactive to environmental stimuli.


Progressive nodular histiocytosis is a rare, normolipemic, non-Langerhans cell histiocytosis characterized by progressive growth of multiple to disseminated, asymptomatic skin lesions that range in appearance from yellow plaques to coalescence-prone red-brown papules, nodules and pedunculated tumors up to 5 cm in size, located typically on the face, trunk and extremities (and rarely on conjuctiva and mucous membranes). Characteristic microscopic findings include a storiform spindle cell infiltrate in the deep dermis with xanthomatized macrophages and some Touton cells in the upper dermis. It is usually not associated with systemic disease.


Progressive non-fluent aphasia (PNFA) is a form of frontotemporal dementia (FTD; see this term), characterized by agrammatism, laborious speech, alexia, and agraphia, frequently accompanied by apraxia of speech (AOS). Language comprehension is relatively preserved.


Progressive non-infectious anterior vertebral fusion (PAVF) is an early childhood spinal disorder characterized by the gradual onset of thoracic and/or lumbar spine ankylosis often in conjunction with kyphosis with distinctive radiological features.

Summary:
Epidemiology
Prevalence is unknown, but PAVF (mostly isolated cases) has been reported in approximately 80-100 cases. Girls (60%) seem slightly more affected than boys.
Clinical description
Onset is in early childhood and often discovered in young children while exploring a spinal deformity. This is the start of the progressive anterior vertebral ankylosis in the thoracic and/or lumbar areas observed during the disease course (months or years after onset) often clinically manifested by thoracolumbar kyphosis. The anterior vertebral ankylosis extends with time to the posterior part. PAVF usually presents with mild pain, stiffness of neck and/or back with developing thoracolumbar kyphosis. Often however PAVF is asymptomatic. Neurological abnormalities are exceptional. PAVF can occur isolated or less frequently, as part of a syndrome. Syndrome associated manifestations include facial dysmorphism, absence of one cervical vertebrae, radio-ulnar synostosis, exostosis, generalized overgrowth, split cord malformation and/or situs inversus totalis (see this term).
Etiology
Etiology is unknown.
Diagnostic methods
PAVF may be discovered fortuitously. MRI and X-ray confirm PAVF when distinctive radiological features of PAVF are present. MRI examination is favored, since the precise degree of the intervertebral ankylosis of the disc condition can be evaluated. The typical anterior vertebral endplate narrowing associated with irregularities and osteosclerosis of the vertebral corners may be visible early on.
Differential diagnosis
Synspondylism, spondylothoracic dysplasia and familial Scheuermann disease should be considered in the differential diagnosis. Other differential diagnoses in case of infection include infectious spondylodiscitis and congenital vertebral block.
Management and treatment
Conservative treatment includes a routine annual or semestrial (during pubertal growth spurt) clinical and medical imaging check-up and a multi-disciplinary approach. It seems very important to prevent sagittal imbalance at a very young age by a regular clinical monitoring and early bracing as soon as hypolordosis appears. At adult age, bracing has a very limited effect. Surgical treatment has to be discussed on an individual basis. In some patients presenting with lumbar hypolordosis, a lordotic restoration using Boston-type braces with progressive correction, assists in addressing chronic pain in addition to class 1 WHO painkillers. PVO (posterior vertebral osteotomies) can be considered in patients when restoring a satisfying sagittal balance is impossible or very challenging. In patients with moderate deformities but with severe chronical pain, posterior intervertebral fusion is useful. Long term follow-up is recommended.
Prognosis
Prognosis is fairly good as it does not involve vital issues. However, almost all patients complain with low back pain and junctional thoraco-lumbar pain.

                            Last update:
                            September 2013

                            - Expert reviewer(s):
                            Pr Nathalie BOUTRY  - Dr Eric NECTOUX


Progressive osseous heteroplasia (POH) is a rare genetic bone disorder characterized clinically by progressive extraskeletal bone formation presenting in early life with cutaneous ossification, that progressively involves subcutaneous and then subsequently deep connective tissues, including muscle and fascia. POH overlaps with a number of related genetic disorders including Albright hereditary osteodystrophy, pseudohypoparathyroidism (see these terms), and primary osteoma cutis, that share the common features of superficial heterotopic ossification in association with inactivating mutations of GNAS gene (20q13.2-q13.3), coding for guanine nucleotide-binding proteins. POH can, however, be distinguished clinically by the deep and progressive nature of the heterotopic bone formation.


Progressive polyneuropathy with bilateral striatal necrosis is a rare, genetic disorder of thiamine metabolism and transport characterized by the childhood-onset of recurrent episodes of flaccid paralysis and encephalopathy, associated with bilateral striatal necrosis and chronic progressive axonal polyneuropathy with proximal and distal muscle weakness, areflexia, contractures and foot deformities.


Progressive pseudorheumatoid arthropathy of childhood

A rare spondyloepiphyseal dysplasia (SED) characterized by an association with progressive arthropathy.

Summary:
Epidemiology
The prevalence of progressive pseudorheumatoid arthropathy (dysplasia) of childhood (PPAC; PPD) has been estimated at 1/1,000,000.
Clinical description
Most patients present the disease before the age of 8 years (the onset varies between 2 and 11 years). Typically, there are no symptoms in the newborn period. The most common signs at diagnosis are progressive stiffness and swelling of small joints of hands (interphalangeal) without obvious signs of inflammation. Other joints are progressively affected: toes, elbows, writs, knees, ankles and spine. Bowing of the legs, motion range limitation, deformities and pain develop gradually, and spread to other joints. Many patients have spinal involvement manifesting as exaggerated lumbar lordosis, thoracic kyphosis, and/or scoliosis. Radiologically, the condition presents as SED (reduced joint space, abnormal and often large epiphyses and platyspondyly) with osteoporosis. Extraskeletal manifestations (besides those secondary to the bony changes) have not been reported. Patients have normal facial appearance and intelligence.
Etiology
The responsible gene CCN6 (mapping to human chromosome 6q22) encodes a secreted growth regulator.
Diagnostic methods
Diagnosis is based on clinical and radiographic findings. Molecular testing is available on research basis.
Differential diagnosis
PPAC can be initially misdiagnosed as juvenile idiopathic (rheumatoid) arthritis but is distinguished on radiographic analysis (especially the platyspondyly and generalised epiphyseal dysplasia) and the absence of inflammatory joint disease. PPAC must be differentiated from juvenile idiopathic arthritis to ensure optimal treatment and to avoid unnecessary exposure to immunosuppressants.
Antenatal diagnosis
Antenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
There is no specific treatment for PPAC. No clear prevention, improvement or slowing the disease course with anti-inflammatory drugs has been demonstrated.
Prognosis
PPAC does not affect life expectancy, but the progressive nature of the disease frequently requires joint replacement by early adulthood.

                            Last update:
                            July 2024

                            - Expert reviewer(s):
                            Pr Katta GIRISHA


Progressive retinal dystrophy due to retinol transport defect is a rare, genetic, metabolite absorption and transport disorder characterized by progressive rod-cone dystrophy, usually presenting with impaired night vision in childhood, progressive loss of visual acuity and severe retinol deficiency without keratomalacia. Association with ocular colobomas, severe acne and hypercholesterolemia has been reported.


Progressive scapulohumeroperoneal distal myopathy

A rare genetic muscular dystrophy characterized by progressive muscle weakness in a scapulo-humero-peroneal and distal distribution, featuring wrist extensor weakness, finger and foot drop, scapular winging, mild facial weakness, contractures of the Achilles tendon, elbow, and shoulder, and diminished or absent deep tendon reflexes. A predilection for the upper extremities has been reported in some patients. Respiratory muscles are spared until late in the disease course. Age of onset, progression, and severity of the disease vary significantly between individuals. Muscle biopsy shows groups of atrophic type I fibers and increased internal nuclei.


Progressive sensorineural hearing loss-hypertrophic cardiomyopathy syndrome

A rare disorder characterized by progressive, late onset, autosomal dominant sensorineural hearing loss, QT interval prolongation, and mild cardiac hypertrophy.


Progressive spondyloepimetaphyseal dysplasia-short stature-short fourth metatarsals-intellectual disability syndrome

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay and intellectual disability, progressive spondyloepimetaphyseal dysplasia, short stature, short fourth metatarsals, and dysmorphic craniofacial features (including microcephaly, hypertelorism, epicanthal folds, mild ptosis, strabismus, malar hypoplasia, short nose, depressed nasal bridge, full lips, small, low-set ears, and short neck). Craniosynostosis, generalized hypotonia, as well as asymmetry of the cerebral hemispheres and mild thinning of the corpus callosum on brain imaging have also been described.


Progressive supranuclear palsy-corticobasal syndrome

An atypical variant of progressive supranuclear palsy (PSP), a rare late-onset neurodegenerative disease, characterized by a variable mixture of progressive asymmetric limb rigidity, apraxia, cortical sensory loss, alien limb, dystonia and bradykinesia that is unresponsive to levodopa. Postural instability and axial rigidity develop as the disease progresses. Neuropathological characteristics includes tau pathology and neuronal loss in specific brain areas, especially in the midfrontal and inferior parietal cortices.


Progressive supranuclear palsy-predominant parkinsonism syndrome

An atypical variant of progressive supranuclear palsy (PSP), a rare late-onset neurodegenerative disease, characterized by prominent early parkinsonism (tremor, limb bradykinesia, axial and limb rigidity) rather than falls and cognitive change. Over the years, patients ultimately develop clinical features characteristic of classical PSP. Neuropathological characteristics includes tau pathology and neuronal loss in specific brain areas, especially in the subthalamic nucleus and substantia nigra. The tau pathology is less severe than in classical PSP.


