Genotype-Phenotype Correlations by Variant Type in 1531 Persons with Biallelic GJB2 Pathogenic Variants View in own window GJB2 Genotype Class Total of All DFNB1 Hearing Loss Mild Moderate Severe Profound T/T 77.3% 1 0%-3% 10%-12% 25%-28% 59%-64% NT/NT 6.2% 2 53% 26% 8% 13% T/NT 16.5% 3 29%-37% 24%-29% 10%-17% 24%-30% Based on Snoeckx et al [2005].
Tagawa et al [2003] examined a total of 107 unrelated Japanese individuals, including 53 with unclassified LGMD, 28 with Miyoshi myopathy, and 26 with other neuromuscular disorders.
Dysferlinopathies are a group of muscle diseases that have a slow progression of muscle weakness and atrophy (wasting). The diseases in the group are: Miyoshi myopathy , where there is weakness and atrophy (wasting)of the muscles of the legs that are closer to the feet (distal myopathy) Limb-girdle muscular dystrophy type 2B (LGMD2B) , where there is weakness and atrophy of the muscles of the pelvic and shoulder Scapuloperoneal syndrome, where weakness and atrophy affect both the distal legs and shoulder girdle muscles Distal myopathy with anterior tibial onset , where there is weakness of the front part of the leg and foot drop A form of congenital muscular dystrophy that was referred in a few people, and A condition where there are not symptoms but only an elevated level of the muscular enzyme CK in the blood tests. All dysferlinopathies are caused by pathogenic variations (mutations) in the DYSF gene which result in a deficiency of the protein dysferlin (hence, the name), important for the efficient repair of muscle fibers. Inheritance is autosomal recessive. There is no cure or specific treatment. Management depend on the symptoms and is aimed to improve the quality of life and the life expectation.
Somatic Mosaicism Parrini et al. (2004) reported 2 unrelated mildly affected PVNH patients with somatic mosaicism for mutations in the FLNA gene. The first individual was a 28-year-old woman with no family history of neurologic disorders who had generalized seizures since age 14 years and thin noncontiguous heterotopic nodules on MRI.
Periventricular heterotopia is a condition in which the nerve cells (neurons) do not migrate properly during early development of the fetal brain. People with this condition typically develop recurrent seizures (epilepsy) beginning in mid-adolescence. Intelligence is usually normal, but some people may have mild intellectual disability, including difficulty with reading or spelling. Less common features include microcephaly, developmental delay, recurrent infections, and blood vessel abnormalities. Some cases are caused by changes (mutations) in the FLNA gene and are inherited in an X-linked dominant manner.
A number sign (#) is used with this entry because of evidence that periventricular nodular heterotopia-7 (PVNH7) is caused by heterozygous mutation in the NEDD4L gene (606384) on chromosome 18q21. Description Periventricular nodular heterotopia-7 is a neurologic disorder characterized by abnormal neuronal migration during brain development resulting in delayed psychomotor development and intellectual disability; some patients may develop seizures. Other features include cleft palate and 2-3 toe syndactyly (summary by Broix et al., 2016). For a phenotypic description and a discussion of genetic heterogeneity of periventricular heterotopia, see 300049. Clinical Features Broix et al. (2016) reported 6 unrelated children with delayed psychomotor development apparent since infancy, intellectual disability, and poor or absent speech.
For a phenotypic description and a discussion of genetic heterogeneity of periventricular heterotopia, see 300049. Mapping Sheen et al. (2003) described 2 individuals from unrelated families in whom periventricular nodular heterotopia was associated with anomalies of chromosome 5p. Both individuals had complex partial seizures. Magnetic resonance imaging demonstrated bilateral nodular periventricular heterotopia, with subcortical heterotopia or focal gliosis. FISH identified a duplication of 5p15.1 (46,XX,dup(5)(p15.1p15.1)) in one patient. In the other, FISH showed trisomy of 5p15.33 (46,XY,der(14)t(5;14)(p15.33;p11.2)mat).
A number sign (#) is used with this entry because of evidence that periventricular nodular heterotopia-8 (PVNH8) is caused by heterozygous missense mutation in the ARF1 gene (103180) on chromosome 1q42. Description Periventricular nodular heterotopia-8 (PVNH8) is a neurologic disorder characterized by abnormal neuronal migration during brain development, resulting in delayed psychomotor development. Three patients have been reported (Ge et al., 2016). For a phenotypic description and a discussion of genetic heterogeneity of periventricular heterotopia, see PVNH1 (300049). Clinical Features Ge et al. (2016) identified 3 unrelated individuals with periventricular heterotopia. The first patient was a 9-year-old boy with developmental disabilities, speech delay, and attention deficit-hyperactivity disorder in whom previous genetic tests had been nondiagnostic.
A number sign (#) is used with this entry because autosomal recessive periventricular nodular heterotopia with microcephaly (ARPHM) is caused by homozygous mutation in the ARFGEF2 gene (605371) on chromosome 20q13. For a phenotypic description and a discussion of genetic heterogeneity of periventricular heterotopia, see 300049. Clinical Features Sheen et al. (2003) described 2 consanguineous pedigrees with periventricular heterotopia suggesting an autosomal recessive inheritance pattern. Magnetic resonance imaging (MRI) of the brains of affected individuals revealed periventricular nodules of cerebral gray matter intensity, typical of the disorder. One of the families was Turkish with a 2.5-year-old boy and 16-month-old girl affected.
Periventricular nodular heterotopia (PNH) is a brain malformation, due to abnormal neuronal migration, in which a subset of neurons fails to migrate into the developing cerebral cortex and remains as nodules that line the ventricular surface. Classical PNH is a rare X-linked dominant disorder far more frequent in females who present normal intelligence to borderline intellectual deficit, epilepsy of variable severity and extra-central nervous system signs, especially cardiovascular defects or coagulopathy. The disorder is generally associated with prenatal lethality in males.
