X-linked mendelian susceptibility to mycobacterial diseases

X-linked (XR) Mendelian susceptibility to mycobacterial diseases (MSMD; see this term) describes a rare group of immunodeficiencies due to specific mutations in the inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma (IKBKG) or the cytochrome b-245, beta polypeptide (CYBB) genes. They are characterized by mycobacterial infections, occuring in males.

Summary:
Epidemiology
The prevalence is unknown. Six male patients have been reported with XR-MSMD deficiency due to IKBKG mutations and seven male patients have been reported with XR-MSMD deficiency due to CYBB mutations.
Clinical description
XR-MSMD due to IKBKG deficiency affects otherwise healthy male patients. The most common infections seen are Mycobacterium avium, Mycobacterium bovis  BCG and Mycobacterium tuberculosis. An invasive Haemophilus influenza type b infection was reported in one patient. In two cases, mild signs of anhidrotic ectodermal dysplasia (AED; see this term), limited to conical deciduous incisors, were observed. Patients with XR-MSMD due to CYBB deficiency present with disseminated tuberculosis mycobacterial disease (such as BCG or M. tuberculosis). They do not suffer from any other infectious diseases.
Etiology
XR-MSMD is due to hemizygous mutations in the IKBKG or CYBB genes. IKBKG (Xq28) encodes the inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma. This mutation causes defects in T-cell dependant IL-12 production and consequently IFN-gamma production. The mutations disturb the plasticity of the leucine zipper domain (LDZ) helix of IKBKG interfering selectively with the CD40-NEMO-NFkB signaling pathway. These hypomorphic mutations are associated with impaired NF-kB activation of c-Rel containing proteins in response to CD40. The CYBB gene (Xp21.1) encodes the gp91-phox subunit of the phagocyte NADPH oxydase. These mutations do not impair the respiratory burst in granulocytes and monocytes, but they impair macrophages and B-cell lines selectively.
Diagnostic methods
Diagnosis is made by laboratory analysis. IFN-gamma, IL-12p40 and IL-12p70 levels can be measured by ELISA. Low levels of IFN-gamma and IL-12 production by the patients' mononuclear cells upon phytohemagglutinin (PHA) are detected in those with an IKBKG mutation. In addition, an impaired IL-12 production by monocytes upon PHA stimulation by activated T cells is shown. Impaired NADPH activity is demonstrated in vitro in macrophages and B-cell lines in those with a CYBB mutation. A mutational analysis is necessary to identify the exact causative genes involved allowing for the implementation of a specific treatment plan.
Differential diagnosis
Differential diagnoses include other diseases caused by IKBKG mutations such as EDA with immunodeficiency (see this term). It is important to exclude the diagnosis of chronic granulomatous disease (CGD; see this term) caused by CYBB mutations. Other genetic forms of MSMD should also be excluded.
Antenatal diagnosis
This immunodeficiency is not severe and antenatal diagnosis is not necessary.
Genetic counseling
The occurrence of mycobacterial diseases in maternally-related males suggests an X-linked recessive form of MSMD. Genetic counseling is possible when a known mutation is present in the family.
Management and treatment
BCG vaccination should be avoided in those with a known XR-MSMD mutation. Treatment usually involves IFN-gamma therapy in addition to antibiotics.
Prognosis
The prognosis is good.

                            Last update:
                            February 2013

                            - Expert reviewer(s):
                            Dr Jacinta BUSTAMANTE  - Pr Jean-Laurent CASANOVA


X-linked microcephaly-growth retardation-prognathism-cryptorchidism syndrome is a rare syndromic intellectual disability characterized by hypotonia, microcephaly, severe developmental delay, seizures, intellectual disability, growth retardation, cardiac septal defects, cryptorchidism, hypospadias, and dysmorphic features - prominent ears, prognathism, thin upper lip, dental crowding.


X-linked myopathy with excessive autophagy is a childhood-onset X-linked myopathy characterised by slow progression of muscle weakness and unique histopathological findings.

Summary:
Epidemiology
It has been described in about fifteen families.
Clinical description
The first manifestations appear typically in children around 5-10 years of age and include difficulty climbing stairs and running.
Etiology
The Xq28 locus has been associated with the disease.
Diagnostic methods
Muscle fibres are not necrotic but they show excessive autophagic activity and exocytosis of the phagocytosed material.
Genetic counseling
Transmission is X-linked recessive; female carriers are asymptomatic or only mildly affected.
Prognosis
Progression is very slow, longevity is not altered. Many patients need a wheelchair in their 6th decade of life.

                            Last update:
                            June 2006


X-linked myopathy with postural muscle atrophy

A rare progressive muscular dystrophy characterized by an adult-onset scapulo-axio-peroneal myopathy. Clinical presentation includes shoulder girdle atrophy, scapular winging, axial muscular atrophy of postural muscles combined with a generalized hypertrophy. Typically, neck rigidity, rigid spine, Achilles tendon shortening, and respiratory insufficiency later in disease course are present.


X-linked myotubular myopathy-abnormal genitalia syndrome is a rare chromosomal anomaly, partial deletion of the long arm of chromosome X, characterized by a combination of clinical manifestations of X-linked myotubular myopathy and a 46,XY disorder of sex development. Patients present with severe form of congenital myopathy and abnormal male genitalia.


X-linked neurodegenerative syndrome, Bertini type

An X-linked syndromic intellectual disability characterized by congenital ataxia and generalized hypotonia, global developmental delay with intellectual disability, myoclonic encephalopathy, progressive neurological deterioration, macular degeneration, and recurrent bronchopulmonary infections.


X-linked neurodegenerative syndrome, Hamel type

An X-linked syndromic intellectual disability characterized by a few months of normal development, followed by progressive neurodegenerative course with gradual loss of vision, development of spastic tetraplegia, convulsions, microcephaly, failure to thrive, and early death.


X-linked non progressive cerebellar ataxia is a rare hereditary ataxia characterized by delayed early motor development, severe neonatal hypotonia, non-progressive ataxia and slow eye movements, presenting normal cognitive abilities and absence of pyramidal signs. Frequently patients also manifest intention tremor, mild dysphagia, and dysarthria. Brain MRI reveals global cerebellar atrophy with absence of other malformations or degenerations of the central and peripheral nervous systems.


A rare, genetic, primary bone dysplasia with decreased bone density disorder characterized by childhood-onset osteoporosis associated with recurrent, multiple, osteoporotic, long bone fractures and/or vertebral compression fractures, significant height loss in adulthood, low bone mineral density scores, and otherwise no other abnormalities. Heterozygote females may be unaffected or have a milder phenotype.


A rare, genetic, neurological disorder characterized by parkinsonian features (including resting or action tremor, cogwheel rigidity, hypomimia and bradykinesia) associated with variably penetrant spasticity, hyperactive deep tendon reflexes and Babinski sign.


A rare X-linked cerebellar ataxia, characterized by a combination of upper and lower motor neuron signs, with an age of onset in the first or second decade, slow progression, and normal intelligence. Typical features of cerebellar dysfunction include gait and limb ataxia, intention tremor, dysmetria, dysdiadochokinesia, dysarthria, nystagmus, and hyperreflexia. Further phenotypic features are pes cavus, scoliosis, muscle atrophy, and peripheral sensory and motor nerve abnormalities.


X-linked recessive ocular albinism (XLOA) is a rare disorder characterized by ocular hypopigmentation, foveal hypoplasia, nystagmus, photodysphoria, and reduced visual acuity in males.