Progressive supranuclear palsy-progressive non-fluent aphasia syndrome

An atypical variant of progressive supranuclear palsy (PSP), a rare late-onset neurodegenerative disease, characterized by an initial presentation of an isolated speech and language disorder (apraxia of speech, agrammatism, and phonemic errors) years before developing other motor features of PSP. Neuropathological characteristics includes tau pathology and neuronal loss in specific brain areas, especially in the temporal cortex and superior frontal gyrus.


Progressive supranuclear palsy-pure akinesia with gait freezing syndrome

An atypical variant of progressive supranuclear palsy (PSP), a rare late-onset neurodegenerative disease, characterized by progressive freezing of gait, speech and writing early in the disease course. Later, axial rigidity, and facial immobility can occur, and supranuclear downgaze paresis may emerge after a decade. Neuropathological characteristics include tau pathology and neuronal loss in specific brain areas, especially in the globus pallidus, subthalamic nucleus, and substantia nigra. The tau pathology is less widespread compared to the other PSP sub-types.


A rare late-onset neurodegenerative disease characterized by ocular motor dysfunction, postural instability, akinesia-rigidity, and cognitive dysfunction.

Summary:
Epidemiology
Estimates of prevalence of progressive supranuclear palsy (PSP) range between 1/13,000-34,000. It mainly affects adults older than 50 years of age.
Clinical description
PSP usually manifests during the sixth or seventh decade of life. Five clinical variants have been described with clinicopathological correlations. Classical PSP (Richardson's syndrome) is the most common clinical variant and manifests with slowing of vertical saccadic eye movements, falls due to postural instability, axial akinetic-rigid syndrome, and cognitive impairment. Progressively patients develop other problems such as problems in speech and eventually a supranuclear gaze palsy and difficulties in swallowing. PSP with predominant Parkinsonism (PSP-P) is characterized by prominent early parkinsonism (tremor, limb bradykinesia, axial and limb rigidity) rather than falls and cognitive change. Over the years, patients ultimately develop clinical features characteristic of classical PSP. PSP with progressive gait freezing (PSP-PGF) is characterized by progressive freezing of gait, speech and writing early in the disease course. Later, axial rigidity, and facial immobility can occur, and supranuclear downgaze paresis may emerge after a decade. PSP with predominant corticobasal syndrome (PSP-CBS) is characterized by progressive apraxia/cortical sensory loss and limb rigidity/bradykinesia dystonia/myoclonus. PSP with predominant speech/language disorder (PSP-SL) is characterized by speech anomalies (apraxia of speech, agrammatism, nonfluent/agrammatic variant of primary progressive aphasia). Motor symptoms appear later in the course of the disease. PSP with predominant frontal presentation (PSP-F) presents with frontal cognitive/behavioral symptoms. Other variant manifestations of PSP include PSP with predominant ocular motor dysfunction (PSP-OM), PSP with predominant postural instability (PSP-PI), and PSP with predominant frontal presentation (PSP-F).
Etiology
PSP is a 4R tauopathy composed of a preponderance of four-repeat (exon 10 positive) tau isoforms and a characteristic biochemical profile (doublet tau 64 and tau 69). The MAPT H1-clade specific sub-haplotype, H1c, is a risk factor for this disease. PSP is also characterized by deficits in several neurotransmitter systems (e.g., dopaminergic, cholinergic, GABAergic). The factors that initiate tau-neurodegeneration are unknown.
Diagnostic methods
Diagnosis is based on the clinical picture and neuropsychological evaluation. On autopsy, PSP is characterized neuropathologically by neuronal loss and gliosis with tau-immunoreactive astrocytic plaques and neurofibrillary tangles in the brainstem and basal ganglia more than in cerebral cortex and cerebellum. Differences in the anatomical distribution of accumulation of phosphorylated tau protein correlate with the clinical variants.
Differential diagnosis
Differential diagnosis includes Parkinson disease and other atypical parkinsonian disorders (APD) such as multiple system atrophy and corticobasal degeneration. Similar eye movement abnormalities can occur in Niemann-Pick disease type C and Whipple disease.
Genetic counseling
PSP is a sporadic, non-hereditary disease.
Management and treatment
There is no treatment curing the disease. Some drugs, depending on the clinical variant, reduce morbidity and improve quality of life (e.g., levodopa responsiveness of patients with PSP-Parkinsonism). Amantadine may improve gait freezing, coenzyme Q10 may positively affect motor and cognitive dysfunction, and other anticholinergic medications occasionally improve voice and speech disturbance.
Prognosis
Progressively, patients become wheel-chair dependent due to the frequent falls. Difficulties in breathing and swallowing, and infections are the main causes of death, generally 6-12 years after onset of the disease.

                            Last update:
                            November 2021

                            - Expert reviewer(s):
                            Pr Günter HÖGLINGER | ERN-RND*

                                * European Reference Network


A rare, usually benign, neoplasm of the anterior pituitary gland that results in hyperprolactinemia. The most common clinical manifestations are amenorrhea and infertility in women; and impotence, decreased libido and infertility in men.

Summary:
Epidemiology
In Europe, the prevalence of prolactinoma is reported at between 1/1,600-2,200 (Belgium, UK and Switzerland). A notable female preponderance is observed, particularly among premenopausal women. Prolactinoma accounts for 66% of clinically relevant pituitary adenomas.
Clinical description
Disease onset is usually in the second to fourth decades of life with galactorrhea, amenorrhea and infertility presenting in women and impotence, decreased libido and infertility in men. In male patients prolactinoma may exhibit more aggressive clinical course. Prolactinoma can also cause mass effects (visual field defects, headaches) or psychiatric manifestations (anxiety, depression).
Etiology
Prolactinoma is a prolactin-secreting pituitary adenoma. The mechanism that leads to this benign growth of prolactin secreting cells is still unknown in most cases, however; very rarely, inactivating mutations of the AIP gene (11q13.3) in young patients can rarely lead to sporadic, isolated prolactinoma. Almost all AIP mutation-related prolactinomas are macroadenomas with male predominance and a young age at diagnosis. Hyperprolactinemia inhibits secretion of gonadotropin-releasing hormone (GnRH) in the hypothalamus, which results in decreased follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels, and finally in decreased estrogen (females) and testosterone (males) levels. Prolactin itself stimulates lactation from breast tissue.
Diagnostic methods
Diagnosis includes laboratory hormonal testing showing hyperprolactinemia and decreased sex hormone levels (estrogen in females, testosterone in males). Pituitary adenomas may be visualized by pituitary magnetic resonance imaging (MRI). Tumors are classified according to their size: microadenomas (less than or equal to 10 mm), macroadenomas (greater than 10 mm), or giant adenomas (greater than 40 mm). Pre-menopausal females with prolactinomas usually have microadenomas, while male patients more frequently have macroadenomas.
Differential diagnosis
Prolactinoma can rarely occur as part of multiple endocrine neoplasia type 1 (MEN1) and familial isolated pituitary adenoma (FIPA). Causes of hyperprolactinemia without pituitary adenoma include: pregnancy, lactation, exercise, stress and polycystic ovary syndrome. Pituitary lesions that do not produce prolactin can also cause hyperprolactinemia by pituitary stalk impingement (stalk effect).
Genetic counseling
Prolactinomas usually occur sporadically and with the exception of prolactinoma due to MEN1 or FIPA, the occurrence of prolactinomas as part of inherited syndromes is exceptionally rare. In patients with a pathogenic variant of AIP, the inheritance is autosomal dominant and thus offspring of an affected individual have a 50% risk of inheriting the mutation; however, penetrance is variable.
Management and treatment
Initial therapy is a dopamine agonist (cabergoline or bromocriptine) for normalizing hyperprolactinemia and decreasing tumor size. Dopamine agonist treatment should start at low doses and be titrated upwards gradually according to hormonal response and tolerability. For dopamine analog-resistant patients, changing to another dopamine agonist, increasing the dose of the drug, or neurosurgery may be proposed. Patients receiving high doses of dopamine agonists should be screened and monitored with echocardiography to identify cardiac valve dysfunction. Other medical therapies (e.g. temozolamide) may be needed for aggressive, invasive prolactinomas or rare carcinomas that are refractory to other therapies. Radiotherapy can also be considered in cases where both dopamine agonists and surgery have failed.
Prognosis
Prolactinomas are usually readily controlled with dopamine agonists that improve symptoms/signs and shrink and/or control the pituitary tumor mass. Patients with MEN1 and those harboring mutations in AIP can have a poorer response to therapy.

                            Last update:
                            April 2020

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


Prolidase deficiency is an inherited disorder of peptide metabolism characterized by severe skin lesions, recurrent infections (involving mainly the skin and respiratory system), dysmorphic facial features, variable cognitive impairment, and splenomegaly.

