An autosomal dominant cerebellar ataxia type I that is characterized by very slowly progressive or non-progressive ataxia, dysarthria, oculomotor abnormalities and intellectual disability. Epidemiology Spinocerebellar ataxia type 29 (SCA29) prevalence is unknown. More than 50 cases have been reported in the literature to date. Clinical description SCA29 presents at birth, or shortly after, with manifestations including very slowly progressive or non-progressive gait and limb ataxia causing delayed walking and frequent falling in children. Mild developmental delay, learning difficulties, and language dysfunction are frequently reported. Other manifestations include nystagmus, dysarthria, dysmetria, and dysdiadochokinesia.

A number sign (#) is used with this entry because isolated growth hormone deficiency type IB (IGHD1B) is caused by homozygous or compound heterozygous mutation in the GH1 (139250) gene on chromosome 17q23. Description IGHD type IB is an autosomal recessive disorder characterized by low but detectable levels of GH, short stature (more than 2 SD below the mean for age and sex), delayed bone age, and a good response to rhGH treatment without antibody formation (summary by Alatzoglou et al., 2014). For general phenotypic information and a discussion of genetic heterogeneity of IGHD, see 262400. Clinical Features Cogan et al. (1993) reported members of a consanguineous Saudi Arabian family with typical features of IGHD1B. Abdul-Latif et al. (2000) identified an extended, highly inbred Bedouin kindred with isolated growth hormone deficiency that clinically fulfilled the criteria for type IB.

A number sign (#) is used with this entry because of evidence that osteogenesis imperfecta type VI (OI6) is caused by homozygous mutation in the SERPINF1 gene (172860) on chromosome 17p13.3. Description Osteogenesis imperfecta (OI) comprises a group of connective tissue disorders characterized by bone fragility and low bone mass. The disorder is clinically and genetically heterogeneous. Osteogenesis imperfecta type VI is a severe autosomal recessive form of the disorder (Glorieux et al., 2002; Becker et al., 2011). Clinical Features Glorieux et al. (2002) described a novel form of OI, which they designated OI type VI, in 8 patients (6 males). None of the patients, all of whom had earlier been diagnosed with OI type IV (166220) (Ward et al., 2000), had documented fractures at birth.

A number sign (#) is used with this entry because osteogenesis imperfecta type XI (OI11) is caused by homozygous or compound heterozygous mutation in the FKBP10 gene (607063) on chromosome 17q21. Description Osteogenesis imperfecta (OI) comprises a group of connective tissue disorders characterized by bone fragility and low bone mass. The disorder is clinically and genetically heterogeneous. OI type XI is an autosomal recessive form of OI (summary by Alanay et al., 2010). Clinical Features Alanay et al. (2010) studied 5 consanguineous families from northern Turkey in which a severe progressive deforming type of OI cosegregated with autosomal recessive epidermolysis bullosa simplex (131900), the latter resulting from a defect in keratin-14 (148066). Dentinogenesis imperfecta, a feature of OI type III (259420), was absent.

A number sign (#) is used with this entry because of evidence that osteogenesis imperfecta type IX (OI9) is caused by homozygous or compound heterozygous mutation in the PPIB gene (123841) on chromosome 15q22. Description Osteogenesis imperfecta is a connective tissue disorder characterized clinically by bone fragility and increased susceptibility to fractures. Osteogenesis imperfecta type IX is a severe autosomal recessive form of the disorder (summary by van Dijk et al., 2009). Clinical Features In an inbred Irish Traveller family, Williams et al. (1989) described severe Sillence type II/III (166210/259420) osteogenesis imperfecta in 3 consecutively born children with first-cousin parents. Three other children were unaffected. There had been other infants in the kindred with lethal OI.

A number sign (#) is used with this entry because autosomal recessive osteogenesis imperfecta type XIII (OI13) can be caused by homozygous or compound heterozygous mutation in the BMP1 gene (112264) on chromosome 8p21. Description Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by bone fragility and low bone mass. Due to considerable phenotypic variability, Sillence et al. (1979) developed a classification of OI subtypes based on clinical features and disease severity: OI type I, with blue sclerae (166200); perinatal lethal OI type II, also known as congenital OI (166210); OI type III, a progressively deforming form with normal sclerae (259420); and OI type IV, with normal sclerae (166220). Most cases of OI are autosomal dominant with mutations in 1 of the 2 genes that code for type I collagen alpha chains, COL1A1 (120150) and COL1A2 (120160). Martinez-Glez et al. (2012) described osteogenesis imperfecta type XIII, an autosomal recessive form of the disorder characterized by normal teeth, faint blue sclerae, severe growth deficiency, borderline osteoporosis, and an average of 10 to 15 fractures a year affecting both upper and lower limbs and with severe bone deformity.