Summary:
Epidemiology
The estimated birth prevalence is from 1/60,000 to 1/150,000 live male births.
Clinical description
Nystagmus, sometimes associated with head nodding, usually develops in affected males within the first 3 months of life. It can diminish with time but rarely completely disappears. Best-corrected visual acuity is usually between 20/40 and 20/200, and often improves during childhood. Most patients have photodysphoria, strabismus and absent or reduced stereoacuity. Ocular findings include iris translucency, foveal hypoplasia, hypopigmentation of the fundus and excessive crossing of the nerves from the eye to the brain. Some males have irregular hypopigmented spots on the extremities, but they escape clinical notice. Carrier women, in the vast majority of cases, are asymptomatic. XLOA is less severe in those with dark constitutive skin pigmentation than those who are more lightly pigmented.
Etiology
XLOA is caused by a mutation in the G-protein coupled receptor 143 GPR143 gene located at Xp22.3 that encodes for a membrane glycoprotein found in melanosomes. The few cases where females displayed the same phenotypes as males are thought to have been due to either a homozygous mutation in GPR143, partial monosomy of the X chromosome or X-chromosome inactivation.
Diagnostic methods
Diagnosis is based on the presence of characteristic ocular findings and molecular genetic testing. A family history consistent with X-linked inheritance provides further evidence of XLOA. A GPR143 mutation is found in 90% of affected males. Melanin macroglobules (macromelanosomes) are usually found on skin biopsy but are not pathognomonic. Female obligate carriers are identified by finding patchy mottling or streaking of pigment in the midperipheral retina (pigmentary mosaicism), representing random X inactivation.
Differential diagnosis
Differential diagnoses include various types of oculocutaneous albinism (OCA), blue cone monochromatism, congenital stationary night blindness, ocular albinism with sensorineural deafness, cone dystrophy with supernormal rod response, Leber congenital amaurosis, complete and incomplete achromatopsia, X-linked congenital nystagmus (see these terms), and autosomal dominant infantile nystagmus syndrome.
Antenatal diagnosis
Prenatal testing can be performed when women are known carriers of the GPR143 mutation, using chorionic villus sampling or amniocentesis. Preimplantation genetic diagnosis may be available.
Genetic counseling
XLOA is inherited in an X-linked recessive manner so genetic counseling is possible. Affected males do not transmit the disease causing mutation to their sons but all of their daughters become carriers. Female carriers have a 50% risk of transmitting the mutation to their offspring, whether male or female; however, only sons with the mutation will display the disease. Carrier testing can be offered to at-risk individuals.
Management and treatment
Annual ophthalmologic examinations are recommended for patients under the age of 16, and after that every 2-3 years. Treatment consists of visual correction with eyeglasses or contact lenses. Sunglasses, photochromic lenses or special filter glasses can help to relieve photodysphoria. Extraocular muscle surgery can be performed to restore alignment and/or improve a head posture that is compensatory for nystagmus. Visual aids, changing electronic font size, and special education for the visually impaired may be needed. Patients should wear hats/caps, clothing, and sunscreen on sun-exposed skin to prevent burning and skin cancer.
Prognosis
XLOA is not life threatening. The reduced visual acuity and the social consequences of albinism can however have an impact on a patient's daily life.

                            Last update:
                            April 2013

                            - Expert reviewer(s):
                             Gail SUMMERS


X-linked reticulate pigmentary disorder is an extremely rare skin disease described in only four families to date and characterized in males by diffuse reticulate brown hyperpigmentated skin lesions developing in early childhood and a variety of systemic manifestations (recurrent pneumonia, corneal opacification, gastrointestinal inflammation, urethral stricture, failure to thrive, hypohidrosis, digital clubbing, and unruly hair and flared eyebrows), while in females, there is only cutaneous involvement with the development in early childhood of localized brown hyperpigmented skin lesions following the lines of Blaschko. This disease was first considered as a cutaneous amyloidosis, but amyloid deposits are an inconstant feature.


A rare genetic eye disease characterized by abnormal proliferation of retinal tissue resulting in the formation of retinal folds, thereby causing gliosis and, clinically, variable degrees of visual impairment. No clinical findings other than those associated with the eyes have been demonstrated.


A rare disorder involving multiple structure of the eye characterized by reduced visual acuity in males due to juvenile macular degeneration. Clinical features such as vitreous hemorrhage, retinal detachment, and neovascular glaucoma can be observed in advanced stages.

Summary:
Epidemiology
X-linked retinoschisis prevalence is estimated to range between 1/5,000-1/25,000 males worldwide.
Clinical description
XLRS is a symmetrical bilateral macular disorder with onset in the first decade of life. It manifests with poor vision and reading difficulties. In severe cases, nystagmus may also be observed. Severe cases involve full-thickness retinal detachment that leads to impaired vision or blindness. In more advanced stages of the disease, vitreous hemorrhage, retinal detachment, and neovascular glaucoma, which may induce severe loss of vision, can be seen. Correlation exists between visual acuity, patient age, and OCT features. There is clinical variability. Female carriers rarely have any vision impairment.
Etiology
The disease is caused by mutations on the RS1 gene (Xp22.2-p22.1), including missense, nonsense, frameshift, and splice site mutations, deletions, and insertions. RS1 codes for retinoschisin, an adhesive protein, localized in photoreceptors and bipolar cells, and secreted in the extracellular matrix. In the adult retina, retinoschisin is essential for maintaining the structural and functional integrity of the retina and participates in molecular pathways at the photoreceptor bipolar synapse.
Diagnostic methods
The diagnosis of XLRS can be made clinically, based on fundus appearance. Fundus examination shows microcystic changes of the macular region of the retina and areas of splitting within the nerve fiber layer, or schisis (spoked-wheel pattern), and vitreous veils. Electroretinogram (ERG) usually shows generalized cone system dysfunction with a reduction in the amplitude of the beta-wave and a relative preservation of the negative alpha-wave in scotopic ERG (electronegative rods and mixed ERG) and a normal photopic ERG. Optical coherence tomography (OCT) shows schisis areas in the macular region. There is also a family history consistent with X-linked inheritance. Molecular genetic analysis by direct sequencing of the RS1 gene detects mutations in approximately 90% of patients. NGS panels for Inherited Retinal dystrophies, including the RS1 gene represent also an appropriate approach.
Differential diagnosis
Differential diagnosis includes retinitis pigmentosa and Goldmann-Favre syndrome. The presence of an autosomal recessive inheritance, severe nyctalopia, pigmentary retinopathy, and reduced alpha- and beta-waves on the electroretinogram (ERG) help to differentiate Goldmann-Favre syndrome from XLRS.
Genetic counseling
There are more than 290 mutations described in RS1, most missense (~51%). Nonsense, splicing, small indels and CNVs variants have also been reported. XLRS is inherited in an X-linked manner, with a carrier female having a 50% risk of transmitting the mutation to her offspring. Carrier testing for at-risk female relatives and prenatal diagnosis for pregnancies at increased risk are possible if a RS1 mutation is identified in an affected family member.
Management and treatment
Management includes periodic ophthalmologic examination to monitor progression of XLRS. Additionally, patients are informed about possible ophthalmic complications that can be surgically treated (i.e., retinal detachment, vitreous haemorrhage, cataracts or strabismus). Therefore, patient education and close follow-up are the only clinical alternatives to early identification and treatment of vision-threatening complications.
Prognosis
In XLRS, vision slowly decreases until adolescence, and then in most patients remains relatively stable during young adulthood. The disease does not progress again until the fourth or fifth decade of life, when a significant decline in visual acuity typically occurs.

                            Last update:
                            August 2020

                            - Expert reviewer(s):
                            Dr Carmen AYUSO  - Dr Marta CORTON PÉREZ  -  Marta DEL POZO VALERO  - Dr José María MILLÁN SALVADOR


X-linked scapuloperoneal muscular dystrophy

A rare, genetic, muscular dystrophy disease characterized by the co-occurrence of late onset scapular and peroneal muscle weakness, principally manifesting with distal lower limb and proximal upper limb weakness and scapular winging.


X-linked severe congenital neutropenia is an immunodeficiency syndrome characterized by recurrent major bacterial infections, severe congenital neutropenia, and monocytopenia. It has been described in five males spanning three generations of one family. It is transmitted as an X-linked recessive trait and is caused by mutations in the WAS gene, encoding the WASP protein.


X-linked sideroblastic anemia and spinocerebellar ataxia

A rare syndromic, inherited form of sideroblastic anemia characterized by mild to moderate anemia (with hypochromia and microcytosis) and early-onset, non- or slowly progressive spinocerebellar ataxia.