Summary:
Epidemiology
The exact prevalence is unknown but a prevalence estimate of 1/1,235,000 live births has been suggested. A higher carrier frequency of 1/21 has been reported in the Druze community. Approximately 90 patients from different ethnic groups have been reported in the literature to date, but due to underdiagnosis the exact number is probably higher.
Clinical description
Clinical manifestations and age of onset are quite variable. Prolidase deficiency can present in infancy with splenomegaly. Diarrhea, vomiting, and dehydration may also occur. Dysmorphic facial features include low anterior and posterior hairline, hypertelorism, proptosis, flat nasal bridge, thin vermilion of the upper lip and prognathism. Skin involvement usually appears during childhood (but can appear as early as 6 months and as late as 30 years of age) with severe, chronic, recalcitrant, and painful skin ulcers of the feet, lower legs and, less commonly, the hands. Telangiectasia of the face and hands may precede ulcers as well as erythematous, maculopapular lesions or purpuric lesions. Most patients have some degree of intellectual disability, ranging from mild to severe. Pulmonary (e.g. asthma-like chronic reactive airway disease), immunologic (susceptibility to infections with recurrent episodes of otitis media, sinusitis, pneumonia, and gastroenteritis) and hematologic (e.g. anemia, thrombocytopenia) manifestations have also been reported. Additional, less commonly reported manifestations include short stature, lymphedema, joint laxity, protuberant abdomen, hirsutism, dental dysplasia and keratitis. Some patients, however, remain asymptomatic. An association between prolidase deficiency and systemic lupus erythematosus (SLE; see this term) has been reported.
Etiology
Prolidase deficiency is due to a mutation in the PEPD gene (19q13.11), encoding Xaa-Pro dipeptidase, which plays an important role in the biosynthesis and degradation of collagen. Mutations in this gene lead to impaired collagen synthesis and wound healing.
Diagnostic methods
Diagnosis is based on clinical and laboratory findings. Urine amino acid analysis reveals massive imidodipeptiduria (10-30 mmol/day) in all cases. Patients also usually have elevated liver enzymes, mild anemia, mild thrombocytopenia, hypergammaglobulinemia, and hypocomplementemia. Molecular genetic testing, identifying a mutation in the PEPD gene, confirms diagnosis.
Differential diagnosis
Differential diagnoses include Werner syndrome, beta-thalassemia, vasculitis (see these terms), autosomal dominant and recessive forms of hyper-IgE syndrome, sickle cell disease, pressure ulcers, and arterial and venous insufficiency.
Antenatal diagnosis
Prenatal diagnosis is possible in families with a known disease-causing mutation.
Genetic counseling
Prolidase deficiency is inherited in an autosomal recessive manner. Parents of an affected child should be informed of the 25% risk of transmission to future offspring.
Management and treatment
Treatment is symptomatic. Care should be provided by a multidisciplinary team in order to monitor and treat skin, lung, and immunologic manifestations. Topical proline plus glycine ointment, steroids, methylprednisolone, blood transfusions, plasmapheresis, and topical growth hormone ointment have all been used to treat ulcers, with varying degrees of improvement reported. Antibiotic prophylaxis may be necessary in some cases. In patients with splenomegaly, contact sports should be avoided.
Prognosis
Prognosis varies but patients often have a decreased life-expectancy due to severe and sometimes fatal infections. Quality of life is also reduced due to infections and chronic pulmonary complications. When severe, ulcers can lead to amputation.

                            Last update:
                            April 2016

                            - Expert reviewer(s):
                            Dr Heng WANG


A rare large, multinodular, usually benign, tumor that is generally located in the posterior part of the scalp in aged women (over 50 years). It first appears as a painless nodule that later grows into a solid or partially cystic tumor that is mobile over the underlying subcutaneous tissues. It can present ulceration, inflammation or even bleeding and can cause necrosis of the adjacent tissues.


A rare syndrome described and characterized by prenatal onset of growth deficiency, microcephaly, hypoplastic genitalia, and birth onset of convulsions.


Properdin deficiency is a rare, hereditary, primary immunodeficiency due to a complement cascade protein anomaly characterized by significantly increased susceptibility to Neisseria species infections. It only affects males, typically presenting with severe or fulminant meningococcal disease.


Propionic acidemia (PA) is an organic aciduria caused by the deficient activity of the propionyl Coenzyme A carboxylase and is characterized by life threatening episodes of metabolic decompensation, neurological dysfunction and that may be complicated by cardiomyopathy.

Summary:
Epidemiology
The prevalence rate is probably about 1 in 100,000 live births worldwide. A high prevalence rate is noted in certain countries like Saudi Arabia.
Clinical description
Propionic acidemia can present in one of the following forms: severe neonatal onset, intermittent late onset or a chronic progressive form. In the severe neonatal onset form, the affected infants present with symptoms of metabolic intoxication (poor feeding, vomiting, altered sensorium) and pancytopenia within several hours to weeks after birth. In the intermittent late onset form, the disease presents after a year or even later in life with episodes of metabolic decompensation provoked by periods of catabolic stress like fever, vomiting and trauma. Patients may also present with acute neurological crisis characterized by dystonia, rigidity, choreoathetosis and dementia (due to infarction of basal ganglia). In the chronic progressive form, the disease presents as failure to thrive, chronic vomiting, psychomotor delay, hypotonia, seizures and movement disorders. Intellectual disability, optic neuropathy, cardiomyopathy, long QT syndrome, pancreatitis, dermatitis, and immune dysfunction are known complications.
Etiology
PA is caused by mutations in either the PCCA (13q32) or PCCB (3q21-q22) genes encoding the α- and β-subunits of the propionyl CoA carboxylase.
Diagnostic methods
Extended newborn screening test identifies PA by detecting an elevated level of propionyl carnitine. Symptomatic cases present during metabolic decompensation with acidosis, ketosis, increased anion gap, hyperlactatemia, hyperglycinemia, hyperammonemia, hypoglycemia and cytopenias. Urine analysis by gas chromatography-mass spectrometry reveals a characteristic pattern with 3 hydroxy propionate, methyl citrate, propionyl glycine and propionyl carnitine that persists in between crisis. Confirmation of the diagnosis relies on detection of either deficient enzymatic activity or mutations in PCCA or PCCB genes.
Differential diagnosis
Differential diagnosis includes neonatal sepsis, other branched chain organic acidurias, pyloric stenosis or other common causes of increased anion gap acidosis. In the infantile chronic form, failure to thrive, chronic vomiting and neutropenia may mimic cow milk intolerance, celiac disease (see this term) or immune deficiencies.
Antenatal diagnosis
Prenatal diagnosis can be made by measuring propionyl carnitine, methyl citrate and 3 hydroxy propionate in the amniotic fluid or by DNA assay or direct enzyme assay in families with a known mutation.
Genetic counseling
Inheritance is autosomal recessive.
Management and treatment
Confirmation of the diagnosis is not indispensable to start the treatment. Reversal of catabolism by stopping protein intake and administering non-protein calories in the form of intravenous fluids is the mainstay of treatment of a crisis. Hyperammonemia is treated by administering sodium benzoate, carbamyl glutamate or by hemodialysis. Nutrition management, in particular protein restriction, is a cornerstone to the long term treatment of patients with PA. Growth is regularly monitored. Carnitine supplementation helps in detoxification. Avoiding metabolic decompensation and promptly treating the episodes with standard treatment may improve intellectual outcome.
Prognosis
Early detection and treatment has led to a reduction in the mortality rate in the first year of life and improved survival rates in early and mid-childhood but morbidity in terms of impaired cognitive development remains high. The question whether a liver transplantation can be performed early in infancy to improve the prognosis is still under investigation.

                            Last update:
                            February 2014

                            - Expert reviewer(s):
                            Pr Jean-Marie SAUDUBRAY


Propylthiouracil embryofetopathy is a rare teratologic disease characterized by variable congenital anomalies resulting from maternal treatment and prenatal exposure to propylthiouracil. Anomalies frequently encountered include ear malformations (e.g. accessory auricle, preauricular sinus/fistula/cyst), urinary system malformations (e.g. isolated unilateral kidney, congenital hydronephrosis), gastrointestinal anomalies (e.g. congenital bands with intestinal malrotation) and cardiac defects (e.g. situs inversus dextrocardia, cardiac outflow tract defects).


A rare, autosomal recessive autoinflammatory disorder characterized by early-onset erythematous popular/nodular skin eruptions, recurrent fever, possible joint contractures, lipodystrophy, erythematous inflammatory skin changes, joint and muscle involvement (joint contractures, arthralgia, muscle weakness), and hepatosplenomegaly.

Summary:
Epidemiology
To date less than 50 cases have been reported in the scientific and medical literature; the distribution is worldwide.
Clinical description
The disease presents as spectrum with onset ranging from the neonatal period to childhood, with the majority of reported cases occurring in infancy. The principal manifestations are of pernio-like and/or erythematous lesions and periodic fever. Lesions can be annular, nodular or maculopapular involving the hands and feet or periorbital regions, and may be associated with seasonal variation. Variable skin manifestations include heliotrope-like rash on eyelids, nodular episcleritis, ear and nose chondritis, plantar hyperkeratosis, hyperhidrosis of hands and feet. Lipodystrophy is first noted in the face and upper limbs, giving a characteristic thin and angular facial appearance, and may become generalized to include the abdomen and lower limbs. Lipodystrophy is progressive and irreversible. Joint contractures affect mainly the hands and feet at first but can later spread to other joints and can cause pain and joint deformities. Fingers may appear long and clubbed. Arthralgia without arthritis may be noted. Hepatosplenomegaly is frequently reported and delayed physical development (low height and weight) is possible. Other less common manifestations include conjunctivitis, short stature, and attacks of aseptic meningitis, seizures, microcytic anemia.
Etiology
The disease is due to loss of function variants in the gene PSMB8 (6p21.3) encoding the beta5i subunit of immunoproteasome. In all reported Japanese patients, the disease is due to the homozygous c.602G>T (p.Gly201Val) variant. The immunoproteasome is involved in proteolysis and maintenance of cell homeostasis. If proteolysis is disrupted, this can lead to an increase in interferon (IFN) signaling and cell stress. This dysregulation of the IFN pathway is thought to be responsible for the manifestations seen in this disease. Some cases remain to be genetically determined, indicating the possibility of other disease-causing genes.
Diagnostic methods
Diagnosis is based on clinical presentation and family history and confirmed by genetic testing. In Japan, clinical diagnosis is established on presentation of five or more major clinical characteristics (autosomal recessive heritability, skin rash, periodic fever, nodular erythema, lipodystrophy ranging from localized to near generalized, muscular atrophy, elongated clubbed fingers or joint contractures, hepato-splenomegaly, or calcification in the basal ganglia). Histopathologic examination of skin biopsy reveals focal mononuclear cell infiltration with vasculopathy. Laboratory findings include constantly elevated serum C-reactive protein (CRP) levels and hyper-gamma-globulinemia. Autoantibody titers increase as the disease progresses in some but remain negative in others. Molecular genetic testing can identify disease causing variants, confirming diagnosis.
Differential diagnosis
Differential diagnoses include cryopyrin-associated periodic syndrome, mucopolysaccharidosis, familial partial lipodystrophy, systemic lupus erythematosus, lupus erythematosus panniculitis, dermatomyositis, Sjögren syndrome, inclusion body myositis, Aicardi-Goutières syndrome, and Weber-Christian disease.
Genetic counseling
The pattern of inheritance is autosomal recessive and genetic counseling should be offered to affected families. Where both parents are unaffected carriers, there is a 25% risk of transmission to offspring at each pregnancy.
Management and treatment
There is no effective therapeutic regimen. Fever and skin lesions respond well to systemic steroid administration but usually reoccur after tapering. Biologics (notably tocilizumab and baricitinib) have been used to varying effect; however, randomized controlled trials are lacking. These treatments are all ineffective in halting lipodystrophy progression.
Prognosis
Life expectancy can be compromised, with death often the result of multi-organ inflammation. Quality of life is largely affected as patients suffer from reduced activity, fever, pain and repeated episodes of severe inflammation.