A number sign (#) is used with this entry because this form of autosomal recessive osteogenesis imperfecta (OI8) is caused by homozygous or compound heterozygous mutation in the LEPRE1 gene (P3H3; 610339) on chromosome 1p32. Description Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by bone fragility and low bone mass. Due to considerable phenotypic variability, Sillence et al. (1979) developed a classification of OI subtypes based on clinical features and disease severity: OI type I, with blue sclerae (166200); perinatal lethal OI type II, also known as congenital OI (166210); OI type III, a progressively deforming form with normal sclerae (259420); and OI type IV, with normal sclerae (166220). Most forms of OI are autosomal dominant with mutations in one of the 2 genes that code for type I collagen alpha chains, COL1A1 (120150) and COL1A2 (120160). Cabral et al. (2007) described a form of autosomal recessive OI, which they designated OI type VIII, characterized by white sclerae, severe growth deficiency, extreme skeletal undermineralization, and bulbous metaphyses.

Osteogenesis imperfecta type III (OI type III) is a form of osteogenesis imperfecta , a group of genetic conditions that primarily affect the bones. In OI type III, specifically, a diagnosis can often be made shortly after birth as fractures (broken bones) during the newborn period simply from handling the infant are common. Other signs and symptoms vary significantly from person to person but may include severe bone fragility, bone malformations, short stature, dental problems ( dentinogenesis imperfect ), macrocephaly (unusually large head), hearing loss, and blue sclerae (whites of the eyes). Most affected people are unable to walk without assistance. OI type III is caused by changes (mutations) in the COL1A1 or COL1A2 genes and is inherited in an autosomal dominant manner. Treatment is based on the signs and symptoms present in each person.

Osteogenesis imperfecta type III is a severe type of osteogenesis imperfecta (OI; see this term), a genetic disorder characterized by increased bone fragility, low bone mass and susceptibility to bone fractures. The main signs of type III include very short stature, a triangular face, severe scoliosis, grayish sclera, and dentinogenesis imperfecta (DI; see this term). Epidemiology The overall prevalence of OI is estimated at between 1/10,000 and 1/20,000 but the prevalence of type III is unknown. Etiology OI type III can be autosomal dominant and caused by mutations of the COL1A1 and COL1A2 genes (17q21.31-q22 and 7q22.1 respectively), or it can be autosomal recessive and caused by mutations of the CRTAP gene (3p22) (sometimes described as OI type VII) or the LEPRE1 gene (1p34) (sometimes described as OI type VIII) or the PPIB gene (15q21-q22) (sometimes described as OI type IX).

A number sign (#) is used with this entry because of evidence that osteogenesis imperfecta X (OI10) is caused by homozygous mutation in the SERPINH gene (600943) on chromosome 11q13. Description Osteogenesis imperfecta (OI) comprises a group of connective tissue disorders characterized by bone fragility and low bone mass. The disorder is clinically and genetically heterogeneous. OI type X is an autosomal recessive form characterized by multiple bone deformities and fractures, generalized osteopenia, dentinogenesis imperfecta, and blue sclera (Christiansen et al., 2010). Clinical Features Christiansen et al. (2010) reported a child with a severe deforming form of OI who was born to a clinically normal consanguineous Saudi Arabian couple and was the only affected member in the extended family. At birth he was noted to have a triangular face, relative macrocephaly, bitemporal narrowing, blue sclerae, micrognathia, and relatively short limbs with bowing at the thighs.

A number sign (#) is used with this entry because autosomal recessive osteogenesis imperfecta type XV (OI15) is caused by homozygous or compound heterozygous mutation in the WNT1 gene (164820) on chromosome 12q13. Description Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by bone fragility and low bone mass. Due to considerable phenotypic variability, Sillence et al. (1979) developed a classification of OI subtypes based on clinical features and disease severity: OI type I, with blue sclerae (166200); perinatal lethal OI type II, also known as congenital OI (166210); OI type III, a progressively deforming form with normal sclerae (259420); and OI type IV, with normal sclerae (166220). Most forms of OI are autosomal dominant with mutations in one of the 2 genes that code for type I collagen alpha chains, COL1A1 (120150) and COL1A2 (120160). Keupp et al. (2013) and Pyott et al. (2013) described osteogenesis imperfecta type XV, an autosomal recessive form of the disorder characterized by early-onset recurrent fractures, bone deformity, significant reduction of bone density, short stature, and, in some patients, blue sclera.