Summary:
Epidemiology
X-linked sideroblastic anemia and ataxia (XLSA-A) prevalence is unknown. Less than 20 genetically confirmed patients have been reported to date.
Clinical description
.XLSA-A usually presents before the age of 3 years. Anemia is usually asymptomatic. In males, spinocerebellar symptoms are apparent in childhood and can include delayed walking, predominantly truncal ataxia, dysmetria and dysdiadochokinesis. Dysarthria and intention tremor are sometimes present. Ataxia may improve over time, but in the fifth to sixth decade of life a slow deterioration of walking is noted. Upper motor neuron signs in the legs such as equivocal or extensor plantar responses, brisk deep tendon reflexes and unsustained ankle clonus are sometimes present. Strabismus, as well as mild learning disability and depression, have also been reported in some, but intellectual abilities are generally within the normal range. Hepatic and systemic iron overload does not occur. Females are clinically asymptomatic.
Etiology
XLSA-A is caused by mutations in the ABCB7 gene (Xq13.3), encoding a mitochondrial ATP-binding cassette (ABC) transporter protein, which plays a role in heme production and iron homeostasis. A pathogenic variant in this gene alters the availability of reduced iron and therefore disrupts heme biosynthesis. The ABCB7 gene is highly expressed in both the bone marrow and the cerebellum, which may explain ataxia.
Diagnostic methods
Diagnosis is based on the presence of characteristic neurological and blood test findings. Mild to moderate hypochromic, microcytic anemia is noted in all males and both whole blood total erythrocyte protoporphyrin (TEP) and zinc erythrocyte protoporphyrin (ZnEP) are elevated. Bone marrow examination demonstrates the presence of increased iron stores with ring sideroblasts and peripheral blood smear reveals Pappenheimer bodies. In the majority of cases magnetic resonance imaging (MRI) shows cerebellar atrophy/hypoplasia. Female carriers display hematological abnormalities. Molecular genetic testing identifies a ABCB7 gene variation, confirming the diagnosis.
Differential diagnosis
The main differential diagnosis includes other forms/causes of ataxia that typically present before the age of 3 years such as ataxia-telangiectasia, infantile-onset spinocerebellar ataxia, congenital disorder of glycosylation, and cerebellar malformations (e.g. Dandy-Walker malformation). Ataxia with vitamin E deficiency, Friedreich ataxia, ataxia - oculomotor apraxia type 1 and 2, and X linked sideroblastic anemia , the most common form of congenital sideroblastic anemia (without ataxia), should also be excluded.
Antenatal diagnosis
Prenatal testing is possible in families with a known ABCB7 mutation.
Genetic counseling
The pattern of inheritance is X-linked recessive and gentic counselling should be offerend to affected families. Where the female is a carrier, the risk to male offspring inheriting the disease is 50%, female offspring have a 50% risk of being carriers. Where a male is affected, female offspring are obligate carriers, and male offspring do not inherit the pathogenic mutation.
Management and treatment
There is no cure for XLSA-A and treatment is symptomatic. Anemia does not require treatment. Early physical therapy may aid in the acquisition of gross motor skills. Ankle fixation orthoses and walkers may be required to aid with mobility. Weighted eating utensils promote independent skills in children. Speech therapy is recommended for those with dysarthria. Crutches or a wheelchair may be needed by some patients.
Prognosis
While prognosis information is limited due to very few existing reports, XLSA-A does not appear to have a significant impact on life expectancy. Quality of life, however, can be significantly affected.

                            Last update:
                            June 2020

                            - Expert reviewer(s):
                            Pr Soumeya BEKRI


X-linked sideroblastic anemia is a constitutional microcytic, hypochromic anemia of varying severity that is clinically characterized by manifestations of anemia and iron overload and that may respond to treatment with pyridoxine and folic acid.

Summary:
Epidemiology
Prevalence is unknown. Around 200 cases and fewer than 100 unrelated probands are described in the literature.
Clinical description
The anemia can present at any age from birth to the 9th decade. Some patients are asymptomatic and are detected incidentally by hematological screening or through a family study. Clinical features are those of anemia and/or iron overload such as pallor, fatigue, weakness. Breathlessness, mild splenomegaly, cardiac problems, abnormal liver function, hyperglycemia, glucose intolerance and skin hyperpigmentation are seen more rarely.
Etiology
SA is due to inherited or de novo mutations in the ALAS2 gene (Xp11.21) encoding the erythroid form of delta amino levulinic acid synthase (ALAS2), which altered function leads to impaired heme synthesis. The increased ineffective and expanded erythropoiesis leads to increased absorption of dietary iron and a risk of iron overload. Female carriers are usually unaffected, however, one quarter of probands are female who have X-chromosome inactivation skewed against the unaffected allele and almost half of the female probands have macrocytic rather than microcytic red blood cells due to the heterozygous inheritance of a severe/null allele.
Diagnostic methods
Diagnosis requires a full blood and reticulocyte count, measurement of iron stores, exclusion of thalassemia as a cause, bone marrow aspirate showing ringed sideroblasts, and mutation analysis of the ALAS2 gene.
Differential diagnosis
The differential diagnosis should include other types of inherited sideroblastic anemia and in case of macrocytic red cells in females also acquired myelodysplasia (refractory anemia with ringed sideroblasts or RARS (see these terms). Most female carriers show some evidence of microcytic, hypochromic red blood cells but hematological parameters cannot be relied upon for genetic counseling purposes and DNA analysis is required
Antenatal diagnosis
Prenatal diagnosis is rarely indicated or requested, but should be offered in case of family history.
Genetic counseling
Genetic counseling for the family of affected individuals is recommended, as early diagnosis in a child may be of great benefit for treatment of anemia and prevention of iron overload, the main cause of early death in the past.
Management and treatment
Treatment is supportive and involves hematological monitoring, the surveillance of iron levels, lifetime pyridoxine supplementation in those who respond and folic acid supplementation. Pyridoxine response varies in degree and is rarely complete. Prophylactic occasional phlebotomy can be performed to prevent iron overload, if anemia is very mild or corrected by pyridoxine. If iron overload has already developed, phlebotomy, iron chelation or a combination of both can be used to normalize iron levels. In some cases iron depletion may simultaneously increase the hemoglobin level. Blood transfusions may be needed on occasion but are only required on a regular basis for those most severely affected.
Prognosis
Prognosis is variable but for patients with pyridoxine-responsive anemia whose iron stores are kept low, normal life expectancy should be achievable

                            Last update:
                            July 2013

                            - Expert reviewer(s):
                            Pr Clara CAMASCHELLA


X-linked skeletal dysplasia-intellectual disability syndrome

A rare genetic syndrome characterized by skeletal anomalies, including short stature, ridging of the metopic suture, a fusion of cervical vertebrae, thoracic hemivertebrae, scoliosis, sacral hypoplasia, short middle phalanges. Patients also had a moderate intellectual disability and abducens palsies. Glucose intolerance and imperforate anus were also described.


A complex, hereditary, spastic paraplegia characterized by delayed motor development, spasticity, and inability to walk, later progressing to quadriplegia, motor aphasia, bowel and bladder dysfunction. Patients also present with vision problems and mild intellectual disability. The disease affects only males.


X-linked spastic paraplegia type 34 is a pure form of hereditary spastic paraplegia characterized by late childhood- to early adulthood-onset of slowly progressive spastic paraplegia with spastic gait and lower limb hyperreflexia, brisk tendon reflexes and ankle clonus. Lower limb pain and reduced lower limb vibratory sense is also reported in some older adult patients.


X-linked spasticity-intellectual disability-epilepsy syndrome

A rare ARX-related epileptic encephalopathy characterized by infantile onset of myoclonic epilepsy with generalized spasticity, severe global developmental delay, and moderate to profound intellectual disability. Obligate female carriers show subtle, generalized hyperreflexia. Late onset progressive spastic ataxia has also been reported.


X-linked spinocerebellar ataxia type 3 is a form of spinocerebellar degeneration characterized by onset in infancy of hypotonia, ataxia, sensorineural deafness, developmental delay, esotropia, and optic atrophy, and by a progressive course leading to death in childhood. It has been described one family with at least six affected males from five different sibships (connected through carrier females). It is transmitted as an X-linked recessive trait.


A rare X-linked spinocerebellar ataxia characterized by ataxia, pyramidal tract signs and adult-onset dementia. The disease manifests during early childhood with delayed walking and tremor. The pyramidal signs appear progressively and by adulthood memory problems and dementia gradually become apparent.