A number sign (#) is used with this entry because it represents a contiguous gene deletion syndrome. Clinical Features Cardoso et al. (2009) reported 3 unrelated children, 2 boys and a girl, with severe mental retardation, epilepsy, and bilateral periventricular heterotopia limited to the subependymal region of the temporal and occipital horns of the lateral ventricles. Other features included hypotonia, delayed motor development, no speech acquisition, and minor dysmorphic facial features, such as high forehead, depressed nasal bridge, and hypertelorism. One of the patients also showed polymicrogyria on brain MRI. Cytogenetics Using array CGH, Cardoso et al. (2009) identified a de novo deletion of chromosome 5q14.3-q15 in 3 unrelated patients with periventricular heterotopia. The deletions ranged in size from 6.3 to 17 Mb, and shared a common deleted region spanning 5.8 Mb.
A number sign (#) is used with this entry because of evidence that periventricular nodular heterotopia-6 (PVNH6) is caused by heterozygous mutation in the ERMARD gene (615532) on chromosome 6q27. One such family has been reported. Clinical Features Conti et al. (2013) reported a 7-year-old girl with delayed psychomotor development, delayed speech, strabismus, and onset of seizures with hypsarrhythmia at age 3 months. Brain MRI showed bilateral periventricular nodular heterotopia in the frontal horns. Cytogenetics By array CGH of 155 patients with brain malformations, Conti et al. (2013) identified 12 patients with heterozygous deletions of chromosome 6q27 involving the ERMARD gene. Eight of the deletions occurred de novo, and 2 were inherited from an affected parent.
This may combine with low levels of cytokines to cause HACE. [25] Diagnosis and prevention [ edit ] Generally, high-altitude pulmonary edema (HAPE) or AMS precede HACE. [3] In patients with AMS, the onset of HACE is usually indicated by vomiting, headache that does not respond to non-steroidal anti-inflammatory drugs , hallucinations, and stupor. [16] [20] In some situations, however, AMS progresses to HACE without these symptoms. [16] HACE must be distinguished from conditions with similar symptoms, including stroke , intoxication, psychosis , [2] diabetic symptoms, meningitis , [20] or ingestion of toxic substances. [5] It should be the first diagnosis ruled out when sickness occurs while ascending to a high altitude. [7] HACE is generally preventable by ascending gradually with frequent rest days while climbing or trekking. [26] [20] Not ascending more than 1,000 metres (3,300 ft) daily and not sleeping at a greater height than 300 metres (980 ft) more than the previous night is recommended. [27] The risk of developing HACE is diminished if acetazolamide or dexamethasone are administered. [16] Generally, the use of acetazolamide is preferred, but dexamethasone can be used for prevention if there are side effects or contraindications. [28] Some individuals are more susceptible to HACE than others, [20] and physical fitness is not preventive. [29] Age and sex do not by themselves affect vulnerability to HACE. [5] Treatment and prognosis [ edit ] Patients with HACE should be brought to lower altitudes and provided supplemental oxygen, [18] and rapid descent is sometimes needed to prevent mortality. [30] Early recognition is important because as the condition progresses patients are unable to descend without assistance. [9] Dexamethasone should also be administered, [16] although it fails to ameliorate some symptoms that can be cured by descending to a lower altitude. [9] It can also mask symptoms, and they sometimes resume upon discontinuation. [20] Dexamethasone's prevention of angiogenesis may explain why it treats HACE well. [17] Three studies that examined how mice and rat brains react to hypoxia gave some credence to this idea. [17] [25] If available, supplemental oxygen can be used as an adjunctive therapy, or when descent is not possible.
Summary Clinical characteristics. Koolen-de Vries syndrome (KdVS) is characterized by developmental delay / intellectual disability, neonatal/childhood hypotonia, dysmorphisms, congenital malformations, and behavioral features. Psychomotor developmental delay is noted in all individuals from an early age. The majority of individuals with KdVS function in the mild-to-moderate range of intellectual disability. Other findings include speech and language delay (100%), epilepsy (~33%), congenital heart defects (25%-50%), renal and urologic anomalies (25%-50%), and cryptorchidism (71% of males). Behavior in most is described as friendly, amiable, and cooperative. Diagnosis/testing.
Koolen-de Vries syndrome is a disorder characterized by developmental delay and mild to moderate intellectual disability. People with this disorder typically have a disposition that is described as cheerful, sociable, and cooperative. They usually have weak muscle tone (hypotonia) in childhood. About half have recurrent seizures (epilepsy). Affected individuals often have distinctive facial features including a high, broad forehead; droopy eyelids (ptosis); a narrowing of the eye openings (blepharophimosis); outer corners of the eyes that point upward (upward-slanting palpebral fissures); skin folds covering the inner corner of the eyes (epicanthal folds); a bulbous nose; and prominent ears. Males with Koolen-de Vries syndrome often have undescended testes (cryptorchidism).
A rare multisystem disorder characterized by neonatal/childhood hypotonia, mild to moderate developmental delay or intellectual disability, epilepsy, dysmorphic facial features, hypermetropia, congenital heart anomalies, congenital renal/urologic anomalies, musculoskeletal problems, and a friendly/amiable disposition. Epidemiology The prevalence of this disorder is unknown; however, the prevalence of the 17q21.31 deletion is approximately 1/55,000 individuals. The prevalence of single nucleotide variants (SNVs) in KANSL1 cannot be ascertained with precision owing to the limited number of cases identified thus far. Males and females are affected equally. Clinical description Hypotonia is most evident between the neonatal period and infancy with poor sucking and slow feeding, but may persist throughout life. Feeding difficulties may require hospitalization and/or nasogastric tube feeding in some neonates.
Koolen de Vries syndrome is a disorder characterized by developmental delay, mild to moderate intellectual disability, congenital malformations, and behavioral features. Developmental delay is noted from an early age. Other problems include weak muscle tone (hypotonia) in childhood, recurrent seizures (epilepsy), and distinctive facial features. Males with Koolen de Vries syndrome often have undescended testes (cryptorchidism). Other symptoms may include defects in the walls between the chambers of the heart (septal defects) or other heart defects, kidney problems, and skeletal anomalies such as foot deformities. It is caused by mutations in the KANSL1 gene, or by the loss of a small amount of genetic material in chromosome 17 that includes the KANSL1 gene (chromosome 17 q21.31 microdeletion).
