Spondylocostal dysostosis is a group of conditions characterized by abnormal development of the bones in the spine and ribs. In the spine, the vertebrae are misshapen and fused. Many people with this condition have an abnormal side-to-side curvature of the spine (scoliosis). The ribs may be fused together or missing. These bone malformations lead to short, rigid necks and short midsections. Infants with spondylocostal dysostosis have small, narrow chests that cannot fully expand. This can lead to life-threatening breathing problems. Males with this condition are at an increased risk for inguinal hernia , where the diaphragm is pushed down, causing the abdomen to bulge out.

A number sign (#) is used with this entry because of evidence that autosomal recessive spondylocostal dysostosis-3 (SCDO3) is caused by homozygous or compound heterozygous mutation in the LFNG gene (602576) on chromosome 7p22. For a phenotypic description and a discussion of genetic heterogeneity of spondylocostal dysostosis, see 277300. Clinical Features Sparrow et al. (2006) reported a proband of Lebanese background who presented with extensive congenital vertebral anomalies; long, slender fingers; and camptodactyly of the left index finger. X-ray and magnetic resonance imaging (MRI) scans showed multiple vertebral ossification centers in the thoracic spine, which showed fitted angular shapes similar to those seen in the patient with spondylocostal dysostosis (SCDO2; see 608681) caused by mutation in the MESP2 gene (605195) (Whittock et al., 2004). Severe foreshortening of the spine was emphasized by comparison of the patient's arm span (186.5 cm) with adult height (155 cm; lower segment 92.5 cm).

A number sign (#) is used with this entry because autosomal recessive spondylocostal dysostosis-2 (SCDO2) is caused by homozygous or compound heterozygous mutation in the MESP2 gene (605195) on chromosome 15q26. Description Spondylocostal dysostosis is a term given to a heterogeneous group of disorders characterized by abnormal vertebral segmentation. For a general phenotypic description and a discussion of genetic heterogeneity of the disorder, see SCDO1 (277300). Clinical Features Whittock et al. (2004) studied a consanguineous Lebanese Arab family in which 2 offspring were affected with spondylocostal dysostosis. Affected individuals presented with trunkal shortening and short necks but no other abnormalities.

A number sign (#) is used with this entry because autosomal recessive spondylocostal dysostosis-1 (SCDO1) is caused by homozygous or compound heterozygous mutation in the DLL3 gene (602768) on chromosome 19q13. Description The spondylocostal dysostoses are a heterogeneous group of axial skeletal disorders characterized by multiple segmentation defects of the vertebrae (SDV), malalignment of the ribs with variable points of intercostal fusion, and often a reduction in rib number. The term 'spondylocostal dysostosis' is best applied to those phenotypes with generalized SDV and a broadly symmetric thoracic cage (summary by Gucev et al., 2010). Genetic Heterogeneity of Spondylocostal Dysostosis Other forms of SCDO include SCDO2 (608681), caused by mutation in the MESP2 gene (605195) on chromosome 15q26; SCDO3 (609813), caused by mutation in the LFNG gene (602576) on chromosome 7p22; SCDO4 (613686), caused by mutation in the HES7 gene (608059) on chromosome 17p13; SCDO5 (122600), caused by mutation in the TBX6 gene (602427) on chromosome 16p11; and SCDO6 (616566), caused by mutation in the RIPPLY2 gene (609891) on chromosome 6q14. Clinical Features Lavy et al. (1966) observed 4 of 7 offspring of a third-cousin marriage who had characteristic vertebral anomalies including hemivertebrae and block vertebrae accompanied by deformity of the ribs.

Spondylocostal dysostosis is a group of conditions characterized by abnormal development of bones in the spine and ribs. The bones of the spine (vertebrae) are misshapen and abnormally joined together (fused). Many people with this condition have abnormal side-to-side curvature of the spine (scoliosis ) due to malformation of the vertebrae. In addition to spinal abnormalities, some of the rib bones may be fused together or missing. Affected individuals have short, rigid necks and short torsos because of the bone malformations.