A rare, genetic primary bone dysplasia disorder characterized by disproportionate short stature with mesomelic short limbs, leg bowing, lumbar lordosis, brachydactyly, joint laxity and a waddling gait. Radiographs show platyspondyly with central protrusion of anterior vertebral bodies, kyphotic angulation and very short long bones with dysplastic epiphyses and flarred, irregular, cupped metaphyses.


Type I xanthinuria, a type of classical xanthinuria (see this term), is a rare autosomal recessive disorder of purine metabolism (see this term) characterized by the isolated deficiency of xanthine dehydrogenase, causing hyperxanthinemia with low or absent uric acid and xanthinuria, leading to urolithiasis, hematuria, renal colic and urinary tract infections, while some patients are asymptomatic and others suffer from kidney failure. Less common manifestations include arthropathy, myopathy and duodenal ulcer.


Type II xanthinuria, a type of classical xanthinuria (see this term), is a rare autosomal recessive disorder of purine metabolism (see this term) characterized by the deficiency of both xanthine dehydrogenase and aldehyde oxidase, leading to the formation of urinary xanthine urolithiasis and leading, in some patients, to kidney failure. Other less common manifestations include arthropathy, myopathy and duodenal ulcer, while some patients remain asymptomatic.


A rare, systemic disease characterized by normolipidemic mucocutaneous xanthomatosis with histiocytic cells proliferation and secondary deposition of lipid in the dermis. Clinically, multiple, grouped, coalescent, yellowish red to brown papulonodular lesions in the skin and mucous membranes are present. Less often internal organs are affected, in particular pituitary gland and/or hypothalamus. Patients present with characteristic mucocutaneous lesions, diabetes insipidus, dysphagia, dyspnea, hoarseness of voice, and blurred vision.


Xeroderma pigmentosum variant is a milder subtype of xeroderma pigmentosum (XP; see this term), a rare genetic photodermatosis characterized by severe sun sensitivity and an increased risk of skin cancer.

Summary:
Epidemiology
It is observed in approximately 20% of XP patients and approximately 50 cases have been reported in the literature.
Clinical description
It is often diagnosed in the late teens or early 20s. Patients present with skin lesions, generally at the sun-exposed parts of the body which develop into skin cancer at about 20-30 years of age with a 1,000 times higher frequency than that of the general population. No neurological manifestations are observed.
Etiology
The disease is due to mutations in the POLH gene (XPV) (6p21.1-p12) encoding the error-prone DNA-polymerase eta (pol-eta) which performs trans-lesion synthesis past ultraviolet (UV) photoproducts.
Genetic counseling
Transmission is autosomal recessive.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Hiva FASSIHI


Xeroderma pigmentosum-Cockayne syndrome complex

Xeroderma pigmentosum/Cockayne syndrome complex (XP/CS complex) is characterized by the cutaneous features of xeroderma pigmentosum (XP) (see this term) together with the systemic and neurological features of Cockayne syndrome (CS; see this term).

Summary:
Epidemiology
Less than 30 cases have been described to date.
Clinical description
The disease manifests during infancy. Patients present with cutaneous UV-sensitive lesions that generally develop into skin cancer, and also develop characteristic CS manifestations such as microcephaly, hydrocephalus, cachexia, premature aging, dwarfism, skin atrophy, arteriosclerosis, progressive hearing loss, cognitive deficit, spasticity, ataxia, pigmentary retinopathy and optic atrophy. In contrast to the neurological abnormalities of XP which are predominantly secondary to neuronal degeneration, in XP/CS complex, dysmyelination typical of CS is observed.
Etiology
Affected individuals have mutations in one of three XP genes: ERCC3 (2q21), ERCC2 (19q13.3), or ERCC5 (13q22-q34). Recently, one patient with XP/CS complex and additional features of Fanconi anemia (see this term) was reported with a mutation in the ERCC4 gene (16p13.3).
Genetic counseling
Transmission is autosomal recessive and genetic counseling is possible.

                            Last update:
                            March 2014

                            - Expert reviewer(s):
                            Dr Hiva FASSIHI


Xeroderma pigmentosum (XP) is a rare genodermatosis characterized by extreme sensitivity to ultraviolet (UV)-induced changes in the skin and eyes, and multiple skin cancers. It is subdivided into 8 complementation groups, according to the affected gene: classical XP (XPA to XPG) and XP variant (XPV) (see these terms).

Summary:
Epidemiology
It has an estimated prevalence of 1/1,000,000 in the USA and Europe, with higher figures in other countries (e.g. Japan, North Africa and Pakistan), particularly in communities with a high degree of consanguinity.
Clinical description
The severity of the clinical manifestations and the age of onset are extremely variable and are in part dependent on exposure to sunlight and the complementation group. Approximately 50% of affected individuals have acute sun sensitivity from the first few months of life, presenting with severe sunburn and/or persistent erythema which takes weeks to resolve. Others do not show any sunburn reaction and gradually develop marked freckling at sun exposed sites. Individuals have dry skin and hypo- or hyperpigmented lesions. There is a greater than 10,000-fold increased risk of non-melanoma skin cancers, and a 2,000 fold increased risk of melanoma under the age of 20 when compared to the general population. Patients with classical XP develop skin cancer generally before the age of 20, while patients with XP variant start to develop skin cancer at about 20-30 years of age. Ocular abnormalities include keratitis resulting in corneal opacification and vascularization. Photophobia is common. Ocular squamous cell carcinoma and melanoma are common. Neurologic abnormalities of varying severity have been reported in about 30% of cases. These include acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, spasticity, ataxia, seizures and progressive cognitive impairment. De Sanctis-Cacchione syndrome is a term that was originally attributed to XP cases with severe neurological abnormalities but it is no longer in general use.
Etiology
XP is caused by mutations in 8 genes involved in DNA repair. Seven of these genes, XPA to XPG (ERCC5), are involved in nucleotide excision repair (NER). XPV, or POLH, encodes the DNA polymerase eta, which is required to replicate DNA containing UV-induced damage.
Diagnostic methods
Diagnosis is based on clinical symptoms and is confirmed by cellular tests for defective DNA repair (e.g. unscheduled DNA synthesis (UDS) test in cultured skin fibroblasts) and UV hypersensitivity. Reduced UDS and hypersensitivity to UV-induced killing confirm the diagnosis of XP. A normal UDS and specific sensitivity to UV in the presence of caffeine confirm the diagnosis of XP variant.
Differential diagnosis
Differential diagnoses include trichothiodystrophy, Cockayne syndrome, cerebrooculofacioskeletal syndrome (COFS), UV-sensitive syndrome, erythropoietic protoporphyria, and Rothmund-Thomson syndrome (see these terms).
Antenatal diagnosis
Prenatal diagnosis through measurement of UDS in cultured chorionic villus cells or amniocytes has been reported.
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Patients must avoid sun exposure (application of sun cream, UV protective clothing, indoor protection with UV blocking films). Management requires a multidisciplinary approach. Regular skin and eye review and appropriate management of any cancerous lesions is essential. Vitamin D deficiency is common and supplements should be prescribed.
Prognosis
There is no cure for XP but sun avoidance and regular follow-up to assess and treat any skin cancers increases life expectancy. For those with no neurological disease and rigorous UV protection, the prognosis is good. However the neurological abnormalities are progressive and can result in a shortened lifespan.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Hiva FASSIHI


A rare syndromic type of cerebral malformation characterized by aprosencephaly (absence of telencephalon and diencephalon), oculo-facial anomalies (i.e. ocular hypotelorism or cyclopia, malformatiobsence of nasal structures, cleft lip), preaxial limb defects (i.e. hypoplastic hands, absent halluces) and various other anomalies including ambiguous genitalia, imperforate anus, and vertebral anomalies. The syndrome is thought to have an autosomal recessive mode of inheritance.


X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection and neoplasia is a rare combined T and B cell immunodeficiency characterized by recurrent sinopulmonary and viral infections, persistent elevated Epstein-Barr virus (EBV) viremia and increased susceptibility to EBV-associated B-cell lymphoproliferative disorders. Immunological analyses show normal lymphocyte count or mild to moderate lymphopenia, inverted CD4:CD8 T-cell ratio and hypogammaglobulinemias.


A rare chromosomal anomaly characterized by complex glycerol kinase deficiency, congenital adrenal hypoplasia, intellectual disability and/or Duchenne muscular dystrophy that usually affect males. The clinical features depend on the deletion size and the number and type of involved genes.