Rare genetic disorder caused by a deletion of six genes 17q21.31 microdeletion syndrome (Koolen–de Vries syndrome) Other names Koolen–De Vries syndrome, Koolen de Vries syndrome, Koolen De Vries syndrome 17q21.31 microdeletion syndrome , also known as Koolen–de Vries syndrome ( KdVS ), is a rare genetic disorder caused by a deletion of a segment of chromosome 17 which contains six genes. This deletion syndrome was discovered independently in 2006 by three different research groups. [1] [2] [3] [4] [5] [6] [7] [8] [9] Contents 1 Presentation 2 Genetics 2.1 Affected genes 3 Diagnosis 4 Treatment 5 History 6 References 7 Further reading 8 External links Presentation [ edit ] The symptoms associated with this syndrome are variable, but common features include: low birthweight , low muscle tone at birth, poor feeding in infancy (often requiring feeding by tube for a period) and oromotor dyspraxia together with moderate developmental delays and learning disabilities but amiable behaviour. Other clinically important features include epilepsy , heart defects ( atrial septal defect , ventricular septal defect ) and kidney/urological anomalies. Silvery depigmentation of strands of hair have been noted in several patients. With age, there is an apparent coarsening of facial features. 17q21.3 was reported simultaneously in 2006 by three independent groups, with each group reporting several patients, and is now recognised to be one of the more common recurrent microdeletion syndromes . [1] [2] [3] In 2007, a patient with a small duplication in same segment of DNA was described. [10] An overview of the clinical features of the syndrome, by reviewing 22 individuals with a 17q21.31 microdeletion, estimated the disorder is present in 1 in every 16,000 people. [5] Genetics [ edit ] The recurrent deletion is between 500 and 650 kilobases (Kb) in size encompassing at least six genes, among them the microtubule-associated protein tau ( MAPT ).
The extent of vascular and skin involvement was similar in the patients with true vascular EDS and in those with LDS type 2; only joint laxity was significantly more prevalent in those with LDS type 2 (12 of 12 vs 18 of 28, p = 0.03). Loeys et al. (2006) presented the clinical characteristics of a series of 40 probands who exhibited a phenotype consistent with LDS type 1, including 10 previously described patients (Loeys et al., 2005).
A number sign (#) is used with this entry because Loeys-Dietz syndrome-2 (LDS2) is caused by heterozygous mutation in the TGFBR2 gene (190182) on chromosome 3p24. For a general phenotypic description and a discussion of genetic heterogeneity of Loeys-Dietz syndrome, see LDS1 (609192). Clinical Features Boileau et al. (1990) described a large French family in which multiple members in an autosomal dominant pedigree pattern exhibited some of the skeletal and cardiovascular features of the Marfan syndrome (154700) but lacked ocular abnormalities. Boileau et al. (1993) considered that the patients fulfilled criteria for the MASS (mitral valve, aortic, skeleton, and skin) phenotype (see 157700), but might represent a distinct clinical entity. The proband was a man who died at age 39 years from aortic dissection.
Loeys–Dietz syndrome Other names Aortic aneurysm syndrome due to TGF-beta receptors anomalies This condition is inherited in an autosomal dominant manner [1] Pronunciation / ˌ l oʊ iː z ˈ d iː t s / LOH -eez- DEETS [2] Specialty Cardiology , rheumatology , medical genetics Loeys–Dietz syndrome ( LDS ) is an autosomal dominant genetic connective tissue disorder. It has features similar to Marfan syndrome and Ehlers–Danlos syndrome . [3] [4] [5] The disorder is marked by aneurysms in the aorta , often in children, and the aorta may also undergo sudden dissection in the weakened layers of the wall of the aorta. Aneurysms and dissections also can occur in arteries other than the aorta. Because aneurysms in children tend to rupture early, children are at greater risk for dying if the syndrome is not identified. Surgery to repair aortic aneurysms is essential for treatment. There are five types of the syndrome, labelled types I through V, which are distinguished by their genetic cause.
Loeys-Dietz syndrome is a rare genetic connective tissue disorder characterized by a broad spectrum of craniofacial, vascular and skeletal manifestations with four genetic subtypes described forming a clinical continuum.
Loeys-Dietz syndrome is a connective tissue disorder that causes aortic aneurysms , widely spaced eyes ( hypertelorism ), cleft palate and/or split uvula (the little piece of flesh that hangs down in the back of the mouth) and twisting or spiraled arteries (arterial tortuosity). Other findings include craniosynostosis, extropia (eyes that turn outward), micrognathia, structural brain abnormalities, intellectual deficit , and congenital heart disease . Signs and symptoms vary among individuals. This condition is inherited in an autosomal dominant manner with variable clinical expression. This condition is called Loeys-Dietz syndrome type 1 when affected individuals have cleft palate, craniosynostosis, and/or hypertelorism. Individuals without these features are said to have Loeys-Dietz syndrome type 2.
Summary Clinical characteristics. Lipoid proteinosis (LP) is characterized by deposition of hyaline-like material in various tissues resulting in a hoarse voice from early infancy, vesicles and hemorrhagic crusts in the mouth and on the face and extremities, verrucous and keratotic cutaneous lesions on extensor surfaces (especially the elbows), and moniliform blepharosis (multiple beaded papules along the eyelid margins and inner canthus). Extracutaneous manifestations may include epilepsy, neuropsychiatric disorders, and spontaneous CNS hemorrhage. Males and females are affected equally. Generally, the disease course is chronic and fluctuating. Affected individuals have a normal life span unless they experience laryngeal obstruction. Diagnosis/testing. The diagnosis of lipoid proteinosis is established in a proband with characteristic clinical findings and either identification of biallelic ECM1 pathogenic variants on molecular genetic testing or characteristic histologic and/or immuno-labeling findings on skin biopsy.