A number sign (#) is used with this entry because of evidence that autosomal recessive osteogenesis imperfecta type XVI (OI16) is caused by homozygous mutation in the CREB3L1 gene (616215) on chromosome 11p11. Mildly affected heterozygous family members have been reported. OI16 has also been reported in 1 family with a contiguous gene deletion including the CREB3L1 gene on chromosome 11p11.2. Description Osteogenesis imperfecta type XVI (OI16) is characterized by prenatal onset of multiple fractures of ribs and long bones, blue sclerae, decreased ossification of the skull, and severe demineralization. Heterozygous family members may exhibit recurrent fractures with minimal trauma, osteopenia, and blue sclerae (Keller et al., 2018; Lindahl et al., 2018). Clinical Features Symoens et al. (2013) reported a Turkish family in which 2 sibs had osteogenesis imperfecta.

Astrom and Soderhall (2002) performed a prospective observational study using disodium pamidronate (APD) in 28 children and adolescents (aged 0.6 to 18 years) with severe OI or a milder form of the disease, but with spinal compression fractures.

Overview Balance problems can make you feel dizzy, as if the room is spinning, unsteady, or lightheaded. You might feel as if the room is spinning or you're going to fall down. These feelings can happen whether you're lying down, sitting or standing. Many body systems — including your muscles, bones, joints, eyes, the balance organ in the inner ear, nerves, heart and blood vessels — must work normally for you to have normal balance. When these systems aren't functioning well, you can experience balance problems.

Description In moyamoya disease, stenosis of the intracranial portion of the internal carotid artery leads to secondary establishment of intracranial compensatory anastomoses at different levels (leptomeninges, basal ganglia, and transdural) (summary by Sakurai et al., 2004). For a general phenotypic description and a discussion of genetic heterogeneity of moyamoya disease, see MYMY1 (252350). Mapping Sakurai et al. (2004) searched for loci linked to moyamoya disease in 12 Japanese families using 428 microsatellite markers and found significant evidence for linkage to 8q23 (maximum lod score of 3.6 at marker D8S546) and suggestive evidence for linkage to 12p12 (maximum lod score of 2.3 at marker D12S1690).

Disease characterized by constriction of brain arteries Moyamoya disease T1-weighted MR image of moyamoya disease. Flow void in the basal ganglia is indicated by the arrow. Specialty Neurosurgery Moyamoya disease is a disease in which certain arteries in the brain are constricted. Blood flow is blocked by constriction and blood clots ( thrombosis ). [1] A collateral circulation develops around the blocked vessels to compensate for the blockage, but the collateral vessels are small, weak, and prone to bleeding , aneurysm and thrombosis. On conventional MR angiography , these collateral vessels have the appearance of a "puff of smoke" (described as "もやもや ( moyamoya )" in Japanese). [1] When moyamoya is diagnosed by itself, with no underlying correlational conditions, it is diagnosed as moyamoya disease. This is also the case when the arterial constriction and collateral circulation are bilateral.

Moyamoya disease is a rare, progressive, blood vessel disease caused by blocked arteries at the base of the brain in an area called the basal ganglia. The name "moyamoya" means "puff of smoke" in Japanese and describes the look of the tangled vessels that form to compensate for the blockage. This condition usually affects children, but can affect adults. Affected people are at increased risk for blood clots, strokes , and transient ischemic attacks (TIAs) which are frequently accompanied by seizures and muscular weakness, or paralysis on one side of the body. Affected people may also have disturbed consciousness, speech deficits (usually aphasia), sensory and cognitive impairments, involuntary movements, and vision problems. Researchers believe that Moyamoya disease is an inherited condition because it tends to run in families.