A rare syndromic intellectual disability characterized by developmental delay and intellectual disability, learning and behavioral problems, short stature, thin and sparse hair, mild dysmorphic features, tapering fingers and later onset of scoliosis, obesity and cardiovascular problems (cardiomegaly and cardiomyopathy). Females have normal intelligence.


Xp22.3 microdeletion syndrome is a microdeletion syndrome resulting from a partial deletion of the chromosome X. Phenotype is highly variable (depending on length of deletion), but is mainly characterized by X linked ichthyosis, mild-moderate intellectual deficit, Kallmann syndrome, short stature, chondrodysplasia punctata and ocular albinism. Epilepsy, attention deficit-hyperactivity disorder, autism and difficulties with social communication can be associated.


Xq12-q13.3 duplication syndrome is a rare chromosomal anomaly syndrome, resulting from the partial duplication of the long arm of chromosome X, characterized by global developmental delay, autistic behavior, microcephaly and facial dysmorphism (including down-slanting palpebral fissures, depressed nasal bridge, anteverted nares, long philtrum, down-slanting corners of the mouth). Seizures have also been reported in some patients.


An X-linked retinal dystrophy characterized by choroideremia, causing in affected males progressive nyctalopia and eventual central blindness. Obesity, moderate intellectual disability and congenital mixed (sensorineural and conductive) deafness are also observed. Female carriers show typical retinal changes indicative of the choroideremia carrier state.


A rare, X-linked, multiple congenital anomalies/dysmorphic malformation-intellectual disability syndrome characterized by developmental delay, mild to moderate intellectual disability, speech disturbance, behavioral problems (such as anxiety, hyperactivity, and aggressiveness) and mild facial dysmorphism (including facial hypotonia, thin arched eyebrows, ectropion, epicanthus, malar flatness, thick vermillion of the lips and prognathia). Additional variable manifestations include short stature, skeletal and genital anomalies, seizures, and autism spectrum disorders. Brain imaging may reveal cerebellar vermis hypoplasia, thin corpus callosum, and enlarged subarachnoid spaces.


Xq27.3q28 duplication syndrome is a recently described syndrome characterized by short stature, hypogonadism, developmental delay and facial dysmorphism.

Summary:
Epidemiology
It has been clinically and molecularly characterized in 3 male members from the same family.
Clinical description
Facial features include deep-set eyes, bulbous nasal tip and thin lips. Hypogonadism is due to primary gonadal failure. Patients also had some features which are probably caused by testosterone deficiency such as a high-pitched voice, sparse body hair and small hands and feet. Carrier females present with a short stature and early menopause.
Etiology
This syndrome is caused by an Xq27.3q28 interstitial duplication encompassing the FMR1 and AFF2  genes but not the MECP2 gene. This duplication was characterized by comparative genomic hybridization (CGH) microarray and fluorescence in situ hybridization (FISH).
Genetic counseling
Transmission is X-linked.

                            Last update:
                            July 2011

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


XY type gonadal dysgenesis-associated anomalies syndrome

A rare syndrome with 46,XY difference of sex development characterized by mild developmental delay and streak gonads associated with short stature, cardiac, renal, musculoskeletal, and ectodermal abnormalities (the latter including scalp defects and unusual hair whorls), and dysmorphic facial features (such as preauricular pits, short columella, and small nares). There have been no further descriptions in the literature since 1980.


A rare congenital disorder of glycosylation characterized by moderate intellectual disability, short stature, mild skeletal changes and distinctive facial features with coarse face, synophyrs and deep nasolabial ridges. Skeletal features include broad ribs, stocky long bones, short femoral necks with coxa valga, clinodactyly and broad thumbs.


Yellow fever (YF), caused by YF virus, is a zoonotic disease characterized by fever and constitutional symptoms, with the potential to progress to severe and fatal viral hemorrhagic fever with shock and multi-organ system failure.

Summary:
Epidemiology
YF is endemic to the tropics of the Americas and Africa, where collectively an estimated 5,000-200,000 clinical cases and 30,000 deaths occur annually, the vast majority in Africa.
Clinical description
Most infections are mild or asymptomatic. After an incubation period of 3-6 days, patients typically present with the abrupt onset of non-specific signs and symptoms including fever, malaise, headache, chest pain, and myalgia/arthralgia, followed rapidly by gastrointestinal (nausea, vomiting, diarrhea) symptoms. Most cases will then resolve. In a minority, after a quiescent period of a few days, more severe manifestations ensue, including jaundice, hepato-renal failure, hemorrhage, shock, and meningoencephalitis. Disease is usually mild in children. Clinical laboratory findings typically include elevated hepatic transaminases and proteinuria.
Etiology
Over 25 different viruses cause viral hemorrhagic fever. YF virus is a member of the virus family Flaviviridae, genus Flavivirus. The virus is maintained in a cycle between monkeys and forest canopy mosquitoes. Sporadic cases occur when humans are bitten by these mosquitoes (sylvatic YF). Larger outbreaks occur when humans bring the virus back to more settled environments, where the urban container-breeding mosquito Aedes aegypti can spread YF virus directly between humans (urban YF). Sanitation and mosquito control measures have virtually eliminated urban yellow fever in the Americas, but urban outbreaks continue to be noted in Africa, where 90% of all YF virus infections occur.
Diagnostic methods
Common diagnostic modalities include cell culture, serologic testing by enzyme linked immunosorbent assay (ELISA) or indirect fluorescent antibody (IFA), and reverse transcription polymerase chain reaction (RT-PCR). Because no commercial assays are presently available, these tests are typically performed only in a few specialized laboratories.
Differential diagnosis
YF is difficult to distinguish from a host of other febrile illnesses, at least early in the course of disease. Other viral hemorrhagic fevers, malaria, typhoid fever, leptospirosis, rickettsial infection (see these terms), viral hepatitis and meningococcemia need to be excluded.
Management and treatment
As there is presently no antiviral drug available for YF, treatment is supportive, following the guidelines for treatment of severe septicemia. Insecticide-treated bed nets and/or room screens should be used in open-air settings to prevent further transmission. The YF-17D live attenuated vaccine is highly efficacious, conferring long-term protection in over 95% of recipients within 10 days. YF-17D is indicated for persons over 9 months of age who are traveling to or living in YF endemic areas. Vaccination is contraindicated in children <4 months old and pregnant women and caution is advised in persons with egg allergy, the immunocompromised, children 4-9 months of age and elderly persons, especially if the risk is minimal, such as trips restricted to attending conferences in modern urban hotels with no rural exposure.
Prognosis
Case fatality rates in symptomatic cases are 20-50%. Shock, tachycardia, bleeding, oliguria, proteinuria and azotemia confer a poor prognosis. Although convalescence may be prolonged, survivors usually have no lasting sequelae.

                            Last update:
                            December 2012

                            - Expert reviewer(s):
                            Dr Daniel BAUSCH  -  Andrew BENNETT


A rare, syndromic nail anomaly disease characterized by the variable triad of characteristic yellow nails, chronic respiratory manifestations, and primary lymphedema.