                            Last update:
                            November 2020

                            - Expert reviewer(s):
                            Dr Abhimanyu GARG


A rare complex overgrowth syndrome characterized by progressive overgrowth of the skeleton, skin, adipose, and central nervous systems.

Summary:
Epidemiology
Approximately 200 cases of Proteus syndrome (PS) have been reported to date. The prevalence is estimated to be less than 1/1,000,000 live births.
Clinical description
Proteus syndrome presents in a wide range of severity and anatomic distribution. Individuals usually have no signs or symptoms at birth but onset of overgrowth typically occurs in the first 2 years of life. This often manifests as overgrowth of the hands or legs. Skeletal overgrowth is progressive and may involve the limbs, the skull, and spine. Cerebriform connective tissue nevi (CCTN) typically occur on the feet or hands during childhood beginning as small nodules that coalesce to the cerebriform lesion. Vascular malformations, most commonly venous or capillary, and epidermal nevi may occur in the first months of life and generally stabilize with time. Neurological features include hemimegalencephaly, developmental delay and intellectual disability. Additional features include cystic lung disease, and an increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE). Tumors may arise in individuals and are mainly benign, particularly gonadal cystadenoma, parotid adenoma, and meningioma, but rare malignant tumors have been reported.
Etiology
Somatic activating variants in AKT1 are associated with Proteus syndrome. The most common is the c.49G>A (p.Glu17Lys) variant but others have been reported.
Diagnostic methods
Diagnosis should be based on phenotype and genotype. This dyadic approach has been proposed with use of a scoring system. The score includes the following features of Proteus syndrome: CCTN (5 points), asymmetric bony overgrowth (5 points), organ/visceral overgrowth (5 points), cystic lung disease (2 points), dysregulated adipose tissue (2 points), vascular malformations (2 points), tumors associated with Proteus syndrome (1 point), history of DVT or PE (2 points), and a facial phenotype (2 points). Presence of prenatal overgrowth or ballooning overgrowth (-5 points each) may favor a diagnosis of other than Proteus syndrome, such as PIK3CA-related overgrowth spectrum. In the absence of a somatic AKT1 variant, a score of 15 or greater indicates a clinical diagnosis of Proteus syndrome. If a somatic AKT1 variant is present, a score of 10 or greater indicates a diagnosis of AKT1- related Proteus syndrome. Genetic testing requires sampling of an affected tissue, such as a skin biopsy. Blood is not an appropriate source for genetic testing.
Differential diagnosis
Differential diagnoses include PIK3CA-related overgrowth spectrum disorders such as Klippel-Trenaunay syndrome and CLOVES syndrome, as well as other disorders of overgrowth such as PTEN hamartoma tumor syndrome (PHTS), neurofibromatosis type 1, Ollier disease, and Maffucci syndrome.
Antenatal diagnosis
Prenatal testing is not performed as PS is a mosaic disorder and not inherited.
Genetic counseling
Proteus syndrome is not thought to be inherited because the activating AKT1 variant is hypothesized to be lethal in the heterozygous state. There are reports of individuals with Proteus syndrome who have unaffected children.
Management and treatment
Treatment requires a multidisciplinary approach and must be tailored to an individual's unique presentation. Surgical interventions used to control overgrowth include physeal arrest, epiphysiodesis, and spinal fusion. Physical and occupational therapy is critical as custom designed orthotics or footwear may be necessary. Dermatological care along with management of malodor (if present) is needed for those with CCTN. Perioperative anticoagulation prophylaxis should be strongly considered as PE is the leading cause of death. Individuals should be counseled about the risk of tumor predisposition. Psychosocial counseling can be beneficial for individuals and their families. Targeted therapy using AKT inhibitors to mitigate disease progression is ongoing in clinical trials.
Prognosis
Prognosis varies depending on the severity of complications.

                            Last update:
                            May 2024

                            - Expert reviewer(s):
                            Dr Christopher OURS


A rare genetic disease characterized by patients presenting with a multitude of clinical features of Proteus syndrome without meeting the diagnostic criteria for the disease.

Summary:
Epidemiology
The prevalence is unknown. There have been only 7 case reports of patients with proteus-like syndrome; 5 out of 7 were confirmed to have a germline pathogenic PTEN variant.
Clinical description
Proteus-like syndrome has the clinical features of Proteus syndrome but lacks some of the required criteria necessary for diagnosis. The main clinical features include skeletal overgrowth, hamartomous overgrowth of multiple tissues, cerebriform connective tissue nevi, vascular malformations and linear epidermal nevi.
Etiology
Mutations in the PTEN gene are found in more than half of Proteus-like syndrome cases, making them a part of the PTEN harmatoma tumor syndrome (PHTS) group. To date, mutations in AKT1 have not been reported in Proteus-like patients. It is possible that Proteus-like patients will have somatic mosaic or germline mutations in genes encoding other components of the phosphatidylinositol 3-kinase signaling pathway.
Diagnostic methods
Clinical diagnosis can be made using the Proteus syndrome clinical criteria. Individuals who present with clinical features but do not meet the clinical criteria for Proteus syndrome are diagnosed clinically as having Proteus-like syndrome. Germline genetic testing for a pathogenic PTEN variant can confirm a genetic diagnosis of Proteus-like syndrome.
Differential diagnosis
The differential diagnosis includes Proteus syndrome and PTEN hamartoma tumor syndromes (PHTS) such as Cowden syndrome.
Antenatal diagnosis
Antenatal diagnosis is in theory possible if the pathogenic variant has previously been identified in the family. It has not been described in the literature.
Genetic counseling
Inheritance is autosomal dominant in those with a PTEN mutation, with a high de novo rate. Genetic counseling should be offered to at-risk family members to inform them of their health risks and the 50% transmission risk for each pregnancy.
Management and treatment
Germline PTEN pathogenic variants predispose to a wide spectrum of benign and malignant tumors and surveillance recommendations for PTEN carriers including Proteus-like syndrome, have been described under the term of PTEN hamartoma tumor syndrome (PHTS) and Cowden syndrome. Management and surveillance for Proteus-like syndrome with a germline PTEN pathogenic variant would be as described for PHTS, which includes the following: 1) annual comprehensive physical examination starting at age 18 or 5 years before youngest age of diagnosis of cancer in the family, with attention to thyroid exam; 2) yearly dermatological exam for children and adults; 3) yearly thyroid ultrasound from the time of diagnosis; 4) monthly breast self-examination from age 18, clinical breast examination annually from age 25, and annual MMG staring from age 30-35; 5) endometrial cancer screening by biopsy can be considered starting age 35; 6) colonoscopies starting from age 35 and repeating every 5 years; 7) management tailored to clinical presentation and personalized follow-up with annual clinical review has been suggested in literature. More data is required to optimize screening and management for Proteus-like syndrome patients.
Prognosis
Prognosis could be dependent on the risk associated with the development of cancer.

                            Last update:
                            December 2023

                            - Expert reviewer(s):
                             Manasadevi KARTHIKEYAN  - Dr Joanne NGEOW


Proton-pump inhibitor-responsive esophageal eosinophilia (PPI-REE) is a rare, gastroenterologic disease characterized by typical clinical, endoscopic and histological features of eosinophilic oesophagitis (i.e. symptomatic oesophageal dysfunction associated with eosinophil-predominant mucose infiltrate) which completely remits upon proton pump inhibitor therapy.


The proximal 16p11.2 microdeletion syndrome is a chromosomal anomaly characterized by developmental and language delays, mild intellectual disability, social impairments (autism spectrum disorders), mild variable dysmorphism and predisposition to obesity.