A number sign (#) is used with this entry because of evidence that moyamoya disease-5 (MYMY5) is caused by heterozygous mutation in the ACTA2 gene (102620) on chromosome 10q23. See also familial thoracic aortic aneurysm-6 (AAT6; 611788), which is an allelic vascular disorder. Description Moyamoya disease is a cerebrovascular disorder caused by stenotic changes of terminal portions of the internal carotid arteries accompanied by surrounding fine arterial collateral vessels. These vascular networks resemble a 'puff of smoke' (Japanese: moyamoya) in angiographic imaging (summary by Roder et al., 2011). For a general phenotypic description and a discussion of genetic heterogeneity of moyamoya disease, see MYMY1 (252350).

Description Moyamoya is the name given to a cerebral angiographic picture of bilateral intracranial carotid artery occlusion associated with telangiectatic vessels in the region of the basal ganglia. The Japanese word moyamoya means 'something hazy like a puff of cigarette smoke, drifting in the air.' Hemiplegia of sudden onset and epileptic seizures constitute the prevailing presentation in childhood, while subarachnoid bleeding occurs more frequently in adults (summary by Suzuki, 1986). Genetic Heterogeneity of Moyamoya Disease The MYMY1 locus maps to chromosome 3p. See also susceptibility to moyamoya disease-2 (MYMY2; 607151), caused by variation in the RNF213 gene (613768) on chromosome 17q25; MYMY3 (608796), which maps to chromosome 8q23; MYMY5 (614042), caused by mutation in the ACTA2 gene (102620) on chromosome 10q23; and MYMY6 with achalasia (615750), caused by mutation in the GUCY1A3 gene (139396) on chromosome 4q32.

Overview Moyamoya disease is a rare blood vessel disorder in which the carotid artery in the skull becomes blocked or narrowed. The carotid artery is a major artery that brings blood to the brain. When it's blocked, blood flow to the brain is reduced. Tiny blood vessels then develop at the base of the brain in an attempt to supply the brain with blood. The condition may cause a ministroke, known as a transient ischemic attack , or a stroke . It also can cause bleeding in the brain. Moyamoya disease can affect how well the brain functions and can cause cognitive and developmental delays or disability.

Moyamoya disease (MMD) is a rare intracranial arteriopathy involving progressive stenosis of the cerebral vasculature located at the base of the brain causing transient ischemic attacks or strokes. Epidemiology The incidence of MMD is highest in Asian populations but MMD occurs in many other ethnic groups. The incidence ranges from 1/280,000 to 1/89,000 in Japan and China to1/1,100,000 in the US. The prevalence in Japan is estimated to be 1/30,000-1/9,500. Clinical description There are two peak incidence ages: young children (5-9 years) and adults (mid-40s). Involvement is usually bilateral but unilateral cases are reported. Disease manifestations are highly variable.

Sjögren-Larsson syndrome is a condition characterized by dry, scaly skin (ichthyosis); neurological problems; and eye problems. These symptoms are apparent by early childhood and usually do not worsen with age. Affected infants tend to be born prematurely. At birth the skin is red (erythema), but later in infancy the skin becomes dry, rough, and scaly with a brownish or yellowish tone. Mild to severe itchiness (pruritus) is also common. These skin abnormalities are generally dispersed over the whole body, most severely affecting the nape of the neck, the torso, and the extremities. The skin of the face is usually not affected. People with this condition may also have neurological signs and symptoms.

Not to be confused with Sjögren's syndrome , an autoimmune disorder which can cause many problems including dry skin. Sjögren–Larsson syndrome Other names SLS Two brothers (21 and 25 years old) with generalized dryness of skin with fine scales mainly around the umbilicus and in the flexural folds, one of Sjögren–Larsson syndrome characteristics. Specialty Medical genetics Sjögren–Larsson syndrome is a rare autosomal recessive form of ichthyosis with neurological symptoms. [1] : 485 [2] : 564 [3] It can be identified by a triad of medical disorders. The first is ichthyosis , which is a buildup of skin to form a scale-like covering that causes dry skin and other problems. The second identifier is paraplegia which is characterized by leg spasms.

A rare neurocutaneous disorder caused by an inborn error of lipid metabolism and characterized by congenital ichthyosis, intellectual deficit, and spasticity. Epidemiology Prevalence is estimated at 1/250,000 worldwide, but the syndrome is more common in Sweden due to a founder effect. Clinical description Clinical features develop perinatally and during infancy. Patients tend to be born preterm. Hyperkeratosis is usually present at birth and progresses to a generalized ichthyosis, particularly prominent on flexural areas, the nape of the neck, the trunk and the extremities. Pruritus is a prominent feature. Erythematous dermatitis is often present at birth, and then tends to fade with increasing age.