Lipoid proteinosis is a condition that results from the formation of numerous small clumps (deposits) of proteins and other molecules in various tissues throughout the body. These tiny clumps appear in the skin, upper respiratory tract , the moist tissues that line body openings such as the eyelids and the inside of the mouth (mucous membranes), and other areas. The first symptom of this condition is usually a hoarse voice, which is due to deposits in the vocal cords. In infancy the hoarseness is expressed as a weak cry. The voice abnormalities persist throughout life and can ultimately cause difficulty speaking or complete loss of speech. Involvement of the throat, tonsils, and lips can result in breathing problems and upper respiratory tract infections.
A number sign (#) is used with this entry because of evidence that lipoid proteinosis is caused by homozygous or compound heterozygous mutation in the ECM1 gene (602201) on chromosome 1q21. Description Lipoid proteinosis of Urbach and Wiethe is a rare autosomal recessive disorder typified by generalized thickening of skin, mucosae, and certain viscera. Classic features include beaded eyelid papules and laryngeal infiltration leading to hoarseness. The disorder is clinically heterogeneous, with affected individuals displaying differing degrees of skin scarring and infiltration, variable signs of hoarseness and respiratory distress, and in some cases neurologic abnormalities such as temporal lobe epilepsy. Histologically, there is widespread deposition of hyaline (glycoprotein) material and disruption/reduplication of basement membrane (summary by Hamada et al., 2002 and Hamada et al., 2003).
Lipoid proteinosis (LP) is a rare genodermatosis characterized clinically by mucocutaneous lesions, hoarseness developing in early childhood and, at times, neurological complications. Epidemiology Incidence and prevalence are not known. More than 300 cases (ages 6 to 67 years) have been reported worldwide. Most patients are of European ancestry (Dutch or German). A founder effect is reported among large kindreds in South Africa. Many cases are also reported from the Middle East and India. The disease is more commonly seen in consanguineous unions. Clinical description A wide range of clinical signs is noted and disease severity is variable, while the course is usually slowly progressive.
Lipoid proteinosis (LP) of Urbach and Wiethe is a rare condition that affects the skin and the brain. The signs and symptoms of this condition and the disease severity vary from person to person. The first sign of LP is usually a hoarse cry during infancy. Affected children then develop characteristic growths on the skin and mucus membranes in the first two years of life. Damage to the temporal lobes (the portions of the brain that process emotions and are important for short-term memory) occurs over time and can lead to seizures and intellectual disability. Other signs and symptoms may include hair loss, oligodontia , speech problems, frequent upper respiratory infections, difficulty swallowing, dystonia, and learning disabilities.
They identified 3 major QTLs: STR1, STR2, and STR3, with lod scores of 7.4, 4.7, and 3.0, respectively. These 3 QTLs accounted for 28% of the overall phenotypic variants.
Machin et al. (1987) reported the pathologic findings in a sister and brother who died at ages 28 and 22, respectively. Visceral neuropathy was found as the basis of extensive intestinal diverticular disease.
Summary Clinical characteristics. Coffin-Lowry syndrome (CLS) is usually characterized by severe-to-profound intellectual disability in males; less severely impaired individuals have been reported. Neuropsychiatric concerns can include behavioral problems, loss of strength, progressive spasticity or paraplegia, sleep apnea, or stroke. Stimulus-induced drop attacks (SIDAs) in which unexpected tactile or auditory stimuli or excitement triggers a brief collapse but no loss of consciousness are present in approximately 20% of affected individuals. Typically SIDAs begin between mid-childhood and the teens. Characteristic facial features may be more apparent with age. Upper-extremity differences may be subtle and include short, soft, fleshy hands with tapered fingers as well as fleshy forearms.
A rare X-linked syndromic intellectual disability characterized by global development delay, postnatal growth retardation leading to short stature, facial dysmorphism, short hands with tapering fingers and progressive skeletal abnormalities including kyphoscoliosis and pectus carinatum/excavatum. Intellectual disability ranges from mild to severe. Epidemiology The exact prevalence is not known but is estimated to be 1/50,000 to 1/100,000. Male patients are generally moderately to severely affected while most female carriers have mild features. Clinical description Severe clinical presentation was reported in the first male patients described. Following the wide application of molecular genetic testing, the phenotype is now recognized as very variable.
Coffin-Lowry syndrome is a genetic condition that affects many parts of the body. The signs and symptoms and severity vary from person to person; however, males are typically more severely affected than females. Signs and symptoms may include distinct facial findings, short stature, microcephaly, kyphoscoliosis , other skeletal abnormalities, stimulus-induced drop episodes , intellectual disability and delayed development. Mutations in the RPS6KA3 gene cause the syndrome. It is inherited in an X-linked dominant fashion. Treatment is symptomatic.
Coffin-Lowry syndrome is a condition that affects many parts of the body. The signs and symptoms are usually more severe in males than in females, although the features of this disorder range from very mild to severe in affected women. Males with Coffin-Lowry syndrome typically have severe to profound intellectual disability and delayed development. Affected women may be cognitively normal, or they may have intellectual disability ranging from mild to profound. Beginning in childhood or adolescence, some people with this condition experience brief episodes of collapse when excited or startled by a loud noise.
These included mild allergic reactions towards the enzyme, which may snowball into anaphylaxis , a life-threatening allergy. [28] Other side effects are headaches , nausea , vomiting , chest discomfort and abnormal blood pressure. [29] Gene Therapy [ edit ] AVM are genetic diseases caused by mutations of the genes. [5] In this way, AVM can be addressed with gene therapy .
Description Infantile-onset autophagic vacuolar myopathy is characterized by increased cardiac and skeletal muscle glycogen with normal acid maltase (GAA; 606800). Skeletal muscle biopsy shows characteristic intracytoplasmic vacuoles that stain for sarcolemmal proteins and complement proteins. Similar pathologic findings are seen in Danon disease (300257), caused by mutation in the LAMP2 gene (309060) on chromosome Xq24, and X-linked myopathy with excessive autophagy (XMEA; 310440), which has been mapped to Xq28. Clinical Features Atkin et al. (1984) described fatal infantile cardiac glycogenosis without acid maltase deficiency in a male hydropic newborn. Verloes et al. (1997) reported a boy with infantile onset of lethal hypertrophic vacuolar cardiomyopathy.