Axial skeleton growth disorder Jarcho-Levin Syndrome Radiograph depicting typical skeletal features of Jarcho-Levin syndrome, subtype spondylothoracic dysplasia . Note fanlike configuration of the ribs, with extensive posterior fusion, along with multiple vertebral segmentation defects. Specialty Medical genetics Spondylocostal dysostosis , also known as Jarcho-Levin syndrome (JLS) , is a rare, heritable axial skeleton growth disorder. It is characterized by widespread and sometimes severe malformations of the vertebral column and ribs , shortened thorax , and moderate to severe scoliosis and kyphosis . Individuals with Jarcho-Levin typically appear to have a short trunk and neck, with arms appearing relatively long in comparison, and a slightly protuberant abdomen .

A rare condition of variable severity associated with vertebral and rib segmentation defects and characterised by a short neck with limited mobility, winged scapulae, a short trunk, and short stature with multiple vertebral anomalies at all levels of the spine. Epidemiology The incidence and prevalence are unknown. The disease seems to be more frequent in the Puerto Rican population. Clinical description Autosomal recessive spondylocostal dysostosis (ARSD) is usually diagnosed in the neonatal period. The main skeletal malformations include fusion of the vertebrae, hemivertebrae, and rib fusion with other rib malformations. Deformity of the chest and spine (severe scoliosis, kyphoscoliosis and lordosis) is a natural consequence of these malformations and leads to a dwarf-like appearance.

Spondylothoracic dysostosis (STD) is a rare condition that affects the bones of the spine and the ribs. The term “Jarcho-Levin syndrome” in many cases is used as a synonym for STD, and sometimes as a synonym for another condition known as spondylocostal dysostosis , which has several common features with STD. Also, the term “Jarcho-Levin syndrome” is often used for all radiologic features that include defects of the vertebrae and abnormal rib alignment. Signs and symptoms of STD are generally present at birth and may include short-trunk dwarfism (a short body with normal length arms and legs); a small chest cavity; misshapen and abnormally-fused vertebrae (bones of the spine); and fused ribs at the part nearest the spine. Affected people may also have life-threatening breathing problems and recurrent lung infections, which can significantly reduce lifespan.

A number sign (#) is used with this entry because spondylocostal dysostosis-4 (SCDO4) is caused by homozygous or compound heterozygous mutation in the HES7 gene (608059) on chromosome 17p13. For a general phenotypic description and a discussion of genetic heterogeneity of spondylocostal dysostosis (SCDO), see SCDO1 (277300). Clinical Features Sparrow et al. (2008) described a consanguineous family of Caucasian Mediterranean origin in which the proband was diagnosed prenatally with hydrocephalus and myelomeningocele, and at birth was found to have a bell-shaped, symmetric, and shortened thorax, lumbosacral myelomeningocele, ectopic and stenotic anus, and talipes. Radiologic examination showed shortening of the spine, with multiple and contiguous vertebral segmentation defects involving all spinal regions, but mainly the thoracic spine. The ribs had very crowded origins on the left side, and were irregularly aligned with variable points of fusion along their length on the right side.

Spondylothoracic dysostosis is a condition characterized by malformation of the bones of the spine and ribs. The bones of the spine (vertebrae) do not develop properly, which causes them to be misshapen and abnormally joined together (fused). The ribs are also fused at the part nearest the spine (posteriorly), which gives the rib cage its characteristic fan-like or "crab" appearance in x-rays. Affected individuals have short, rigid necks and short torsos because of the bone malformations. As a result, people with spondylothoracic dysostosis have short bodies but normal-length arms and legs, called short-trunk dwarfism.