Sjogren-Larsson syndrome (SLS) is an inborn error of lipid metabolism , characterized by congenital ichthyosis (dry, scaly skin), intellectual disability, and spasticity (stiffness and involuntary muscle spasms). The syndrome is caused by mutations in the gene called FADH (fatty aldehyde dehydrogenase) and is inherited in an autosomal recessive fashion . Treatment is symptomatic.

A number sign (#) is used with this entry because of evidence that 3M syndrome-2 (3M2) is caused by homozygous or compound heterozygous mutation in the OBSL1 gene (610991) on chromosome 2q35. Description 3M syndrome-2 (3M2) is characterized by low birth weight and short stature, relative macrocephaly, lumbar hyperlordosis, and prominent heels. Dysmorphic facial features include triangular face with frontal bossing and midface hypoplasia, anteverted nares with fleshy nasal tip, and full fleshy lips (Hanson et al., 2009). For a general phenotypic description and a discussion of genetic heterogeneity of 3M syndrome, see 3M1 (273750). Clinical Features Temtamy et al. (2006) reported 2 Egyptian brothers and an unrelated Egyptian boy who exhibited the characteristic features and radiologic findings of 3M syndrome, including low birth weight, short stature, malar hypoplasia, anteverted nostrils with a fleshy nasal tip, long philtrum, pointed full chin, short broad neck, broad chest with transverse grooves of the anterior thorax, and hyperlordosis.

In 2 sisters Fuhrmann et al. (1972) described a form of dwarfism with disproportionately tall vertebral bodies (i.e., reduced anteroposterior dimension). Other features were very slender, caudally directed lower ribs, coxa vara, and a cordate pelvis. Since the parents were not related and the mother showed minor changes (short stature and somewhat tall vertebrae), dominant inheritance with variable expressivity was suggested. Radiology - Disproportionately tall vertebral bodies Skel - Slender, caudally directed lower ribs - Coxa vara - Cordate pelvis Growth - Dwarfism Inheritance - Autosomal dominant ▲ Close

3M syndrome is a growth disorder that causes short stature, characteristic facial features, and skeletal abnormalities. Intelligence is normal. The name comes from the initials of three researchers who first identified it: Miller, McKusick, and Malvaux. 3M syndrome is caused by mutations in one of three genes: CUL7 , OBSL1 , and CCDC8 . It is inherited in an autosomal recessive pattern. Diagnosis is based on the presence of clinical features. Genetic testing can confirm the diagnosis and identify the specific gene involved. Treatment is aimed at addressing the growth and skeletal problems and may include surgical bone lengthening, adaptive aids, and physical therapy.

A number sign (#) is used with this entry because 3M syndrome-3 (3M3) can be caused by homozygous mutation in the CCDC8 gene (614145) on chromosome 19q13. Description The 3M syndrome is characterized by poor postnatal growth and distinctive facial features, including triangular facies, frontal bossing, fleshy tipped nose, and fleshy lips. Other features may include skeletal anomalies and prominent heels (summary by Hanson et al., 2011). For a general phenotypic description and a discussion of genetic heterogeneity of 3M syndrome, see 3M1 (273750). Clinical Features Hanson et al. (2011) described 5 unrelated probands, all born of consanguineous Asian parents, with 3M syndrome.

Mild Canavan disease (CD) is a neurodegenerative disorder characterized by mild speech delay or motor development. Epidemiology Mild CD has been identified in only a few cases. The majority of patients with Canavan disease have the severe form (see this term). In contrast to the severe CD, most mild CD patients are not from Ashkenazi Jewish descent. Clinical description Mild CD usually presents in childhood with mild developmental delay or problems with speech or motor development. Head circumference is usually normal. Retinitis pigmentosa (see this term) may be present. .

Chuvash erythrocytosis is a rare, genetic, congenital secondary polycythemia disorder characterized by increased hemoglobin, hematocrit and erythropoietin serum levels and normal oxygen affinity, which usually manifests with headache, dizziness, dyspnea and/or plethora. Patients present an increased risk of hemorrhage, thrombosis and early death.