For example, in 1992, Ferro performed research in which he studied the recovery of individuals with acute global aphasia, resulting from the five different lesion sites. [24] The first lesion site was in the fronto-tempo-parietal region of the brain; patients with lesions in this location saw the least amount of gains out of all of the participants in the study, and they often never recovered from global aphasia. [24] However, the second lesion site was the anterior, suprasylvian, frontal part of the brain; the third lesion site was the subcortical infarcts; and the fourth lesion site was the posterior, suprasylvian, parietal infarcts. [24] Participants with lesions two, three, and four often recovered to a less severe form of aphasia, such as Broca's or transcortical . [24] The fifth lesion site was a double lesion in both the frontal and temporal infarcts; patients with lesions at this site showed slight improvement. [24] However, studies show that spontaneous improvement, if it happens, occurs within six months, but complete recovery is rare. [28] Studies have shown that persons with global aphasia have improved their verbal and nonverbal speech and language skills through speech and language therapy. [29] [30] One study examined the recovery of a group of individuals who were classified as having global aphasia at 3 months poststroke.
Chassaing et al. (2013) analyzed the STRA6 gene in 28 cases with clinical anophthalmia, including 7 cases of isolated anophthalmia, 14 cases in which it was associated with 1 of the major features of PDAC, and 7 cases with other abnormalities.
A number sign (#) is used with this entry because of evidence that nonsyndromic microphthalmia with coloboma-9 (MCOPCB9) and microphthalmia and/or coloboma with developmental delay (MCOPS15) are caused by homozygous mutation in the ODZ3 gene (TENM3; 610083) on chromosome 4q35. One family with MCOPCB9 has been reported. For a discussion of genetic heterogeneity of isolated colobomatous microphthalmia, see MCOPCB1 (300345). Description MCOPCB9 is characterized by isolated microphthalmia and coloboma (Aldahmesh et al., 2012). MCOPS15 is characterized by microphthalmia and/or coloboma, with developmental delay in which speech appears to be more severely affected than motor abilities. Additional ocular anomalies that have been observed include ptosis, keyhole-shaped pupils, microcornea, sclerocornea, and anterior segment dysgenesis (Chassaing et al., 2016; Stephen et al., 2018; Singh et al., 2019).
A number sign (#) is used with this entry because of evidence that isolated microphthalmia with coloboma-6 (MCOPCB6) is caused by heterozygous mutation in the GDF3 gene (606522) on chromosome 12p13. For a discussion of genetic heterogeneity of isolated colobomatous microphthalmia, see MCOPCB1 (300345). Clinical Features Ye et al. (2010) reported a mother and daughter with colobomatous microphthalmia. The mother had mild bilateral iris colobomata, mild microphthalmia, normal optic discs and electroretinograms (ERGs), and visual acuity of 20/40 in each eye. The more severely affected daughter exhibited mixed horizontal and rotatory nystagmus, bilateral iris coloboma, severe colobomatous microphthalmia, bilateral foveal hypoplasia, abnormally small optic discs with reduced optic nerve diameters on MRI, visual acuity of 20/200, and abnormal ERGs with decreased a and b wave amplitudes.
A number sign (#) is used with this entry because of evidence that isolated microphthalmia with coloboma-5 (MCOPCB5) is caused by heterozygous mutation in the Sonic hedgehog gene (SHH; 600725) on chromosome 7q36. For a discussion of genetic heterogeneity of isolated colobomatous microphthalmia, see MCOPCB1 (300345). Clinical Features Schimmenti et al. (2003) examined an 8-month-old boy with bilateral microphthalmia, bilateral inferonasal coloboma of the iris, a right-sided chorioretinal coloboma involving the entire optic disc and extending into the fovea, and a left-sided uveoretinal coloboma sparing the optic disc and macular area. The boy had no stigmata of holoprosencephaly or other anomalies or malformations, and on follow-up at age 11 years, he was an honors student with no serious medical illnesses. The mother of the proband was initially believed to be phenotypically normal, but thorough ophthalmic examination revealed a subtle right-sided inferonasal iris defect and a minimal uveoretinal coloboma, with a normal left eye.
A number sign (#) is used with this entry because of evidence that isolated microphthalmia and/or coloboma (MCOPCB10) is caused by heterozygous mutation in the RBP4 gene (180250) on chromosome 10q23. Clinical Features Chou et al. (2015) studied a 7-generation pedigree in which 11 family members had microphthalmia or clinical anophthalmia and/or coloboma. The first proband was an 8-year-old girl with bilateral clinical anophthalmia in whom MRI at day 1 of life showed bilateral absence of the eyeballs, with only cystic remnants in the orbits, thin optic nerves, and a small chiasm; there were no brain abnormalities. The right orbital cyst was surgically removed at 8 months; pathology revealed rudimentary eye structures. The second proband was an 11-year-old boy, a second cousin of the first proband, with left clinical anophthalmia and right microphthalmia with ventronasal iris and chorioretinal coloboma.
Description Ocular coloboma is a developmental defect of the eye resulting from abnormal or incomplete fusion of the optic fissure. The defect can be unilateral or bilateral and can involve the cornea, iris, ciliary body, lens, choroid, retina, and/or optic nerves. Clinically, coloboma is often associated with microphthalmia or clinical anophthalmia and can occur as part of complex malformation syndromes (summary by Wang et al., 2012). Genetic Heterogeneity of Isolated Microphthalmia With Coloboma Isolated colobomatous microphthalmia-1 (MCOPCB1) has been mapped to the X chromosome. MCOPCB2 (605738) has been mapped to chromosome 15q12-q15. MCOPCB3 (610092) is caused by mutation in the CHX10 gene (142993) on chromosome 14q24.
Colobomatous microphthalmia is a developmental disorder of the eye characterized by unilateral or bilateral microphthalmia associated with ocular coloboma.