Summary:
Epidemiology
Prevalence and incidence rates are not known, but Yellow nail syndrome (YNS) is considered a rare condition. To date, approximately 400 cases have been reported, mainly as single case reports. The disorder affects males and females equally.
Clinical description
Most cases of YNS are of late onset, after 50 years of age, but the disease has also occasionally been observed in neonates and children. Patients generally complain of slowed or arrested nail growth: the nails become thickened and opaque, with yellowish or green discoloration. The cuticles are absent and the proximal nail fold swollen. Increased transverse curvature is another feature, which may lead to nail plate shedding. Both fingernails and toenails are affected, but severity may vary. Only 1/3 of the patients with nail changes have associated lymphedema and respiratory tract involvement. Nail changes may precede the development of lymphedema or respiratory manifestations by years. Lymphedema is the most consistent associated finding and usually affects the lower limbs. Respiratory conditions include cough, bronchitis, tracheobronchitis, bronchiectasis, chronic sinusitis, chronic respiratory infections, and pleural effusions. YNS may exceptionally be a paraneoplastic disorder (lung cancer).
Etiology
The etiology of YNS has not been elucidated. Impaired lymphatic drainage not due to anatomical abnormalities, but rather to a functional disorder, appears to have a central role.
Diagnostic methods
Nail changes in YNS are pathognomonic and the presence of typical nail alterations is an absolute requirement for the diagnosis. This is because the three main signs (i.e. nail changes, respiratory disorders, and lymphedema) may not be present all at once in the patient.
Differential diagnosis
The most important nail differential diagnoses include chronic paronychia, which shares absence of the cuticle and nail thickening and discoloration, and onychomycosis of the toenails, which produces thickening and onycholysis. Onychogryphosis and acquired pachyonychia should also be considered.
Management and treatment
Spontaneous improvement in nail signs is reported in up to 30% of cases. Oral α‐tocopherol (vitamin E) at high doses, 600 to 1200 international units (IU) daily has been reported to be effective in about half of patients.
Prognosis
Some patients recover fully, but the respiratory condition and the associated symptoms are often chronic. Serious lymphedema and respiratory complications may affect quality of life and periodic follow-up is mandatory. Patients with YNS present several comorbidities other than the respiratory ones, possibly due to their older age, therefore they tipically have a lower life expectancy when compared to the general population.

                            Last update:
                            June 2019

                            - Expert reviewer(s):
                            Pr Bianca Maria PIRACCINI


A rare germ cell tumor characterized by multiple patterns reflecting endodermal extraembryonal differentiation (secondary yolk sac and allantois) or endodermal somatic tissues (intestine, liver, and mesenchyme). The tumors most commonly occur in the second or third decade of life. They are typically located in the gonads, occasionally also in other regions. Patients present with a pelvic mass and/or abdominal pain (females) or an often painless, unilateral testicular mass (males). Elevated serum alpha fetoprotein is a common laboratory finding.


Young adult-onset distal hereditary motor neuropathy is a rare autosomal recessive distal hereditary motor neuropathy characterized by slowly progressive muscular weakness, hypotonia and atrophy of the lower limbs, more pronounced distally, leading to paralysis, and loss of tendon reflexes. Additional features may include pes cavus and mild dysphonia. The upper limbs are relatively spared.


A rare respiratory disease characterized by recurrent sinopulmonary infections and bronchiectasis predominantly in the lower lung fields, as well as azoospermia with reduced fertility, due to production of thick, viscous mucus which causes mild airflow obstruction in the respiratory tract and obstruction of sperm transport in the genital tract. Patients commonly present in adulthood. Sweat gland and pancreatic function are normal. The cause of the syndrome is unknown, however mercury exposure had been proposed as a potential cause.


A rare, genetic, parkinsonian disorder characterized by an age of onset between 21-45 years, rigidity, painful cramps followed by tremor, bradykinesia, dystonia, gait complaints and falls, and other non-motor symptoms. A slow disease progression and a more pronounced response to dopaminergic therapy are also observed in most forms of this disease.

Summary:
Epidemiology
Prevalence of Young onset Parkinson disease (YOPD) in Europe is estimated to be 1/5,000-8,000 (5-10 % of all PD patients). Males are more affected than females (1.7:1). Women develop the disease 2 years later than men.
Clinical description
The age at onset of motor symptoms lies between 21-45 years. The predominant initial motor symptoms include rigidity and painful cramps which may be followed by tremor, bradykinesia, gait complaints and falls. Compared to PD, a lower risk of developing falls and freezing of gait but a higher risk of dystonia, motor fluctuations, and levodopa induced dyskinesia (LID) have been reported. YOPD patients report higher prevalence of non-motor symptoms including apathy, anxiety disorders (including panic disorders, generalized anxiety disorder, and social phobia), depression, psychosis (hallucinations), behavioral disturbances (agitation or impulse control disorder), dementia, and higher concentration difficulties than patients with sporadic or more typical form of PD. Women are more likely to present with tremor or to develop apathy, anxiety, depression, or LID. Likewise, untreated YOPD patients may present with cramps and dystonic postures more often than older PD patients.
Etiology
The exact etiology of YOPD is still unknown. Symptoms of YOPD are thought to result from degeneration of the dopamine producing neurons in the substantia nigra secondary to infectious diseases, pharmacotherapy, or genetic. Mutations in  PRKN (6q25.2-q27), PINK1 (1p36.12), PARK7 (1p36.23), and VPS13C (15q22.2), (21q22.11) genes have also been implicated in some cases of YOPD. The genes PODXL (7q32.3), DNAJC6 (1p31.3) and SYNJ1 (21q22.11) have been implicated in both YOPD and Atypical juvenile parkinsonism.
Diagnostic methods
Diagnosis relies on presence of the clinical symptoms with tremor present in 85% of YOPD patients, an early age at onset, a family history of PD and a positive response to dopaminergic therapy. Diagnosis is confirmed by genetic analysis and cerebral scintigraphy of the dopamine transporters. Final diagnosis is usually made by the presence of lewy bodies in the brain during autopsy.
Differential diagnosis
Differential diagnosis includes atypical juvenile parkinsonism, late onset PD, hereditary essential tremor, Wilson disease, Gaucher disease type 3, Pantothenate kinase-associated neurodegeneration, juvenile Huntington disease and central basal ganglia lesions.
Genetic counseling
In most cases, YOPD is sporadic. However, familial cases have been reported in which an autosomal recessive mode of inheritance have been suggested.
Management and treatment
For symptomatic therapy, an initial treatment with a dopamine receptor agonist maintained at a very low threshold is advised. A switch to or addition of levodopa (L-DOPA) is recommended in cases where treatment response is suboptimal or if problematic adverse effects develop. However, after 5 years of treatment with L-DOPA, 30-40% of patients (59-100% by 10 years) develop dyskinesias and motor fluctuations. Some dopamine receptor agonists may also have antidepressive efficacy. Additional treatments include subthalamic nucleus deep brain stimulation and stereotactic surgery (fetal transplantation, pallidal stimulation, pallidotomy, thalamotomy or both).
Prognosis
The survival rate is favorable, with a median survival age of 30 years. YOPD is also associated with slower disease progression and less cognitive decline until later ages. However, YOPD patients are more likely to have earlier motor complications such as violent and disabling dyskinesias, painful dystonia, and unpredictable and severe motor fluctuations with a greater frequency of occurrence. Poorer quality of life has also been noted resulting from social and psychosocial disturbances.

                            Last update:
                            July 2020

                            - Expert reviewer(s):
                            Dr Coro PAISAN-RUIZ


A rare, genetic, multiple congenital malformation syndrome, characterized by cleidocranial dysplasia (wide fontanelles, calvaria dysostosis, absent or hypoplastic clavicles), absent thumbs and halluces, hypoplastic distal and medial phalanges of fingers, pelvic dysplasia with hip dislocations. Dysmorphic features include sparse scalp hair, protruding eyes, low-set ears, anteverted nares, midfacial hypoplasia, tented upper lip, high arched palate, and micrognathia. Brain malformations are frequently associated. From birth, affected individuals tend to be significantly hypotonic and present with global developmental delay, and respiratory, feeding and swallowing difficulties.


Zebra body myopathy is a benign congenital myopathy, characterised by congenital hypotonia and weakness. Prevalence is unknown. Less than ten patients have been described so far. Muscle biopsy shows zebra bodies and other myopathic changes. Mutations of the alpha-skeletal actin (ACTA1) gene may be involved.


A rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by occipital atretic cephalocele associated with a specific facial dysmorphism (consisting of prominent forehead, narrow palpebral fissures, midface deficiency, narrow, malformed ears, broad nose and nasal root, grooved nasal tip and columella, laterally angulated, hypoplastic nares, short philtrum, thin upper lip, clift lip/palate, severe oligodontia, prominent chin) and large feet with sandal gap. Intellectual disability, developmental delay and hypoplastic finger and toenails have also been reported.


A rare peroxisome biogenesis disorder (the most severe variant of Peroxisome biogenesis disorder spectrum) characterized by neuronal migration defects in the brain, dysmorphic craniofacial features, profound hypotonia, neonatal seizures, and liver dysfunction.