17 alpha(α)-hydroxylase/17,20-lyase deficiency is a condition that affects the function of certain hormone-producing glands called the gonads (ovaries in females and testes in males) and the adrenal glands. The gonads direct sexual development before birth and during puberty and are important for reproduction. The adrenal glands, which are located on top of the kidneys, regulate the production of certain hormones, including those that control salt levels in the body. People with 17α-hydroxylase/17,20-lyase deficiency have an imbalance of many of the hormones that are made in these glands. 17α-hydroxylase/17,20-lyase deficiency is one of a group of disorders, known as congenital adrenal hyperplasias, that impair hormone production and disrupt sexual development and maturation. Hormone imbalances lead to the characteristic signs and symptoms of 17α-hydroxylase/17,20-lyase deficiency, which include high blood pressure (hypertension), low levels of potassium in the blood (hypokalemia), and abnormal sexual development.

46,XY disorder of sex development due to isolated 17,20-lyase deficiency is a rare disorder of sex development due to reduced 17,20-lyase activity that affects individuals with 46,XY karyotype and is characterized by ambiguous external genitalia, including micropenis, perineal hypospadias, bifid scrotum, cryptorchidism, and a blind vaginal pouch. Blood pressure and electrolytes are normal whilst hormonal investigations show normal basal and stimulated levels of cortisol, and low basal and stimulated androgen levels.

Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency Specialty Endocrinology , obstetrics and gynaecology , medical genetics Congenital adrenal hyperplasia due to 17α-hydroxylase deficiency is an uncommon form of congenital adrenal hyperplasia resulting from a defect in the gene CYP17A1 , which encodes for the enzyme 17α-hydroxylase. It causes decreased synthesis of cortisol and sex steroids , with resulting increase in mineralocorticoid production. Thus, common symptoms include mild hypocortisolism , ambiguous genitalia in genetic males or failure of the ovaries to function at puberty in genetic females, and hypokalemic hypertension (respectively). [1] However, partial (incomplete) deficiency is notable for having inconsistent symptoms between patients, [2] and affected genetic (XX) females may be wholly asymptomatic except for infertility. [3] Contents 1 Pathophysiology 1.1 Mineralocorticoid effects 1.2 Glucocorticoid effects 1.3 Sex steroid effects 2 17,20-lyase deficiency 3 Management 4 See also 5 References 6 Further reading 7 External links Pathophysiology [ edit ] 17α-hydroxylase converts pregnenolone and progesterone to their 17α-hydroxy forms. It corresponds to the red arrows in this reaction scheme. This form of CAH results from deficiency of the enzyme 17α-hydroxylase (also called CYP17A1 ). It accounts for less than 5% of the cases of congenital adrenal hyperplasia and is inherited in an autosomal recessive manner with a reported incidence of about 1 in 1,000,000 births. [ citation needed ] The most common abnormal alleles of this condition impair both the 17α-hydroxylase activity and the 17,20-lyase activity of CYP17A1.

A very rare form of congenital adrenal hyperplasia (CAH) characterized by glucocorticoid deficiency, hypergonadotrophic hypogonadism and severe hypokalemic hypertension. Epidemiology It accounts for approximately 1% of all CAH cases. The prevalence is therefore around 1/1,000,000. Clinical description Both a sex steroid and glucocorticoid deficiency are present. Common manifestations include undervirilization in males, primary amenorrhea in females and lack of pubertal development in both sexes. Hypertension, often accompanied by hypokalemia, can also develop due to the mineralocorticoid excess seen in this disease.

Progeria-short stature-pigmented nevi is a progeroid disorder characterised by low birthweight, short stature, multiple pigmented nevi and lack of facial subcutaneous fat. Epidemiology Less than ten cases have been described so far. Clinical description Other clinical features include immunodeficiency, high-pitched voice and progressive hearing and visual loss. Motor and intellectual development is normal or slightly impaired.

Facioscapulohumeral muscular dystrophy is a disorder characterized by muscle weakness and wasting (atrophy). This condition gets its name from the muscles that are affected most often: those of the face (facio-), around the shoulder blades (scapulo-), and in the upper arms (humeral). The signs and symptoms of facioscapulohumeral muscular dystrophy usually appear in adolescence. However, the onset and severity of the condition varies widely. Milder cases may not become noticeable until later in life, whereas rare severe cases become apparent in infancy or early childhood. Weakness involving the facial muscles or shoulders is usually the first symptom of this condition.