A number sign (#) is used with this entry because of evidence that isolated colobomatous microphthalmia-7 (MCOPCB7) is caused by heterozygous mutation in the ABCB6 gene (605452) on chromosome 2q35. For a discussion of genetic heterogeneity of isolated colobomatous microphthalmia, see MCOPCB1 (300345). Mapping In members of a 3-generation Chinese family with autosomal dominant iris and chorioretinal coloboma who were negative for mutation in known coloboma-associated genes, Wang et al. (2012) performed genomewide linkage analysis and found linkage to chromosome 2q35. This family was originally reported by Dong et al. (2009). Molecular Genetics In a 3-generation Chinese family with autosomal dominant iris and chorioretinal coloboma mapping to chromosome 2q35 and known to be negative for mutation in known coloboma-associated genes, Wang et al. (2012) sequenced the exons of 76 candidate genes and identified a heterozygous missense mutation in the ABCB6 gene (L811V; 605452.0006) that segregated with disease in the family and was not found in DNA samples from 600 ethnically matched controls. Subsequent analysis of ABCB6 in 116 sporadic Indian coloboma patients, 63 of whom had microphthalmia and coloboma, 21 isolated coloboma, and 32 aniridia, who were all negative for mutation in 9 known coloboma genes, revealed heterozygosity for a different missense mutation (A57T; 605452.0007) in 3 unrelated patients with microphthalmia and coloboma; the mutation was not found in DNA samples from 200 ethnically matched controls.
A number sign (#) is used with this entry because isolated colobomatous microphthalmia-3 (MCOPCB3) is caused by homozygous mutation in the CHX10 gene (142993) on chromosome 14q24. For a discussion of genetic heterogeneity of isolated colobomatous microphthalmia, see MCOPCB1 (300345). Clinical Features Zlotogora et al. (1994) studied isolated colobomatous microphthalmia in multiple relatives of 5 consanguineous families. Microphthalmia was unilateral or bilateral; additional eye findings included microcornea and colobomas of the iris, choroid, optic discs, and/or optic nerve. The intelligence of all the affected members was normal. Three of the families were in an Iranian Jewish community where Zlotogora et al. (1994) suggested that the putative gene may have an unusually high frequency.
For a discussion of genetic heterogeneity of isolated colobomatous microphthalmia, see MCOPCB1 (300345). Clinical Features Morle et al. (2000) studied a 5-generation Sephardic Jewish family in which 7 of 38 members had either unilateral or bilateral microphthalmia of variable severity inherited as an autosomal dominant trait with incomplete penetrance. The inclusion criterion for the diagnosis of microphthalmia was reduction of the total axial length to less than 20 mm in at least 1 eye, determined by ultrasonography. Five of the 7 affected individuals had an ocular prosthesis in at least 1 eye. Two individuals were of uncertain status, since they had ocular anomalies but normal axial length bilaterally.
For a discussion of genetic heterogeneity of isolated microphthalmia with coloboma, see MCOPCB1 (300345). Isolated microphthalmia associated with colobomatous cyst results from a defect in the closure of the embryonic fissure at the 7- to 20-mm stage of development. Microphthalmia can be associated with either a small, clinically undetectable cyst, or a large, typically inferior cyst that deforms the eye and its surroundings. It is usually unilateral, although bilateral cases have been described. Porges et al. (1992) described 5 cases of microphthalmia with colobomatous cyst in 3 separate sibships of a highly inbred kindred.
They concluded that abnormal homocysteine metabolism could be attributed to thermolabile MTHFR in 28% of hyperhomocysteinemic patients with premature vascular disease.
Homocystinuria due to MTHFR deficiency is a genetic condition that results from poor metabolism of folate (also called vitamin B9), due to a lack of working enzyme called MTHFR. The gene that tells our body how to make the enzyme is also called MTHFR . At least 40 rare MTHFR gene variants have been found in people with decreased or no working enzyme. Very common gene variants (C677T and A1298C) can cause some decrease in enzyme function. People with homocystinuria due to MTHFR deficiency tend to have two rare variants or sometimes a rare variant and a common variant.
Homocystinuria due to methylene tetrahydrofolate reductase (MTHFR) deficiency is a metabolic disorder characterised by neurological manifestations. Epidemiology The prevalence is unknown. Clinical description Onset usually occurs during the first year of life with severe neurological signs, recurrent apnoea, microcephaly and convulsions. There is no megaloblastic anaemia. There are some forms with onset during childhood, adolescence, or adulthood beginning with mental regression, ataxia, and, most often, common psychiatric disorders of the schizophrenic type that may be linked to cerebrovascular accidents. Other symptoms such as subacute degeneration of the spinal chord have been reported. Etiology It is caused by mutations in the MTHFR gene (1p36.3). MTHFR deficiency results in abnormal intracellular folic acid metabolism and prevents reduction of 5-10 methylenetetrahydrofolate to 5-methyltetrahydrofolate, the methyl donor for the remethylation of homocysteine into methionine.
Methylenetetrahydrofolate reductase deficiency Other names MTHFR Methylenetetrahydrofolate reductase deficiency is the most common genetic cause of elevated serum levels of homocysteine ( hyperhomocysteinemia ). It is caused by genetic defects in MTHFR , which is an important enzyme in the methyl cycle. [1] Common variants of MTHFR deficiency are asymptomatic and have only minor effects on disease risk. [2] Severe variants (from nonsense mutations) are vanishingly rare. [3] Contents 1 Symptoms 2 Causes 3 Diagnosis 4 Management 5 Prognosis 6 Epidemiology 7 See also 8 References 9 External links Symptoms [ edit ] The common MTHFR deficiencies are usually asymptomatic, although the 677T variant can cause a mildly increased risk of some diseases. For individuals homozygous in the 677T variant, there is a mildly elevated risk of thromboembolism (odds ratio 1.2), [4] and stroke (odds ratio 1.26). [5] There is also an elevated risk of neural tube defects among children of individuals with the C677T polymorphism (odds ratio 1.38). [6] For cardiovascular risk, common MTHFR deficiencies were once thought to be associated but meta-analyses indicate that correlation this was an artifact of publication bias. [ clarification needed ] [7] [8] Causes [ edit ] MTHFR is the rate-limiting enzyme in the methyl cycle, which includes the conversion of homocysteine into methionine. Defects in variants of MTHFR can therefore lead to hyperhomocysteinemia . [9] There are two common variants of MTHFR deficiency. In the more significant of the two, the individual is homozygous for the 677T polymorphism.