Summary:
Epidemiology
The birth prevalence of Peroxisome biogenesis disorder (PBD) is estimated to be around 1/50,000 in North America, and around 1/500,000 in Japan. The highest incidence of Zellweger syndrome (ZS) was reported in the Saguenay-Lac St Jean region of Quebec (around 1/12,000).
Clinical description
Onset is in the neonatal period, reflecting both organ malformations that occurred in utero and progressive disease due to ongoing peroxisome dysfunction. Infants present with characteristic dysmorphic craniofacial features (flattened facies, large anterior fontanel, split sutures, prominent high forehead, flattened occiput, upslanting palpebral fissures, epicanthal folds, and broad nasal bridge), profound hypotonia and seizures. Macrocephaly or microcephaly, high arched palate, micrognathia and redundant neck skin folds may be present. Skeletal abnormalities (chondrodysplasia punctata, most often in the patella and hips) and subcortical renal cysts are frequent. There is often failure to thrive, hepatomegaly, jaundice, and coagulopathy. Eye findings include cataracts, glaucoma, pigmentary retinopathy, nystagmus, corneal clouding and optic nerve atrophy. Visual changes and loss are progressive. Sensorineural hearing loss may be present. Cryptorchidism and hypospadias (male) and clitoromegaly (female) may occur. CNS function is severely affected and infants have profound psychomotor delay.
Etiology
PBD is caused by mutations in one of 13 PEX genes encoding peroxins. Mutations in these genes lead to abnormal peroxisome biogenesis.
Diagnostic methods
ZS is often suspected on physical examination and confirmed with biochemical evaluation. Plasma very-long-chain fatty acid (VLCFA) levels indicate defects in peroxisomal fatty acid metabolism with elevated plasma concentrations of C26:0 and C26:1 and elevated ratios of C24/C22 and C26/C22. Erythrocyte membrane concentrations of plasmalogens C16 and C18 are reduced. Plasma pipecolic acid levels are increased. Sequence analysis of the 13 PEX genes can be performed. MRI can be used to identify perisylvian polymicrogyria, and other developmental brain malformations.
Differential diagnosis
The main differential diagnoses include Usher syndrome I and II, other PBD disorders (see these terms), single enzyme defects in peroxisome fatty acid beta-oxidation, and disorders that feature severe hypotonia, neonatal seizures, liver dysfunction or leukodystrophy.
Antenatal diagnosis
Prenatal screening for VLCFA levels and plasmalogen synthesis can be performed on cultured amniocytes and chorionic villus sampling in suspected or high-risk pregnancies. If disease causing alleles in the carrier parents have been identified, prenatal diagnosis by DNA testing can be performed as well as preimplantation genetic diagnosis.
Genetic counseling
ZS is inherited in an autosomal recessive manner, so genetic counseling is possible.
Management and treatment
There is no cure for ZS. Standard epileptic drugs are used for seizure control. Hepatic coagulopathy can be treated with vitamin K supplementation while cholestasis may require the provision of all fat soluble vitamins. A gastrostomy tube may be needed to allow for adequate calorie intake. Foods rich in phytanic acids (i.e. cow's milk) should be restricted. Supplementation of mature bile acids, cholic and chenodeoxycholic acid may help improve liver disease in infants with severe hepatopathy. As ZS patients cannot biosynthesize DHA, it can also be provided.
Prognosis
Regardless of interventions, prognosis is poor with most infants dying within the first year of life secondary to respiratory compromise related to infection or intractable epilepsy.

                            Last update:
                            December 2012

                            - Expert reviewer(s):
                            Dr Nancy BRAVERMAN


Zellweger-like syndrome without peroxisomal anomalies

A rare mitochondrial disorder characterized by facial dysmorphism similar to that seen in Zellweger syndrome (see this term), such as frontal bossing, high forehead, upslanting palpebral fissures, hypoplastic supraorbital ridges, and epicanthal folds, and in addition, pale skin, profound hypotonia, developmental delay, and minor metabolic anomalies. No peroxysomal defects, however, have been reported. Transmission is thought to be autosomal recessive.


Zika virus disease is an emerging Aedes mosquito-born virus disease characterized by a clinical course that may be asymptomatic or mild with fever, conjunctivitis, muscle and joint pain, headache, exanthema, but may also be associated with severe neurological (meningitis, meningoencephalitis and myelitis) and auto-immune (Guillain-Barre syndrome) complications, as well as a potential increase of birth defects (microcephaly) if the infection occurs during pregnancy.


A rare genetic multiple congenital anomalies syndrome characterized by gingival fibromatosis, coarse facial appearance, and absence or hypoplasia of nails or terminal phalanges of hands and feet.

Summary:
Epidemiology
About 50 patients have been reported to date.
Clinical description
Zimmermann Laband (ZLS) is characterized by the presence of a progressive, diffuse, gingival hypertrophy, often with multiple unerupted teeth and skeletal deformities of maxillary arches; a coarse facial appearance which includes a bulbous, soft nose, thickened lips, thick and floppy ears; and absence or hypoplasia of the terminal phalanges and nails of hands and feet. More variable features include hyperextensibility of joints, hepatosplenomegaly, mild hirsutism, and hearing loss. Intellectual disability is occasional and usually mild to moderate. The overgrown gingival tissues can affect the ability to speak.
Etiology
ZLS is genetically heterogeneous. Heterozygous gain of function missense variants in KCNH1 (1q32.2), and KCNN3 (1q21.3) genes have been described and, more rarely, recurrent missense variants in the ATP6V1B2 (8p21.3) gene. Zimmermann-Laband syndrome is allelic to Temple Baraitser syndrome (TBS) which is also caused by gain-of-function mutations in the KCNH1 gene, and is characterized by global developmental delay and severe intellectual disability, epilepsy, hypoplasia/aplasia of the nails of the thumb and great toe, and facial dysmorphism. As both syndromes have been described with the same variant, and some patients with KCNH1 variants are reported without full-blown TBS or ZLS, it is likely that TBS, and ZLS are part of a broader KCNH1-related disorder.
Diagnostic methods
Confirmation of the clinical diagnosis is based on KCNH1, KCNN3, and ATP6V1B2 sequencing by targeted sanger sequencing, or via NGS (next generation sequencing) multigene panel including KCNH1, KCNN3, and ATP6V1B2, as well as other genes that may be part of the differential diagnosis.
Differential diagnosis
ZLS has overlapping features with a few different diseases which include : FHEIG syndrome (characterized by facial dysmorphism, hypertrichosis, epilepsy, intellectual disability/developmental delay, and gingival overgrowth) resulting from gain-of-function KCNK4 variants, Cantú syndrome, and DOORS syndrome as well as other defined syndromes of hirsutism and coarsening of the face. Some ATP6V1B2 variants are responsible for autosomal dominant deafness-onychodystrophy (DDOD) syndrome, a syndromic form of deafness which shares features with ZLS, such as anomalies of digits, nails, and teeth. Variants in ATP6V1B2 have also been reported in patients with epilepsy, intellectual disability and mild gingival and nail abnormalities. Some patients with ABCC9 variants also have gingival hypertrophy and, rarely, hypoplasia of terminal phalanges. Isolated gingival fibromatosis has been documented as a dominantly transmissible trait.
Antenatal diagnosis
For parents of an index individual, prenatal diagnosis in subsequent pregnancies should be discussed.
Genetic counseling
Although familial aggregation with different inheritance patterns has been reported, all genetically confirmed ZLS to date follow an autosomal dominant mode of in inheritance, most cases resulting from a de novo mutation.
Management and treatment
Management and treatment are based on the phenotype. Orthodontic treatment may be needed.
Prognosis
Prognosis depends on the phenotype. The syndrome is not life-threatening.

                            Last update:
                            April 2021

                            - Expert reviewer(s):
                            Pr Catheline VILAIN | ITHACA*

                                * European Reference Network


Zinc-responsive necrolytic acral erythema

A rare skin disease characterized initially by erythematous patches with superficial necrosis, at later stages by hyperkeratotic plaques with a rim of dusky erythema, of exclusively acral distribution with a predilection for the lower extremities, and universal association with hepatitis C virus infection. Patients typically experience pruritus or pain. Serum zinc levels may or may not be decreased, although oral zinc supplementation often improves the condition.


Zollinger-Ellison syndrome (ZES) is characterized by severe peptic disease (ulcers/esophageal disease) caused by hypergastrinemia secondary to a gastrinoma resulting in increased gastric acid secretion.