A rare neuromuscular disease characterized by progressive muscle weakness with focal involvement of the facial, shoulder and limb muscles. Epidemiology Facioscapulohumeral muscular dystrophy (FSHD) is a rare familial disease with an estimated prevalence from 1/8,000 to 1/20,000. It is the third most common form of hereditary myopathy. Clinical description Onset occurs at any age. Disease progression is usually slow but some patients display periods of stability followed by periods of rapid deterioration. Early onset of FSHD is associated with more widespread muscle weakness.

A number sign (#) is used with this entry because facioscapulohumeral muscular dystrophy-1 (FSHD1) is associated with contraction of the D4Z4 macrosatellite repeat (see 606009) in the subtelomeric region of chromosome 4q35. In unaffected individuals, the D4Z4 array consists of 11 to 150 repeat units (corresponding to EcoRI fragments of 41 to 350 kb), whereas FSHD patients have contraction of the repeat units from 1 to 10 (corresponding to EcoRI fragments of 10 to 35 kb). Borderline fragment sizes (35 to 40 kb) must be interpreted with caution (summary by Mostacciuolo et al., 2009). The genetics of FSHD is, however, complex, and detection of a D4Z4-reduced allele may not be sufficient for diagnosis (see DIAGNOSIS below and Scionti et al., 2012). Description Facioscapulohumeral muscular dystrophy is the third most common hereditary disease of muscle after Duchenne (DMD; 310200) and myotonic (160900) dystrophy.

Muscle involvement from medical imaging perspective [ edit ] Medical imaging (CT and MRI) has shown muscle damage that doesn't cause obvious symptoms. [22] A single MRI study shows the teres major muscle to be commonly affected. [23] The semimembranosus muscle , part of the hamstrings , is commonly affected, [17] [25] [26] with one author stating it to be "the most frequently and severely affected muscle." [1] Also, MRI shows that the rectus femoris is more often affected than the other muscles of the quadriceps, [25] the medial gastrocnemius is more often affected than the lateral gastrocnemius, [25] [26] and the iliopsoas muscle is very often spared. [26] [1] Non-musculoskeletal [ edit ] The most common non-musculoskeletal manifestation of FSHD is mild retinal blood vessel abnormalities, such as telangiectasias or microaneurysms, with one study placing the incidence at 50%. [ citation needed ] These abnormal blood vessels generally do not affect vision or health, although a severe form of it mimics Coat's disease , a condition found in about 1% of FSHD cases and more frequently associated with large 4q35 deletions. [1] [27] High-frequency hearing loss can occur in those with large 4q35 deletions, but otherwise is no more common compared to the general population. [1] Breathing can be affected, associated with kyphoscoliosis and wheelchair use; it is seen in one-third of wheelchair-bound patients. [ citation needed ] However, ventilator support (nocturnal or diurnal) is needed in only 1% of cases. [1] [28] Genetics [ edit ] The genetics of FSHD are complex, culminating in abnormal expression of the DUX4 gene. [1] [5] In those without FSHD, DUX4 is expressed during embryogenesis and, at some point, becomes repressed in all tissues except the testes . ... The term facioscapulohumeral dystrophy is introduced . [81] 1982 Padberg provides the first linkage studies to determine the genetic locus for FSHD in his seminal thesis "Facioscapulohumeral disease." [16] 1987 The complete sequence of the Dystrophin gene ( Duchenne’s MD ) is determined. [82] 1991 The genetic defect in FSHD is linked to a region (4q35) near the tip of the long arm of chromosome 4 . [83] 1992 FSHD, in both familial and de novo cases , is found to be linked to a recombination event that reduces the size of 4q Eco R1 fragment to < 28 kb (50–300 kb normally). [56] 1993 4q Eco R1 fragments are found to contain tandem arrangement of multiple 3.3-kb units (D4Z4), and FSHD is associated with the presence of < 11 D4Z4 units. [55] A study of seven families with FSHD reveals evidence of genetic heterogeneity in FSHD. [84] 1994 The heterochromatic structure of 4q35 is recognized as a factor that may affect the expression of FSHD, possibly via position-effect variegation . [85] DNA sequencing within D4Z4 units shows they contain an open reading frame corresponding to two homeobox domains, but investigators conclude that D4Z4 is unlikely to code for a functional transcript. [85] [86] 1995 The terms FSHD1A and FSHD1B are introduced to describe 4q-linked and non-4q-linked forms of the disease. [87] 1996 FSHD Region Gene1 ( FRG1 ) is discovered 100 kb proximal to D4Z4. [88] 1998 Monozygotic twins with vastly different clinical expression of FSHD are described. [14] 1999 Complete sequencing of 4q35 D4Z4 units reveals a promoter region located 149 bp 5' from the open reading frame for the two homeobox domains, indicating a gene that encodes a protein of 391 amino acid protein (later corrected to 424 aa [89] ), given the name DUX4 . [90] 2001 Investigators assessed the methylation state ( heterochromatin is more highly methylated than euchromatin ) of DNA in 4q35 D4Z4. ... ISBN 978-0-323-35317-5 . ^ a b c Snider, L; Geng, LN; Lemmers, RJ; Kyba, M; Ware, CB; Nelson, AM; Tawil, R; Filippova, GN; van der Maarel, SM; Tapscott, SJ; Miller, DG (28 October 2010). "Facioscapulohumeral dystrophy: incomplete suppression of a retrotransposed gene" .