Summary:
Epidemiology
The prevalence of proximal 16p11.2 microdeletion syndrome is estimated at 1/5,000 in the general population. Proximal 16p11.2 microdeletion syndrome is a common etiology in autism spectrum disorder (ASD) estimated at approximately 1:150 individuals diagnosed with ASD.
Clinical description
The clinical presentation of proximal 16p11.2 microdeletion syndrome can be extremely variable, ranging from intellectual deficiency with multiple congenital anomalies, autism, cognitive and language problems, to a normal phenotype. Nearly all individuals do present with some degree of developmental delay including a cognitive delay and a language delay specifically in the onset and development of expressive language (childhood apraxia of speech) as well as to a lesser extent feeding difficulties, linked to hypotonia and a delay in gross and fine motor and coordination skills. Furthermore, they often present with autistic features. Intellectual disability is usually mild but can be absent. About half of affected individuals have a tendency to be overweight. Dysmorphic features may be present but are often mild and inconsistent. Additional less frequent features reported include hypotonia, EEG abnormalities, psychiatric disease other than ASD and minor cardiac anomalies.
Etiology
The proximal 16p11.2 microdeletion syndrome most commonly refers to a distinct deletion of approximately 593 kb at chromosomal coordinates 29.5-30.1 Mb comprising 24 genes. The relationship between genotype and clinical phenotype remains elusive. Patients with larger deletions including this region or patients with a more distally located (coordinates 28.73-28.95 Mb), smaller (200 kb) 16p11.2 deletion are not described here.
Diagnostic methods
Diagnosis is based on clinical manifestations leading to chromosomal analysis. Molecular techniques that may be used for the genetic characterization of the proximal 16p11.2 microdeletion include fluorescence in situ hybridization (FISH), Multiplex Ligation-dependent Probe Amplification (MLPA), Microarray-based Comparative Genomic Hybridization (aCGH) and quantitative polymerase chain reaction (qPCR). Electroencephalographic (EEG) testing is performed in cases with seizures.
Differential diagnosis
Differential diagnosis includes many entities presenting with a developmental delay with or without autistic features and minor dysmorphisms.
Antenatal diagnosis
In cases with a family history, preimplantation genetic diagnosis or prenatal testing is technically feasible by amniocentesis or chorionic villus sampling and cytogenetic analyses, but genetic counseling for affected individuals should be provided before starting a family. The outcome of the genetic diagnosis cannot accurately predict the clinical phenotype.
Genetic counseling
Proximal 16p11.2 microdeletion syndrome is a contiguous deletion syndrome. Proximal 16p11.2 microdeletions almost always appear de novo, but may, in a small number of cases, be inherited from affected parents in an autosomal dominant manner.
Management and treatment
Management involves a regular assessment by appropriate specialists and tailored neurodevelopmental therapies. Early diagnosis and access to therapies with attention to speech and language are recommended together with nutritional education and weight management.
Prognosis
Prognosis depends on the severity of clinical manifestations. Long-term clinical follow-up studies are not available to date. One may expect that the long-term health consequences of obesity occurring in the general population will also occur in individuals with proximal 16p11.2 microdeletion syndrome.

                            Last update:
                            June 2013

                            - Expert reviewer(s):
                            Pr Raoul HENNEKAM


Proximal 16p11.2 microduplication syndrome is a rare chromosomal anomaly syndrome resulting from a partial duplication of the short arm of chromosome 16 characterized by developmental delay and intellectual disability of a highly variable degree, autism spectrum, obsessive-compulsive, attention deficit hyperactivity disorder, speech articulation abnormalities, muscular hypotonia, tremor, hyper- or hyporeflexia, seizures, microcephaly, neuroimaging abnormalities, decreased body mass index and schizophrenia or bipolar disorder later on in life.


Proximal myopathy with extrapyramidal signs is a rare, hereditary non-dystrophic myopathy characterized by proximal muscle weakness, delayed motor development, learning difficulties, and progressive extrapyramidal motor signs including chorea, dystonia and tremor. Variable additional features have been reported - ataxia, microcephaly, ophthalmoplegia, ptosis, and optic atrophy.


Proximal myopathy with focal depletion of mitochondria

A rare genetic neuromuscular disease characterized by late onset of mild, progressive, proximal muscle weakness, severe myalgias during and after exercise, and susceptibility to rhabdomyolysis. Intellectual disability is mild or absent. There are no abnormalities of the skin. Muscle biopsy shows focal depletion of mitochondria especially at the center of muscle fibers, surrounded by enlarged mitochondria at the periphery.


A rare myotonic dystrophy of juvenile or adult-onset characterized by mild and fluctuating myotonia, muscle weakness, and rarely cardiac conduction disorders.

Summary:
Epidemiology
Prevalence estimates of around 1/100,000 in Germany and 1/600,000 in the United Kingdom have been suggested. Most cases have been reported in individuals of European origin (mainly in Eastern Europe with a founder effect).
Clinical description
The clinical presentation is marked by significant variability as is the age of onset (juvenile to late adulthood). The primary manifestations include muscle weakness (with early involvement of neck flexors or finger flexors, later involving hip girdle muscles), myotonia, and possibly severe fluctuating or episodic muscle pain, and stiffness. Cataracts, hypogonadism or testicular failure in males, insulin insensitivity, excessive sweating, cognitive abnormalities are rare features. Cardiac disorders are rare and may include conduction abnormalities (atrioventricular and bundle branch block) and cardiac arrhythmias. Gastrointestinal complications are common and can include constipation, dysphagia, and abdominal pain. Increased risk of cancer involving colon, brain and pancreas has been reported. The phenotype may be particularly mild in a large number of affected individuals.
Etiology
The disease is caused by a CCTG expansion in the first intron of the cellular nucleic acid binding protein gene (CNBP; 3q21). Mutant alleles have 75 to 11,000 uninterrupted CCTG repeats. The pathogenesis is poorly understood.
Diagnostic methods
There may be considerable difficulty and delay in the diagnosis due to the wide clinical spectrum and non-specific manifestations. The diagnosis is based on molecular genetic testing.
Differential diagnosis
There are several overlapping features with Steinert myotonic dystrophy; whilst the diseases are similar, they are genetically distinct and have different courses and management requirements. The main difference is the absence of congenital form, which is seen in Steinert myotonic dystrophy.
Antenatal diagnosis
Prenatal diagnosis is possible in affected families with an index patient.
Genetic counseling
The pattern of inheritance is autosomal dominant. Genetic counselling should be provided to affected families. There is a 50% risk of disease transmission to offspring from an affected parent. A parent with intermediate CCTG repeat expansion is considered to have a premutation and thus there is a risk of transmitting the disorder to their offspring.
Management and treatment
Management primarily involves monitoring of cataracts, insulin metabolism, and cardiac conduction.
Prognosis
The prognosis is generally good with no impact on life expectancy.

                            Last update:
                            September 2020

                            - Expert reviewer(s):
                            Pr Giovanni MEOLA


A rare renal tubular disease characterized by impaired ability of the proximal tubule to reabsorb bicarbonate from the glomerular filtrate leading to hyperchloremic metabolic acidosis.

Summary:
Epidemiology
Prevalence is unknown but isolated hereditary pRTA is very rare. Drug-induced pRTA occurs relatively frequently.
Clinical description
Onset of hereditary pRTA occurs in childhood, manifesting initially with very alkaline urine due to bicarbonate wastage. Autosomal recessive pRTA (AR pRTA) is associated with severe growth retardation leading to short stature, intellectual disability and ocular abnormalities such as band keratopathy, cataracts, and glaucoma. Growth retardation and reduced bone density, due to metabolic acidosis, are seen in autosomal dominant pRTA (AD pRTA). Hypokalemia may be present in some cases of pRTA and can occasionally cause symptoms of hypokalemic periodic paralysis. Rickets and osteomalacia are common due to vitamin D deficiency and phosphate wasting. In cases where pRTA is associated with primary Fanconi syndrome, glycosuria, aminoaciduria, phosphaturia, uric acid wastage and tubular proteinuria can occur.
Etiology
Isolated pRTA can be acquired or is inherited either recessively (in most cases) or dominantly. AR pRTA is due to a mutation in the SLC4A4 gene (4q13.3) that encodes the electrogenic sodium bicarbonate cotransporter 1 (kNBC1). AD pRTA is due to mutations in a gene that has not yet been identified. As the proximal tubule reabsorbs around 80% of the filtered load of bicarbonate, a defect in it leads to the loss of bicarbonate. Certain drugs can be responsible for the development of acquired pRTA. Carbonic anhydrase inhibitors cause isolated pRTA while others (including oxaplatin, ifosfamide, adefovir, tenofovir, cidofovir, valproic acid, aminoglycosides, topiramate and didanosine) can all cause pRTA associated with Fanconi syndrome. In glomerular diseases, pRTA has been rarely reported and attributed to associated tubular damage and, in some cases, has been associated with multiple myeloma..
Diagnostic methods
Unlike patients with distal RTA (dRTA), patients with pRTA retain the ability to lower urine pH < 5.5 when the plasma HCO3- is low enough and below the renal threshold for tubular HCO3- reabsorption. Diagnosis involves the demonstration of urinary HCO3- wastage (increased fractional HCO3- excretion). An HCO3- titration test confirms a diagnosis of pRTA by demonstrating an exaggerated increase in urinary HCO3- excretion and urine pH as plasma HCO3- rises above the renal threshold. Molecular genetic analysis can identify a mutation in the SLC4A4 gene.
Differential diagnosis
The main differential diagnosis is dRTA. Other inherited proximal tubulopathies such as oculocerebrorenal syndrome, Dent disease and glycogen storage disease due to GLUT2 deficiency should be excluded.
Antenatal diagnosis
Prenatal diagnosis is possible in AR pRTA where the pathogenic variants have previously been identified in a family member but is not applicable in AD forms.
Genetic counseling
In families with AR pRTA genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy. In families with AD pRTA genetic counselling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy.
Management and treatment
Treatment depends on the etiology of the disease. Inherited pRTA requires life-long bicarbonate replacement therapy. Large amounts of bicarbonate (10-15 mEq/kg/day) are needed to normalize serum bicarbonate in children. Thiazide diuretics (e.g. hydrochlorothiazide 25-50 mg daily) are also sometimes prescribed in order to enhance bicarbonate reabsorption and thereby reduce the amount of bicarbonate needed. Plasma potassium should be monitored, and a mixture of sodium and potassium bicarbonate (or citrate) salts can be necessary in some cases. Drug induced pRTA is usually reversible by cessation of the drug.
Prognosis
With proper treatment the prognosis of acidosis is good, but associated extrarenal features impact on patient outcome.