The diagnosis of EE is suggested by clinical findings and the laboratory findings of increased blood lactate levels, C4- and C5-acylcarnitine esters, plasma thiosulphate, and urinary ethylmalonic acid. ... Clinical findings Global neurologic impairment Early-onset progressive psychomotor regression Seizures Dystonia Diffuse microvasculature injury Petechiae and/or purpura Orthostatic acrocyanosis Hemorrhagic suffusions of mucosal surfaces Chronic hemorrhagic diarrhea Preliminary laboratory findings Increased blood lactate levels (normal range: 6-22 mg/dL) Increased blood C4-acylcarnitine esters (normal range: <0.9 μmol/L) [Merinero et al 2006, Zafeiriou et al 2007] * Increased blood C5-acylcarnitine esters (normal range: <0.3 μmol/L) [Merinero et al 2006, Zafeiriou et al 2007] * Increased plasma thiosulphate (normal range: <4 μmol/L) Increased urinary ethylmalonic acid (normal range: <10 μmol/mmol creatinine) evaluated on spot urine [Merinero et al 2006, Zafeiriou et al 2007] * More data are needed to define the range of C4/C5 acylcarnitine elevation in individuals with molecularly proven EE. ... Tandem mass spectroscopy can identify C4 elevation in a NBS dried blood spot; however, NBS for EE is not available in the US as there is no definitive treatment (see Therapies Under Investigation). Note: (1) NBS may be performed elsewhere in the world. (2) C4 elevation can also be found in primary short-chain acyl-CoA dehydrogenase (SCAD) deficiency [McHugh et al 2011]; an algorithm (pdf) from the American College of Medical Genetics can be used to distinguish the two disorders.

The ETHE1 enzyme is part of a pathway that breaks down sulfide (H 2 S), a molecule that is critical at very low levels for normal cell functioning but is toxic at high levels.

Symptoms are present at birth and tend to get worse over time. These include low muscle tone, spasms of the arms and legs, seizures, and developmental delay.

Animal Model Tiranti et al. (2009) found that Ethe1-null mice developed the cardinal features of ethylmalonic encephalopathy, including poor growth, reduced motor activity, early death, low cytochrome c oxidase (COX) in muscle and brain, and increased urinary excretion of ethylmalonic acid. ... INHERITANCE - Autosomal recessive GROWTH Other - Failure to thrive HEAD & NECK Eyes - Retinal lesions with tortuous vessels CARDIOVASCULAR Vascular - Orthostatic acrocyanosis ABDOMEN Gastrointestinal - Chronic diarrhea SKIN, NAILS, & HAIR Skin - Petechiae - Orthostatic acrocyanosis NEUROLOGIC Central Nervous System - Developmental regression - Developmental delay - Mental retardation - Pyramidal symptoms - Extrapyramidal symptoms - Ataxia - Hypotonia - Seizures - Hyperintense lesions in the basal ganglia on MRI LABORATORY ABNORMALITIES - Lactic acidemia - Ethylmalonic aciduria - Methylsuccinic aciduria - Cytochrome c oxidase deficiency in skeletal muscle and brain - Increased serum C4 and C5 acylcarnitine esters - Increased urinary isobutyryl glycine - Increased urinary 2-methylbutyryl glycine - Increased urinary thiosulphate MISCELLANEOUS - Onset in first months of life - Patients are often of Mediterranean origin - Death usually occurs in first decade of life MOLECULAR BASIS - Caused by mutation in the ETHE1 gene (ETHE1, 608451.0001 ) ▲ Close

Ethylmalonic encephalopathy Ethylmalonic encephalopathy has an autosomal recessive pattern of inheritance . Specialty Medical genetics Ethylmalonic encephalopathy ( EE ) is a rare autosomal recessive inborn error of metabolism . Patients affected with EE are typically identified shortly after birth, with symptoms including diarrhea , petechiae and seizures . [1] [2] The genetic defect in EE is thought to involve an impairment in the degradation of sulfide intermediates in the body. Hydrogen sulfide then builds up to toxic levels. [3] EE was initially described in 1994. [4] Most cases of EE have been described in individuals of Mediterranean or Arabic origin. [3] Contents 1 Signs and symptoms 2 Pathophysiology 3 Diagnosis 4 Treatment 5 References 6 External links Signs and symptoms [ edit ] Neurologic signs and symptoms include progressively delayed development, weak muscle tone ( hypotonia ), seizures, and abnormal movements. The body's network of blood vessels is also affected. Children with this disorder may experience rashes of tiny red spots ( petechiae ) caused by bleeding under the skin and blue discoloration in the hands and feet due to reduced oxygen in the blood ( acrocyanosis ).