Incidence of Clinical Features in Males with X-OS with an Identified MID1 Pathogenic Variant View in own window Clinical Feature # of Males with Clinical Feature / Total # of Males Hypertelorism 82/82 Hypospadias 65/85 Laryngotracheoesophageal defects 46/85 Intellectual disability and/or developmental delay 28/85 Cleft lip//palate 42/85 Congenital heart defects 20/85 Anal defects 18/85 Brain abnormalities 18/35 1 Fontanella et al [2008], Li et al [2015] 1.
Opitz G/BBB syndrome is a genetic condition that causes several abnormalities along the midline of the body. "G/BBB" represents the first letters of the last names of the families first diagnosed with this disorder and "Opitz" is the last name of the doctor who first described the signs and symptoms. There are two forms of Opitz G/BBB syndrome, X-linked Opitz G/BBB syndrome and autosomal dominant Opitz G/BBB syndrome. The two forms are distinguished by their genetic causes and patterns of inheritance. The signs and symptoms of the two forms are generally the same. Nearly everyone with Opitz G/BBB syndrome has wide-spaced eyes (ocular hypertelorism ).
A number sign (#) is used with this entry because of evidence that the X-linked form of Opitz GBBB syndrome (GBBB1) is caused by mutation in the MID1 gene (300552) on Xp22. Description The Opitz GBBB syndrome is a congenital midline malformation syndrome characterized by hypertelorism, hypospadias, cleft lip/palate, laryngotracheoesophageal abnormalities, imperforate anus, developmental delay, and cardiac defects (So et al., 2005). This disorder was first reported as 2 separate entities, BBB syndrome and G syndrome; subsequent reports of families in which the BBB and G syndromes segregated within a single kindred suggested that they represent a single entity. Genetic Heterogeneity See also GBBB2 (145410), caused by mutation in the SPECC1L gene (614140) on chromosome 22q11. Clinical Features Robin et al. (1996) compared the phenotypic features of the X-linked and autosomal (145410) forms of the Opitz syndrome.
Opitz G/BBB syndrome is an inherited condition that affects several structures along the midline of the body. The most common features are wide-spaced eyes and defects of the larynx, trachea, and/or esophagus causing breathing problems and difficulty swallowing. Affected males usually have a urethra opening on the underside of the penis ( hypospadias ). Other features can include mild intellectual disability, cleft lip and/or a cleft palate , heart defects, an obstruction of the anal opening ( imperforate anus ), agenesis of the corpus callosum , and facial abnormalities. These features may vary, even among members of the same family. There are two forms of Opitz G/BBB syndrome, which are distinguished by their genetic causes and patterns of inheritance.
A number sign (#) is used with this entry because of evidence that autosomal dominant Opitz GBBB syndrome (GBBB2) is caused by heterozygous mutation in the SPECC1L gene (614140) on chromosome 22q11.2. The phenotype can also result from heterozygous deletion at chromosome 22q11.2. Deletion in the same region may also result in DiGeorge syndrome (188400) and velocardiofacial syndrome (192430). Heterozygous mutation in the SPECC1L gene can also cause isolated oblique facial clefting-1 (OBLFC1; 600251). Description Features of the Opitz GBBB syndrome include hypertelorism or telecanthus; laryngotracheoesophageal cleft; clefts of lip, palate, and uvula; swallowing difficulty and hoarse cry; genitourinary defects, especially hypospadias in males and splayed labia majora in females; mental retardation; developmental delay; and congenital heart defects.
Cytogenetics Rittner et al. (1988) found increased chromosomal breakage rate (ICBR) in 27 of 28 patients with systemic sclerosis; 5 patients with CREST syndrome, 4 with incomplete CREST, 1 with overlapping syndrome, and 18 with progressive systemic sclerosis were studied.
Systemic sclerosis (SSc) is a generalized disorder of small arteries, microvessels and connective tissue, characterized by fibrosis and vascular obliteration in the skin and organs, particularly the lungs, heart, and digestive tract. There are two main subsets of SSc: diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc (lcSSc) (see these terms). A third subset of SSc has also been observed, called limited Systemic Sclerosis (lSSc) or systemic sclerosis sine scleroderma (see these terms). Epidemiology The prevalence is estimated at about 1/6,500 adults. Women are predominantly affected (F/M sex ratio around 4:1). Clinical description The disease usually manifests between 40 and 50 years of age.
Systemic scleroderma is an autoimmune disorder that affects the skin and internal organs. It is characterized by the buildup of scar tissue (fibrosis) in the skin and other organs. The fibrosis is caused by the body's production of too much collagen, which normally strengthens and supports connective tissues. The signs and symptoms of systemic scleroderma usually begin with episodes of Raynaud's phenomenon , which can occur weeks to years before fibrosis. This may be followed by puffy or swollen hands before the skin becomes thickened and hard.
This form, nephrogenic fibrosing dermopathy or nephrogenic systemic fibrosis, [28] [29] [30] [31] has been linked to exposure to gadolinium -containing radiocontrast . [32] Bleomycin [33] (a chemotherapeutic agent) and possibly taxane chemotherapy [34] may cause scleroderma, and occupational exposure to solvents has been linked with an increased risk of systemic sclerosis. [35] Pathophysiology [ edit ] Overproduction of collagen is thought to result from an autoimmune dysfunction, in which the immune system starts to attack the kinetochore of the chromosomes.
Other features included generalized hypotonia and hypertonia of extremities, hand flapping, sleeping difficulties, attention deficit-hyperactivity disorder, seizures, and behavioral abnormalities such as agitation and aggression. In 4 of 28 probands who had been diagnosed with FEVR and who did not have a mutation in known FEVR genes, Robitaille et al. (2014) identified heterozygous mutations in the KIF11 gene (see MOLECULAR GENETICS) as well as features suggestive of MCLMR such as microcephaly.