                            Last update:
                            March 2022

                            - Expert reviewer(s):
                            Pr Gema ARICETA  - Dr Daniel BATLLE


A rare, genetic proximal spinal muscular atrophy characterized by degeneration of alpha motor neurons in the anterior horns of the spinal cord and lower brain stem manifesting with onset of severe and progressive muscle weakness in the first 6 months of life and presenting with severe, generalized hypotonia and weakness,. Dysphagia and respiratory impairment may also be present at presentation or appear at a later stage. Classically, before the advent of recent therapies, type 1 patients never achieved sitting without support.

Summary:
Epidemiology
The average prevalence of proximal spinal muscular atrophy (SMA) is estimated at 1/12,000, of which approximately 60% account for type 1.
Clinical description
Disease onset occurs before 6 months of age. The severe, symmetrical muscle weakness affects predominantly proximal limbs but often also involves the extremities. Cries are weak. Poor sucking ability and reduced swallowing are frequent, leading to feeding difficulties. Deep tendon reflexes are absent. Patients have paradoxical breathing, a bell shaped chest and develop respiratory failure. Mild contractures (of the knees and, more rarely, of the elbows), and scoliosis may be present. Classically, patients were not able to achieve sitting without support but this has changed following the availability of new treatments.
Etiology
The disease is a result of degeneration and loss of the lower motor neurons in the spinal cord and the brain stem nuclei. Causal homozygous mutations/deletions in the SMN1 gene (5q12.2-q13.3) are responsible. SMN1 encodes the survival motor neuron protein (SMN) which is known to participate in critical pathways related to RNA processing and transport, and it is believed that motor neurons are particularly vulnerable to impairments in these processes. Modifier genes include SMN2 (5q13.2), a homologous centromeric copy of SMN1, and NAIP (5q13.1), encoding neuronal apoptosis inhibitory protein. The number of copies of the SMN2 is inversely correlated to disease severity.
Diagnostic methods
The diagnosis is clinically suggested by muscle weakness and hypotonia with sparing of the facial muscles, loss of reflexes, typical respiratory pattern with predominance of diaphragmatic movements compared to poor intercostal movements, and tremor. Diagnosis is confirmed by genetic testing of SMN1 deletion/mutation and, if possible, SMN2 copy number testing. Muscle biopsy and electromyography should not be performed in patients with typical presentation.
Differential diagnosis
Differential diagnoses include, other spinal muscular atrophies with infantile onset (infantile-onset X-linked spinal muscular atrophy and spinal muscular atrophy with respiratory distress type 1), congenital muscular dystrophies, congenital myopathies, congenital myasthenic syndromes, some early-onset mitochondrial disorders, and carbohydrate metabolism disorders (glycogen storage disease due to acid maltase deficiency).
Antenatal diagnosis
Antenatal diagnosis is possible through molecular analysis of amniocytes or chorionic villus samples.
Genetic counseling
Transmission is autosomal recessive and thus the risk of transmission to offspring is 25% where both parents are unaffected carriers. However, around 2% of cases are caused by de novo mutations. Genetic counseling should be offered to affected families.
Management and treatment
Symptomatic management is multidisciplinary and aims to improve quality of life. This includes respiratory support (noninvasive ventilation and airway clearance), physiotherapy, gastrostomy, and antibiotic treatment in case of pulmonary infection. In the last few years, nusinersen, an antisense oligonucleotide, has been approved and made available for treatment of all SMA types in Europe and the USA. Clinical trials and real world data have shown that it reduces the risk of death and improves motor milestones in type 1 patients, with a number of patients achieving sitting without support. The best results are seen following early intervention and in presymptomatic patients. Risdiplam (a small molecule) has a also recently successfully completed clinical trials and has become commercially available in US and, for compassionate use, also in Europe. A different approach, using gene therapy, onasemnogene abeparvovec, has also been approved in US and Europe. The results of the clinical trials in young patients also indicate a very high rate of survival beyond 2 years and an improvement of motor function. Real world data are being collected in older patients but are not yet publicly available.
Prognosis
The prognosis is generally poor with most patients dying within the first two years of life due to respiratory failure. Data on long term outcomes with nusinersen treatment and with other drugs are now becoming increasingly available, suggesting long term survival.

                            Last update:
                            January 2021

                            - Expert reviewer(s):
                            Pr Eugenio MERCURI | EURO-NMD*

                                * European Reference Network


A rare, genetic proximal spinal muscular atrophy characterized by degeneration of alpha motor neurons in the anterior horns of the spinal cord and lower brain stem manifesting with onset between 6 to 18 months of age with progressive, proximal muscle weakness, mild to moderate hypotonia and finger polymyoclonour tremor, with areflexia. Motor milestones are classically limited to independent sitting or standing.

Summary:
Epidemiology
In Europe the average prevalence at birth of proximal spinal muscular atrophy (SMA) type 2 is estimated at 1/50,000. Worldwide the prevalence ranges from 1/11,00-175,000.
Clinical description
Disease onset occurs between the ages of 6 and 18 months. Classically, before the advent of the new therapies, affected children achieve sitting independently and may acquire standing but do not acquire independent walking. Progressive proximal muscle weakness is symmetrical and greater in the legs than the arms. Finger trembling is frequent. Scoliosis, joint contractures and ankyloses of the mandible are very common . Progressive respiratory muscle weakness can lead to restrictive lung disease. Cognition is normal.
Etiology
The disease is a result of degeneration and loss of the lower motor neurons in the spinal cord and the brain stem nuclei. Causal homozygous mutations/deletions in the SMN1 gene (5q12.2-q13.3) are responsible. SMN1 encodes the survival motor neuron protein (SMN) which is known to participate in critical pathways related to RNA processing and transport, and it is believed that motor neurons are particularly vulnerable to impairments in these processes. Modifier genes include SMN2 (5q13.2), a homologous centromeric copy of SMN1, and NAIP (5q13.1), encoding neuronal apoptosis inhibitory protein. The number of copies of the SMN2 is inversely correlated to disease severity.
Diagnostic methods
The disease is suspected based on clinical history and examination. The gold standard in diagnosis is genetic testing of SMN1 deletion/mutation and, if possible, SMN copy number testing. Muscle biopsy and electromyography should not be performed in patients with typical presentation.
Differential diagnosis
Differential diagnoses include, congenital muscular dystrophies, congenital myopathies, congenital myasthenic syndromes, neuromuscular junction disease (botulism), and carbohydrate metabolism disorders (glycogen storage disease due to acid maltase deficiency).
Antenatal diagnosis
Antenatal diagnosis is possible through molecular analysis of amniocytes or chorionic villus cells.
Genetic counseling
Transmission is autosomal recessive but around 2% of cases are caused by de novo mutations. Genetic counseling should be offered to affected families.
Management and treatment
Symptomatic management is multidisciplinary and aims to improve quality of life. Assisted airway clearance and non-invasive ventilations are helpful. Physiotherapy and occupational therapy are recommended to prevent scoliosis, maintain joint mobility and promote function and mobility. Antibiotic therapy is required in case of pulmonary infection. The scoliosis may require a corset/back brace for support, and almost invariably needs surgical correction. In the last few years, nusinersen, an antisense oligonucleotide, has been approved and made available for treatment of all SMA types in Europe and the USA. Clinical trials and real world data have shown that it improves motor function in type 2 patients, with a number of patients achieving walking. The best results are seen following early intervention and in presymptomatic patients. Risdiplam (a small molecule) has a also recently, successfully completed a clinical trials and has become commercially available in US and for compassionate use in Europe. Clinical trials are ongoing to identify other potential drug treatments.
Prognosis
Life expectancy for affected individuals is variable but, with the new standards of care, particularly for respiratory insufficiency, the majority of patients survive up to adulthood.

                            Last update:
                            January 2021

                            - Expert reviewer(s):
                            Pr Eugenio MERCURI | EURO-NMD*

                                * European Reference Network


A rare, genetic proximal spinal muscular atrophy characterized by degeneration of alpha motor neurons in the anterior horns of the spinal cord and lower brain stem manifesting with onset of progressive proximal muscle weakness (legs greater than arms) between 18 months and adulthood. Motor development is heterogeneous but walking is typically acquired.