Facioscapulohumeral muscular dystrophy is a disorder characterized by muscle weakness and wasting (atrophy). This condition gets its name from the areas of the body that are affected most often: muscles in the face (facio-), around the shoulder blades (scapulo-), and in the upper arms (humeral). The signs and symptoms of facioscapulohumeral muscular dystrophy usually appear in adolescence. However, the onset and severity of the condition varies widely. Facioscapulohumeral muscular dystrophy results from a deletion of genetic material from a region of DNA known as D4Z4. This region is located near one end of chromosome 4 . It is inherited in an autosomal dominant pattern.

Summary Clinical characteristics. Facioscapulohumeral muscular dystrophy (FSHD) typically presents with weakness of the facial muscles, the stabilizers of the scapula, or the dorsiflexors of the foot. Severity is highly variable. Weakness is slowly progressive and approximately 20% of affected individuals eventually require a wheelchair. Life expectancy is not shortened. Diagnosis/testing. The diagnosis of FSHD1 is established in a proband with characteristic clinical features by identification of a heterozygous pathogenic contraction of the D4Z4 repeat array in the subtelomeric region of chromosome 4q35 on a chromosome 4 permissive haplotype. The diagnosis of FSHD2 is established in a proband by identification of hypomethylation of the D4Z4 repeat array in the subtelomeric region of chromosome 4q35 on a chromosome 4 permissive haplotype. Hypomethylation of the D4Z4 repeat array can be due to a heterozygous pathogenic variant in SMCHD1 or DNMT3B .

Jardine et al. (1994) described 7 affected individuals, 3 men and 4 women, in a 2-generation family segregating a scapulohumeral muscular dystrophy. Weakness began in the shoulders between 12 and 40 years of age. There was no distal weakness in the upper or lower extremities and there were no sensory abnormalities. In several cases, there was marked asymmetry with weakness on the right side more than on the left. There was no demonstrable facial weakness in any of the affected individuals. Male-to-male transmission was not observed. There was only minimal elevation of creatine kinase in some individuals.

5q minus (5q-) syndrome is a type of bone marrow disorder called myelodysplastic syndrome (MDS). MDS comprises a group of conditions in which immature blood cells fail to develop normally, resulting in too many immature cells and too few normal mature blood cells. In 5q- syndrome, development of red blood cells is particularly affected, leading to a shortage of these cells (anemia ). In addition, the red blood cells that are present are unusually large (macrocytic). Although many people with 5q- syndrome have no symptoms related to anemia, especially in the early stages of the condition, some affected individuals develop extreme tiredness (fatigue), weakness, and an abnormally pale appearance (pallor) as the condition worsens.

A rare myelodysplastic syndrome characterized by macrocytic anemia (with or without other cytopenias and/or thrombocytosis), and with del(5q) occurring either in isolation, or with one other cytogenetic abnormality, other than monosomy 7 or del(7q). The bone marrow is typically hypercellular with erythroid hypoplasia and increased numbers of megakaryocytes, which show non-lobated and hypolobated nuclei. Myeloblasts constitute less than 5% of the nucleated bone marrow cells and less than 1% of the peripheral blood leukocytes. Auer rods are absent. Ring sideroblasts may be observed. Patients present with anemia and often thrombocytosis, while thrombocytopenia or pancytopenia are uncommon. Transformation to acute myeloid leukemia may occur in a small number of patients.