Microcephaly lymphoedema chorioretinal dysplasia Other names MLCRD syndrome Microcephaly lymphoedema chorioretinal dysplasia is a genetic condition associated with: Small head ( Microcephaly ) Puffy feet ( Lymphoedema ) Eye problems (Chorio-retinal dysplasia i.e. changes in the retina ) In 1992, Feingold and Bartoshesky described two unrelated children with microcephaly, lymphoedema and chorioretinal dysplasia (MIM 152950) as a distinct entity. Since then there have been further reports of children with these three features (Angle et al. 1994, Fryns et al. 1995, Limwongse et al. 1999, Casteels et al. 2001) Children have also been seen with two of the above features: Microcephaly and lymphoedema Microcephaly and chorioretinal dysplasia with or without intellectual disability Contents 1 Presentation 2 Genetics 3 Diagnosis 4 References 5 External links Presentation [ edit ] The distinct facial feature include upslanting palpebral fissures, a broad nose with rounded tip, long philtrum with a thin upper lip, pointed chin and prominent ears (Vasudevan 2005) Genetics [ edit ] The former (microcephaly and lymphoedema) has been described as an autosomal dominant (MIM 156590) or X-linked trait , while the latter (microcephaly and chorioretinal dysplasia) has been described as autosomal dominant, autosomal recessive (MIM 251270 or Mirhosseini-Holmes-Walton syndrome ) or X-linked trait. Diagnosis [ edit ] This section is empty. You can help by adding to it . ( March 2019 ) References [ edit ] 1. Feingold M, Bartoshesky L (1992) Microcephaly, lymphoedema, and chorioretinal dysplasia: a distinct syndrome? Am J Med Genet; 43:1030-1031. 2. Angle B, Holgado S, Burton BK (1994) Microcephaly, lymphoedema, and chorioretinal dysplasia: report of two additional cases.
Mean family size was 4.9 in the north as compared with 3.5 in the south. In 24 of 28 multiplex families the pattern of inheritance was autosomal dominant.
Keratoconus is an eye condition that affects the shape of the cornea, which is the clear outer covering of the eye. In this condition, the cornea thins and bulges outward, eventually resembling a cone shape. These corneal abnormalities, which worsen over time, can lead to nearsightedness (myopia ), blurred vision that cannot be improved with corrective lenses (irregular astigmatism), and vision loss. Other corneal changes typical of keratoconus that can be seen during an eye exam include iron deposits in the cornea that form a yellow-to-brownish ring, called the Fleischer ring, surrounding the colored part of the eye (iris). Affected individuals may also develop Vogt's striae, which are thin, vertical, white lines in the tissue at the back of the cornea.
Pober et al. (2005) reviewed and classified 203 unrelated cases of Bochdalek-type hernia identified over a 28-year period through a hospital-based surveillance program.
A rare developmental defect during embryogenesis which can be a non-syndromic (70%) or syndromic (30%) diaphragmatic malformation characterized by a posterolateral defect of the diaphragm that allows passage of abdominal viscera into the thorax, leading to respiratory insufficiency and persistent pulmonary hypertension. Epidemiology Congenital diaphragmatic hernia (CDH) is a rare condition occuring in 1-5/10,000 births. Clinical description Newborns display respiratory distress with hypoxia, excavated abdomen with sternal protrusion and in severe cases low APGAR scores at 1 and 5 minutes. Auscultation may reveal a contralateral cardiac displacement and respiratory bruits are absent or decreased on the affected side. Insufficient gas exchange and persistent pulmonary hypertension are associated with hypoplastic lungs.
Congenital diaphragmatic hernia (CDH) is a condition present before birth characterized by abnormal development of the diaphragm . The diaphragm normally separates the organs in the abdomen from those in the chest. The severity of CDH may range from a thinned area in part of the diaphragm, to its complete absence. CDH may allow the stomach and intestines to move through an opening (hernia) into the chest cavity, crowding the heart and lungs. This can then lead to underdevelopment of the lungs (pulmonary hypoplasia), which may cause life-threatening complications.
A number sign (#) is used with this entry because of evidence that diaphragmatic hernia-3 (DIH3) is caused by heterozygous mutation in the ZFPM2 gene (603693) on chromosome 8q23. For a general phenotypic description and a discussion of genetic heterogeneity of congenital diaphragmatic hernia, see (142340). Clinical Features Temple et al. (1994) reported 2 unrelated girls with isolated unilateral congenital diaphragmatic hernia. One child had a left posterolateral diaphragmatic hernia and a balanced reciprocal translocation (8;13)(q22.3;q22) inherited from her unaffected mother. The second child had a right posterolateral diaphragmatic hernia and a de novo balanced reciprocal translocation (8;15)(q22.3;q15).
Lilly et al. (1974) described a family in which 2 brothers and their maternal uncle had congenital, anterior diaphragmatic hernia. Two of the 3 died in infancy of complications. Crane (1979) favored multifactorial inheritance with high male:female sex ratio. Twelve multiplex families were analyzed. Misc - Frequent neonatal death Abdomen - Congenital, anterior diaphragmatic hernia Inheritance - X-linked vs. multifactorial with high male:female sex ratio ▲ Close
For a general phenotypic description and a discussion of genetic heterogeneity of congenital diaphragmatic hernia (CDH), see DIH1 (142340). Cytogenetics Shimokawa et al. (2005) reported a 37-week-old infant with left diaphragmatic hernia who had a 46,XY,del(8)(p23.1p23.1) karyotype. Surgical repair was unsuccessful, and postmortem examination showed hypoplasia of the left lung and atrial septal defect. Microsatellite analysis showed that the deletion was of paternal origin, and his parents did not carry 8p23.1 polymorphic inversion. Shimokawa et al. (2005) stated that this was the fourth report of CDH associated with 8p23.1 deletion (see Pecile et al., 1990; Faivre et al., 1998; Borys and Taxy, 2004).
In New Zealand , Australia , the United Kingdom (excluding Wales ) and most states in the United States , drivers are asked upon application if they wish to be registered as an organ donor. [27] In the United States, if the patient is at or near death, the hospital must notify a transplant organization of the person's details and maintain the patient while the patient is being evaluated for suitability as a donor. [28] The patient is kept on ventilator support until the organs have been surgically removed.