Summary:
Epidemiology
The average prevalence at birth of proximal spinal muscular atrophy (SMA) is estimated at 1/12,000, of which more than 10% account for type 3. Prevalence worldwide ranges between 1/70,00-285,000, although studies are limited.
Clinical description
The disease manifests between 18 months of age and adulthood, typically presenting with frequent falls, difficulty climbing steps and proximal weakness. Patients are subdivided based on age of onset: early onset is between 18 months and 3 years of age (type 3a) and is associated with a plateau in motor development, reduced or absent reflexes, finger polymyoclonus tremor and, frequently, loss of ambulation before or around puberty. Later onset (type 3b), between 3 and 21 years of age, is associated with comparatively milder decline in gross motor function. The muscle weakness predominantly affects the legs and hip muscles and then progresses to the shoulders and arms. Abnormal gait characteristics are common in order to compensate for weakness. Typically, patients are spared scoliosis and respiratory muscle weakness but these may be a feature after loss of ambulation. Cognition is normal.
Etiology
The disease is a result of degeneration and loss of the lower motor neurons in the spinal cord and the brain stem nuclei. Causal homozygous mutations/deletions in the SMN1 gene (5q12.2-q13.3) are responsible. SMN1 encodes the survival motor neuron protein (SMN) which is known to participate in critical pathways related to RNA processing and transport. Modifier genes include SMN2 (5q13.2), a homologous centromeric copy of SMN1, and NAIP (5q13.1), encoding neuronal apoptosis inhibitory protein. Type 3 is associated with 3-4 copy numbers of SMN2.
Diagnostic methods
The disease is suspected based on clinical history and examination. The gold standard in diagnosis is genetic testing of SMN1 deletion/mutation. Muscle biopsy and electromyography should not be performed in a typical presentation.
Differential diagnosis
Differential diagnoses include other disorders of the peripheral nervous system including myopathies or muscular dystrophies (dystrophinopathies, limb girdle muscular dystrophy, metabolic myopathies, or inflammatory myopathies), inflammatory neuropathies (Guillain-Barré syndrome), neuromuscular junction disorders (myasthenia gravis or congenital myasthenic syndromes), and other motor neuron disorders (non-5q form of SMA or late onset hexosaminidase A deficiency).
Antenatal diagnosis
Antenatal diagnosis is possible through molecular analysis of amniocytes or chorionic villus samples.
Genetic counseling
Transmission is autosomal recessive but around 2% of cases are caused by de novo mutations. Genetic counseling should be offered to patients and their families.
Management and treatment
Symptomatic management is multidisciplinary and aims to improve quality of life. Physiotherapy and occupational therapies are recommended and include exercise programs. Clinical evaluations should include timed function tests including the six-minute walk test. Nusinersen, an antisense oligonucleotide, is approved for treatment of SMA in Europe and the USA. Real world data following commercial availability of the drug suggest efficacy in type 3 children and adult patients.
Prognosis
A wheelchair may be required during childhood for some patients (more commonly those with type 3a), whilst others retain the ability to walk into adulthood. Progression is slow and life expectancy is typically normal. Data on long-term outcomes with nusinersen treatment are not currently available.

                            Last update:
                            January 2021

                            - Expert reviewer(s):
                            Pr Eugenio MERCURI | EURO-NMD*

                                * European Reference Network


A rare, genetic proximal spinal muscular atrophy characterized by degeneration of alpha motor neurons in the anterior horns of the spinal cord and lower brain stem manifesting with adult onset, slowly progressive, mild proximal muscle weakness.

Summary:
Epidemiology
The average prevalence at birth of proximal spinal muscular atrophy (SMA) is estimated at 1/12,000 of which approximately 1% are type 4.
Clinical description
Disease onset is typically in the second or third decade of life. The muscle weakness predominantly affects the legs and hip muscles and then progresses to the shoulders and arms. Waddling gait is common. Finger trembling, fasciculation and calf hypertrophy may occur. The clinical picture is similar to that seen in SMA type 3 but the motor weakness is less severe. Cognition is unaffected.
Etiology
The disease is a result of degeneration and loss of the lower motor neurons in the spinal cord and the brain stem nuclei. Causal homozygous mutations/deletions in the SMN1 gene (5q12.2-q13.3) are responsible. SMN1 encodes the survival motor neuron protein (SMN) which is known to participate in critical pathways related to RNA processing and transport, and it is believed that motor neurons are particularly vulnerable to impairments in these processes. The disease is modified by the gene SMN2 (5q13.2), a homologous centromeric copy of SMN1 (5q13.1), the copy number of which is inversely correlated to disease severity.
Diagnostic methods
The diagnosis is based on clinical history and examination. In patients with SMN1 anomalies, the diagnosis may be confirmed by genetic testing. Electromyography and muscle biopsy may be necessary.
Differential diagnosis
Differential diagnoses include the amyotrophic lateral sclerosis, primary lateral sclerosis, Kennedy disease, myasthenia gravis, and carbohydrate metabolism disorders.
Antenatal diagnosis
Prenatal diagnosis is possible for families in which the mutations in the SMN1 gene have been identified.
Genetic counseling
The SMN1 gene deletions are transmitted in an autosomal recessive manner. Genetic counseling should be provided.
Management and treatment
Management is symptomatic, involves a multidisciplinary approach, and aims to improve quality of life. Physiotherapy and occupational therapies are recommended. Walking aids may be required as the disease progresses. Documenting functional status in SMA is important, since all patients show limitations in daily functioning. Nusinersen, an antisense oligonucleotide, is now approved for treatment of SMA in Europe and the USA. There is no data currently available concerning treatment in SMA type 4; however, it is believed that nusinersen may be most effective when started as soon as possible after diagnosis. Other clinical trials are ongoing to identify other potential treatments.
Prognosis
Affected individuals have a normal life expectancy. The greatest morbidity is on quality of life, with impairment of daily activities. Some patients may lose the ability to walk.

                            Last update:
                            January 2021

                            - Expert reviewer(s):
                            Pr Eugenio MERCURI | EURO-NMD*

                                * European Reference Network


A group of neuromuscular disorders characterized by progressive muscle weakness resulting from the degeneration and loss of the lower motor neurons in the spinal cord and the brain stem nuclei.

Summary:
Epidemiology
Prevalence is estimated at around 1/30,000.
Clinical description
Four subtypes have been defined according to the age of onset and severity of the disease: type 1 (SMA1), the most severe form, with onset before six months of age; type 2 (SMA2), with onset between 6 and 18 months of age, type 3 (SMA3), with onset between childhood and adolescence, and type 4 (SMA4), the least severe form, with adult onset (see these terms). All types are characterized by muscle weakness and atrophy of varying severity, particularly affecting the lower limbs and respiratory muscles. The weakness is almost always symmetric and progressive. Scoliosis, muscle retractions, and joint contractures may occur. Constipation and gastroesophageal reflux are frequent.
Etiology
Around 95% of cases of SMA are caused by homozygous deletions (either of exon 7, or of exons 7 and 8) in the SMN1 gene (5q12.2-q13.3) encoding the SMN (survival motor neuron) protein. A second SMN gene (SMN2; 5q13.2) has also been identified and contributes to the production of only 10% of the full-length SMN protein. However, although there is some variation, disease severity in SMA is inversely correlated with the number of copies of the SMN2 gene, with patients with three or four copies more frequently manifesting SMA3/4, rather than SMA1. Deletions of the NAIP (5q13.1) gene have also been identified and may play a role in modifying disease severity.
Diagnostic methods
Diagnosis is based on clinical history and examination and can be confirmed by genetic testing. Electromyography and muscle biopsy may also be performed.
Differential diagnosis
Differential diagnoses include amyotrophic lateral sclerosis, congenital muscular dystrophies, congenital myopathies, primary lateral sclerosis, myasthenia gravis, and carbohydrate metabolism disorders (see these terms).
Antenatal diagnosis
Antenatal diagnosis is feasible through molecular analysis of amniocytes or chorionic villus samples.
Genetic counseling
Transmission of SMN1 and NAIP deletions is autosomal recessive. Around 2% of cases are caused by de novo mutations. Genetic counseling should be offered to patients and their families.
Management and treatment
Clinical trials are ongoing to identify potential drug treatments for SMA, mainly targeted towards increasing the levels of the full length SMN protein. However, at present, management remains symptomatic, involving a multidisciplinary approach that aims to improve quality of life. Physiotherapy and occupational and respiratory therapies are necessary. Noninvasive ventilation and gastrostomy may be required. Antibiotic therapy is used in case of pulmonary infection. The scoliosis and joint manifestations may require surgical correction. Patients may require a wheelchair, or use a corset/back brace for support.
Prognosis
The prognosis depends on the severity of the disease, which generally correlates with the age of onset: earlier-onset forms are generally associated with a poor prognosis, whereas life expectancy may be close to normal in later-onset forms. Death may occur due to respiratory insufficiency and infections.

                            Last update:
                            July 2009

                            - Expert reviewer(s):
                            Dr Haluk TOPALOGLU


A rare genetic bone disorder characterized by ankylosis of the proximal interphalangeal joints, carpal and tarsal bone fusion, and conductive hearing loss in some patients.


A rare X-linked genomic disorder associated with interstitial chromosomal duplications at Xq28 encompassing the MECP2 gene. It is characterized in males by infantile onset hypotonia, severe global developmental delay, intellectual disability, progressive spasticity, seizures, gastrointestinal symptoms and recurrent respiratory infections. In females, the phenotype is more variable.

Summary:
Epidemiology
About 250 patients with cryptic duplications encompassing the MECP2 gene have been reported. The global prevalence of the disorder remains unknown but is estimated to be approximately 1% in males with unexplained X-linked mental retardation.
Clinical description
Clinical presentation is typically in the neonatal period with severe feeding difficulties, hypotonia and global development delay. Whilst affected children may acquire certain development milestones (independent sitting, walking, early speech skills and purposeful hand use) regression is commonly observed. Intellectual disability is moderate to severe in most affected males and speech is most often absent. Behavioral features often include hand stereotypies, bruxism, decreased sensitivity to pain, screaming spells and night laughing. Respiratory infections occur in over three-quarters of males and over one third of females. Seizures develop in over 50% of affected individuals by 9 years of age, and may be daily, weekly or monthly. Non-epileptic seizures have also been described. Progressive spasticity during childhood, predominantly of the lower limbs appears, affects more than 60% of males. Gastrointestinal symptoms may include, constipation, abdominal bloating and infantile gastro-esophageal reflux; gastrointestinal feeding may be required. Scoliosis, divergent strabismus, hypermetropia and facial dysmorphism (large ears, midface hypoplasia, teeth anomalies, open mouth appearance) are frequent. The phenotype and severity in females is highly variable and depends on the level of skewed X-inactivation.
Etiology
The syndrome is due to Xq28 duplications (< 4 Mb) involving the dosage-sensitive gene MECP2.
Diagnostic methods
Diagnosis is based on clinical features and is confirmed by array-comparative genomic hybridization techniques or gene-targeted duplication analysis.
Differential diagnosis
Differential diagnoses include Xq28 functional disomy due to cytogenetically visible rearrangements, int22h1/int22h2-mediated Xq28 duplication syndrome, Prader-Willi syndrome, Alpha thalassemia X-linked intellectual disability syndrome.
Antenatal diagnosis
Prenatal diagnosis is possible for families with a proband and is performed by cytogenetic testing including fluorescence in situ hybridization and/or DNA quantification methods.
Genetic counseling
The pattern of inheritance is X-linked. The recurrence risk is significant if the duplication encompassing the MECP2 gene is inherited from the mother, but very low if the duplication is de novo. There is full disease penetrance in males and variable penetrance in females due the level and type of X-inactivation.
Management and treatment
Management is multidisciplinary and symptomatic only, with special attention to prevent malnutrition and recurrent infections. Educational and rehabilitation support should be offered to all patients.
Prognosis
Malformations do not contribute significantly to the morbidity associated with this syndrome, but early death (before 25 years of age), mostly from respiratory infections, has been reported in 27-39% of patients and may be underestimated. The use of a wheelchair might be necessary in adulthood due to progressive spasticity. Neurological deterioration seems associated with seizures severity.