Summary:
Epidemiology
Annual incidence is estimated at 1-2 cases per million. The condition is slightly more common in females than males (sex ratio of 1.3:1).
Clinical description
ZES is usually diagnosed in the fifth decade of life. Abdominal pain (typically in the upper abdomen) and diarrhea are the most frequent manifestations. Heartburn is often present (44% of cases). Other signs include nausea, vomiting, malabsorption, and weight loss. Some patients present with ulcer complications (gastrointestinal bleeding, perforation and penetration).
Etiology
ZES is caused by a gastrin-secreting tumor (gastrinoma), usually located in the duodenum (50-85% of cases), pancreas, abdominal lymph nodes or, in rare cases, ectopic locations (heart, ovary, liver etc.). ZES can be sporadic (75% of cases) or associated with multiple endocrine neoplasia type 1 (MEN1; see this term), which is transmitted in an autosomal dominant manner. MEN1 is caused by mutations in the MEN1 gene (11q13) encoding menin, a protein which binds and regulates the activity of numerous transcription factors.
Diagnostic methods
Diagnosis of ZES is first suspected on the basis of the clinical manifestations. Elevated fasting serum gastrin (FSG) levels are almost invariably present. FSG levels 10 times higher than normal and a gastric pH of <2 confirm the diagnosis. If the FSG level is elevated less than 10 fold and the gastric pH is <2, secretin stimulation (abnormal: increase >120 pg/ML) and basal acid (abnormal: >15 mEq/hr-basal) tests need to be done. Imaging studies (somatostatin receptor scintigraphy, CT scan, abdominal or endoscopic ultrasound) are required to localize the gastrinoma. Esophagogastroduodenoscopy may be indicated to detect duodenal ulcerations.
Differential diagnosis
Differential diagnoses include other causes of increased acid output and elevated FSG levels: Helicobacter pylori infections, retained gastric antrum, gastric outlet obstruction, renal failure, antral G cell syndromes, idiopathic gastroesophageal reflux or peptic ulcer disease, and physiological causes of hypergastrinemia (atrophic gastritis, pernicious anemia, or use of potent antisecretory drugs).
Antenatal diagnosis
Antenatal genetic testing may allow prenatal diagnosis of MEN1 but not gastrinomas.
Genetic counseling
Genetic counseling should be offered to ZES patients with MEN1.
Management and treatment
Gastric acid hypersecretion must be controlled both in the short- and long-term. Oral H(+)-K(+)-ATPase inhibitors (proton-pump inhibitors; PPIs) are now the drugs of choice because of their long duration of action and potency (administered in once- or twice-a-day doses). Intravenous PPIs are effective when oral drugs cannot be taken. Histamine H2-receptor antagonists can also be effective but frequent high doses are needed by many patients. Management also includes treatment directed at the tumor itself as 60-90% of tumors are malignant. For localized disease in non-MEN1 patients, surgery is recommended. For advanced metastatic disease, numerous antitumor therapies are used including chemotherapy, biotherapy (somatostatin/interferon analogues), embolization of hepatic metastases and aggressive surgery. A number of newer treatments (including somatostatin receptor-mediated radiotherapy, novel chemotherapeutic agents and growth factor/tyrosine kinase inhibitors) are under investigation.
Prognosis
In the absence of liver metastases, the prognosis is favorable (10-year survival rate of 90-100%). Patients with liver metastases (65-75% of patients) have a 10-year survival rate of 20-40%. Patients with MEN1 are rarely cured surgically due to the presence of multiple tumors and lymph node metastases, however, only 15% pursue an aggressive course and 10 year survival is 80-98%.

                            Last update:
                            May 2009

                            - Expert reviewer(s):
                             Robert JENSEN


A rare mycosis caused by ubiquitous, opportunistic fungi of the order Mucorales, characterized by tissue infarction and necrosis due to invasion of the vasculature by hyphae. The spectrum of clinical manifestations depends on the route of infection and includes rhinocerebral, pulmonary, cutaneous, gastrointestinal, renal, and disseminated forms. The disease is usually rapidly progressive and associated with high mortality.


An X-linked recessive retinal disease characterized by fundus hypopigmentation, decrased visual acuity, nystagmus, astigmatism, progressive axial myopia, defective dark adaptation and protanopia.

Summary:
Epidemiology
AIED is a very rare disease originally reported in a family from Aland islands in the Bothnia sea. Some other cases from the Baltic area and other origins have been reported but the clinical features of these cases overlap with X-linked incomplete congenital stationary night blindness (CSNB2; see this term).
Clinical description
AIED is characterized by hypopigmented eye fundus, foveal dysplasia with no foveal reflex that leads to decreased visual acuity, progressive axial myopia, latent nystagmus, astigmatism, night blindness and protan color vision defect. The hypopigmentation is most pronounced in the posterior pole and in the peripapillary region. Female carriers may show slight disturbances of color discrimination and subtle nystagmus.
Etiology
AIED is caused by mutations in the CACNA1F gene. Some mutations in CACNAF1 are associated with CSNB2 suggesting allelism of the two disorders.
Diagnostic methods
Patients with a clinical suspicion of AIED should undergo a complete ophthalmologic examination including funduscopy, visual acuity, refraction defects, electroretinogramm (ERG) and color vision test. Mutation screening of CACNA1F gene including the presence of large deletions in the gene can help the clinical diagnosis.
Differential diagnosis
Differential diagnosis includes X-linked ocular albinism (OA1; see this term) and CSNB2. The lack of misrouting of optic nerve axons excludes OA1 whereas CSNB2 is apparently stationary with a normal fovea and, usually, no color defects.
Genetic counseling
AIED is an X-linked disorder, with a carrier female having a 50% risk of transmitting the mutation to her offspring. Carrier testing for at-risk female relatives is possible. Genetic counseling of the family is recommended.
Management and treatment
No treatment is available except for correction of the myopia.
Prognosis
Except for progression of axial myopia, the disease presents a stationary course.

                            Last update:
                            December 2011

                            - Expert reviewer(s):
                            Dr Carmen AYUSO  - Dr Teresa JAIJO  - Dr José María MILLÁN SALVADOR


Neonatal diabetes mellitus presents as hyperglycemia, failure to thrive and, in some cases, dehydration and ketoacidosis which may be severe with coma, in a child within the first months of life.

Summary:
Epidemiology
Transient (TNDM) and Permanent (PNDM) neonatal diabetes are rare conditions occurring in 1:300,000-400,000 live births.

Clinical description
TNDM infants develop diabetes in the first few weeks of life but go into remission in a few months, with possible relapse to a permanent diabetes state usually around adolescence or as adults. The pancreatic dysfunction may be maintained throughout life, with relapse initiated at times of metabolic stress such as puberty or pregnancy. Patients with TNDM are more likely to have intrauterine growth retardation and less likely to develop ketoacidosis than patients with PNDM. In TNDM, patients are younger at the diagnosis of diabetes and have lower initial insulin requirements. In PNDM, insulin secretory failure occurs in the late fetal or early post-natal period and does not go into remission. Considerable overlap occurs between the two groups, so that TNDM cannot be distinguished from PNDM based on clinical features. Very early onset diabetes mellitus seems to be unrelated to autoimmunity in most instances.

Etiology
A number of conditions are associated with PNDM, some of which have been elucidated at the molecular level. Among these, the very recently elucidated mutations in the KCNJ11 and ABCC8 genes, encoding the Kir6.2 and SUR1 subunit of the pancreatic KATP channel involved in regulation of insulin secretion, account for one third to half of the PNDM cases.

Diagnostic methods
Molecular analysis of chromosome 6 anomalies, and the KCNJ11 and ABCC8 genes encoding Kir6.2 and SUR1, provides a tool to identify TNDM from PNDM in the neonatal period. This analysis also has potentially important therapeutic consequences leading to transfer some patients, those with mutations in KCNJ11 and ABCC8 genes, from insulin therapy to sulfonylureas.

Differential diagnosis

Antenatal diagnosis

Genetic counseling

Management and treatment
Recurrent diabetes is common in patients with 'transient'' neonatal diabetes mellitus and, consequently, prolonged follow-up is imperative. Insulin pump may offer an interesting therapeutic tool in this age group in experienced hands.

Prognosis