While screening a large population of patients with recurrent angioedema of the skin, Bork et al. (2000) identified 10 unrelated women with hereditary angioneurotic edema who had normal C1 inhibitor protein concentration and function, and normal C4 concentration. A more detailed study of these families identified another 26 affected members, who were also all women. Fourteen of the 26 women were studied and all were found to have normal C1 inhibitor concentration and function, and normal C4 concentration. The disease was seen in successive generations, and in offspring of affected mothers the male-to-female sex ratio was shifted to 1/1.5. ... Duration of the disorder extended over decades or many years, either in patients or in family members. Normal C1 inhibitor and C4 concentrations were present in plasma.

HAE is generally referred to as a "dominant" condition because it only takes a mutation in one of the two C1-INH genes in a carrier to cause the disease. [8] [9] The prevalence of HAE is relatively low – between 1 in every 10,000 to 1 in every 50,000 persons. ... In a review of patients who do not have a history of HAE in their family, but who have relatively low levels of mutated C1-INH with persistent angioedema, 25% of new patients who had HAE had C1-INH changes that do not show signs of inheritance. Diagnosis [ edit ] Complement tests C4 ( C ) FB ( A ) C3 CH50 Conditions · ↓ ↓ ↓ PSG , C3 NeF AA ↓ · ↓ · HAE , C4D · · · ↓ TCPD ↓ · /↓ ↓ ↓ SLE ↑ ↑ ↑ ↑ inflammation Recognizing HAE is often difficult due to the wide variability in disease expression. ... Measure: serum complement factor 4 (C4), C1 inhibitor (C1-INH) antigenic protein, C1 inhibitor (C1-INH) functional level if available. Analysis of complement C1 inhibitor levels may play a role in diagnosis. C4 and C2 are complementary components.

Hereditary angioedema (HAE) is a disease characterized by recurrent episodes (also called attacks) of severe swelling of the skin and mucous membranes. The age at which attacks begin varies, but most people have their first one in childhood or adolescence. The frequency of attacks usually increases after puberty. Attacks most often affect 3 parts of the body: Skin - the most common sites are the face (such as the lips and eyes), hands, arms, legs, genitals, and buttocks. Skin swelling can cause pain, dysfunction, and disfigurement, although it is generally not dangerous and is temporary. Gastrointestinal tract - the stomach, intestines, bladder, and/or urethra may be involved.

Two of the 4 had a syndrome combining discoid lupus erythematosus and nondeforming rheumatoid-like arthritis; 1 had mild nephritis. C1 and C4 deficiencies are more often associated with lupus-like illness than is deficiency of C2.

A rare sterol biosynthesis disorder characterized by microcephaly, bilateral congenital cataract, mild developmental delay, growth delay with short stature, psoriasiform dermatitis of variable severity, and immune dysregulation. Behavioral disorder, joint contractures, and arthralgia have also been described.

Pregnancy management : Successful pregnancy with low-fat, high-carbohydrate diet in late-onset MADD has been published. ... Plasma acylcarnitine profile typically shows elevations of C4, C5, C5DC, C6, C8, C10, C12, C14:1, C16, and C18:1. ... Plasma carnitine assay may show a very low free carnitine. In this setting the acylcarnitine profile may be falsely normal. ... Acylcarnitine profile may be normal in the setting of low plasma free carnitine and should be repeated after carnitine supplementation in such cases. ... Pregnancy Management Successful pregnancy with a low-fat, high-carbohydrate diet in late-onset MADD has been published [Creanza et al 2018].

Glutaric acidemia type II usually appears in infancy or early childhood as a sudden episode called a metabolic crisis, in which acidosis and low blood sugar (hypoglycemia) cause weakness, behavior changes such as poor feeding and decreased activity, and vomiting.

Treatment varies depending on the severity and symptoms but often includes a low fat, low protein, and high carbohydrate diet.

Muscle biopsy showed free fatty acid accumulation. Low-fat diet reduced the episodes of muscle weakness. ... She never had metabolic crisis, hypoketotic hypoglycemia, or respiratory failure. Laboratory studies showed low serum carnitine, increased serum acylcarnitine levels, and elevated glutaric, ethylmalonic, 2-hydroxylglutaric, 3-methylglutaconic, and lactic acids in urine. ... Studies of an asp128-to-asn mutation of the ETFB gene (D128N; 130410.0003), identified in a patient with type III disease, showed that the residual activity of the enzyme could be rescued up to 59% of that of wildtype activity when ETFB(D128N)-transformed E. coli cells were grown at low temperature. This suggested that the effect of the ETF/ETFDH genotype in patients with milder forms of MADD, in whom residual enzyme activity allows modulation of the enzymatic phenotype, may be influenced by environmental factors such as cellular temperature.