                            Last update:
                            May 2021

                            - Expert reviewer(s):
                            Dr Mathilde PUJALTE  - Pr Damien SANLAVILLE | ITHACA* - Pr Caroline SCHLUTH BOLARD

                                * European Reference Network


A rare, autosomal dominant neurological disorder due to truncation mutations of the prion protein gene PRNP (20p13) leading to deposition of prion protein amyloid. Onset is usually in the fourth decade of life and reported clinical manifestations include diarrhea, nausea, autonomic failure (areflexia, weakness), neurogenic bladder and urinary infections.


A rare lower urinary tract obstruction (LUTO) characterized by varying degrees of an enlarged urinary bladder, dilated ureters, hydronephrosis, and poorly contractile and disorganized detrusor and ureteral smooth muscle, in association with hypoplastic or absent midline abdominal skeletal musculature, and bilaterally undescended testes in males.

Summary:
Epidemiology
Data on prevalence is limited. Birth prevalence is estimated in Canada and the United states at 1/29,000 and 1/26,500, respectively; 95% of cases occur in males.
Clinical description
The spectrum ranges from mildly affected individuals to lethality. Prune belly syndrome (PBS) often presents antenatally on routine ultrasound with oligohydramnios and a very large, distended bladder, mild to severe bilateral hydroureteronephrosis, fetal ascites and, occasionally, renal dysplasia and a patent urachus. Other anomalies include cryptorchidism, pulmonary hypoplasia, club foot and features of Potter sequence. The syndrome is associated with pulmonary, skeletal, cardiac, and gastrointestinal defects and may be associated with atresia of the urethra. Newborns present with a wrinkled abdomen that later develops a 'pot belly' appearance. There is a predisposition to urinary tract infections due to incomplete bladder emptying in children.
Etiology
Whilst the exact mechanism is still unknown, pathogenesis is mainly related to urethral obstruction or mesodermal developmental defect. Urethral obstruction early in development causes massive bladder distention and urinary ascites that leads to underdevelopment of the abdominal wall musculature and failure of testicular descent. The impaired elimination of urine from the bladder leads to oligohydramnios and, depending on severity, lung hypoplasia and Potter sequence, as well as a profound and lifelong effect on kidney, ureteral and bladder function. Whilst most cases are sporadic, a few cases of siblings have been linked to mutations in CHRM3 (1q43). Several candidate genes have been suggested, but there is limited evidence to support them as a monogenic cause. Copy number variations may cause unexplained genetic cases of PBS.
Diagnostic methods
Diagnosis is usually antenatal. Postnatal diagnosis is based on characteristic clinical findings, assessment of pulmonary function, renal function, ultrasound and voiding cystourethrogram.
Differential diagnosis
Differential diagnoses in utero include megacystis/megaureter, megacystis microcolon intestinal hypoperistalsis syndrome or posterior urethral valves. PBS has also been reported in trisomy 13, 18, 21 and large chromosome 6 deletions.
Antenatal diagnosis
Antenatal diagnosis is based on ultrasound findings. As with all forms of LUTO, counseling should include the spectrum of postatal manifestations.
Genetic counseling
The majority of the cases are sporadic. Autosomal recessive inheritance is reported for CHRM3. Autosomal dominant and X linked inheritance havs been suggested in other familial cases.
Management and treatment
Sonographic monitoring of the urinary tract and amniotic fluid volume is required throughout pregnancy. Early decompression of severe bladder outlet obstruction that contributes to oligohydramnios is advised. Antibiotic prophylaxis is started at birth. Where possible patients are managed conservatively. Indication for early surgery is only mandatory when urethral atresia is present, and when there is a decline in renal function or failure to prevent or eradicate infection using conservative measures . Further treatment may include bilateral orchidopexies, abdominoplasty in addition to potential urologic reconstructive surgery. Transplantation is indicated for renal failure.
Prognosis
The postnatal course of PBS infants is dictated by renal function and by their co-morbidities, and the risk is stratified accordingly. 20% of patients are at a high risk of severe renal dysfunction and pulmonary hypoplasia; another 40% patients have the classic features of PBS with prognosis related to the degree of renal dysplasia, and for who there is a 4% risk of acute renal failure. 40% of patients are low risk with normal renal function and mild phenotypic features of PBS. Prematurity is common and engenders cardiovascular and pulmonary problems. Perinatal mortality rates for PBS are quoted between 10 and 25%.

                            Last update:
                            November 2020

                            - Expert reviewer(s):
                            Dr Giovanni MOSIELLO | EUROGEN*

                                * European Reference Network


A rare genetic syndromic intellectual disability characterized by infantile onset of global developmental delay and profound intellectual disability in association with a heterogeneous spectrum of manifestations, such as features of lower motor neuron disease, hypotonia, spasticity, contractures, seizures, respiratory insufficiency, and optic atrophy, among others. Dysmorphic craniofacial features include microcephaly, tall forehead, bitemporal narrowing, flat nasal bridge, low-set ears, and high-arched palate. Brain imaging may show cerebral and cerebellar atrophy, delayed myelination, and thin corpus callosum.


Pruritic urticarial papules and plaques of pregnancy

A rare skin disease characterized by urticarial papules and plaques with severe pruritus mainly on the abdomen, buttocks, and proximal thighs. The condition usually develops during the third trimester of the first pregnancy, although presentation in the postpartum period, which may also feature other types of skin lesions, has been described in some cases. The symptoms generally resolve within few weeks.


A rare neoplastic disease characterized by the presence of a benign or malignant, pelvic or abdominal tumor (other than ovarian fibroma or fibroma-like and localized outside of the ovaries, fallopian tubes, and broad ligaments) associated with hydrothorax and ascites that resolve after tumor resection. Patients usually present with dyspnea, pelvic mass with or without a tender, distended abdomen and/or weight loss.


A bleeding disorder characterized by mild to moderate mucocutaneous bleeding, which becomes more pronounced during pregnancy or following ingestion of drugs that have anti-platelet activity. This disease is due to hyperresponsive platelets, resulting in thrombocytopenia.


Pseudoachondroplasia is characterized by severe growth deficiency and deformations such as bow legs and hyperlordosis.

Summary:
Epidemiology
Prevalence is estimated at around 1/60,000.
Clinical description
The disorder is usually discovered during the second year of life with the onset of slow growth and walking difficulties. The short stature becomes more prominent with age and the hands and feet appear short and wide. Joint laxity is a general feature, but predominantly affects the hands. Defective epiphyseal growth causes early arthrosis. The limb deformation is caused by metaphyseal lesions.
Etiology
The disorder is caused by small mutations or deletions in the COMP gene (19p13.1) coding for the cartilage oligomeric matrix protein.
Diagnostic methods
Diagnosis is made on the basis of epiphyseal and metaphyseal anomalies detected on radiographs during the second year of life.
Differential diagnosis
The principle differential diagnosis is achondroplasia (see this term), but the craniofacial anomalies present in this disorder are absent in patients with pseudoachondroplasia and radiographic findings differ significantly. Forms of multiple epiphyseal dysplasia (see these terms) may also be included in the differential diagnosis.
Antenatal diagnosis
Prenatal diagnosis is feasible if the mutation has been detected in an affected parent.
Genetic counseling
Transmission is autosomal dominant, but most isolated cases are due to de novo mutations. Genetic counseling may be proposed and the recurrence risk is 50%.
Management and treatment
Treatment is based on physiotherapy, management of the spinal deformation and corrective orthopedic surgery. Intensive physical activity should be avoided. The limb deformation should be corrected surgically at the end of the growth period.
Prognosis
The final height prognosis is variable but the short stature may be moderately severe.

                            Last update:
                            November 2008

                            - Expert reviewer(s):
                            Dr Martine LE MERRER


Pseudoaminopterin syndrome is a developmental anomalies syndrome that resembles the aminopterin embryopathy (see this term) without history of fetal exposure to aminopterin. It is characterized by skull (craniosynostosis and poorly mineralized cranial vault), dysmorphic (ocular hypertelorism, palpebral fissure anomalies, micrognathia cleft lip and/or high arched palate and small and low set/rotated ears) and limb (brachydactyly, syndactyly and clinodactyly) anomalies, associated with mild-to-moderate intellectual deficit and short stature.


Pseudodiastrophic dysplasia is characterized by rhizomelic shortening of the limbs and severe clubfoot deformity, in association with elbow and proximal interphalangeal joint dislocations, platyspondyly, and scoliosis. It has been described in about 10 patients. An autosomal recessive inheritance has been suggested. Pseudodiastrophic dysplasia differs from diastrophic dysplasia (see this term) on the basis of clinical, radiographic, and histopathologic findings. Clubfoot can be treated by surgical therapy, and neonatal contractures and scoliosis can be relieved by physical therapy. Several of the reported patients died in the neonatal period or during infancy.