Schulman et al. (1975) described a mildly retarded adult male with glutathionemia and marked glutathionuria, whose cultured skin fibroblasts showed very low activity of the transpeptidase. Since several studies have suggested that the transpeptidase may play a role in cellular amino acid transport, the lack of amino aciduria and amino acidemia was noteworthy. ... In addition to the previously reported features, he had hypertelorism and low-set ears. The sister was diagnosed at 25 years of age with mild mental retardation, a mild tremor, and mild hyperreflexia.

A disorder that is characterized by increased glutathione concentration in the plasma and urine. Epidemiology Gamma-glutamyl transpeptidase deficiency has been detected in seven patients in five families worldwide. Clinical description Five of the patients also had central nervous system involvement. Etiology Gamma-glutamyl transpeptidase catalyses the first step in the degradation of glutathione. No mutations have been identified in patients with gamma-glutamyl transpeptidase deficiency.

Complement 2 deficiency Specialty Hematology Complement 2 deficiency is a type of complement deficiency caused by any one of several different alterations in the structure of complement component 2 . It has been associated with an increase in infections . [1] [2] It can present similarly to systemic lupus erythematosus (SLE). [3] References [ edit ] ^ Alper CA, Xu J, Cosmopoulos K, et al. (July 2003). "Immunoglobulin deficiencies and susceptibility to infection among homozygotes and heterozygotes for C2 deficiency" (PDF) . J. Clin. Immunol . 23 (4): 297–305. doi : 10.1023/A:1024540917593 . PMID 12959222 . ^ Sherwood L. Gorbach; John G. Bartlett; Neil R. Blacklow (2004). Infectious diseases .

Complement component 2 deficiency is a disorder that causes the immune system to malfunction, resulting in a form of immunodeficiency. Immunodeficiencies are conditions in which the immune system is not able to protect the body effectively from foreign invaders such as bacteria and viruses. People with complement component 2 deficiency have a significantly increased risk of recurrent bacterial infections, specifically of the lungs (pneumonia), the membrane covering the brain and spinal cord (meningitis), and the blood (sepsis ), which may be life-threatening. These infections most commonly occur in infancy and childhood and become less frequent in adolescence and adulthood. Complement component 2 deficiency is also associated with an increased risk of developing autoimmune disorders such as systemic lupus erythematosus (SLE) or vasculitis.

Complement component 2 deficiency (C2D) is a genetic condition that affects the immune system. Signs and symptoms include recurrent bacterial infections and risk for a variety of autoimmune conditions . Infections can be very serious and are common in early life. They become less frequent during the teen and adult years. The most frequent autoimmune conditions associated with C2D are lupus (10-20%) and vasculitis. C2D is caused by mutations in the C2 gene and is inherited in an autosomal recessive fashion.

Overview Cryoglobulins are abnormal proteins in the blood. If you have cryoglobulinemia (kry-o-glob-u-lih-NEE-me-uh), these proteins may clump together at temperatures below 98.6 F (37 C). These gelatinous protein clumps can impede your blood circulation, which can damage your skin, joints, nerves and organs — particularly your kidneys and liver. Cryoglobulinemia care at Mayo Clinic Symptoms Symptoms usually come and go, and may include: Skin lesions. Most people with cryoglobulinemia develop purplish skin lesions on their legs. In some people, leg ulcers also occur. Joint pain. Symptoms resembling rheumatoid arthritis are common in cryoglobulinemia.

Simple cryoglobulinemia occurs when the body makes an abnormal immune system protein called a cryoglobulin. At temperatures less than 98.6 degrees Fahrenheit (normal body temperature), cryoglobulins become solid or gel-like and can block blood vessels. This causes a variety of health problems. Many people with cryoglobulins will not experience any symptoms. If symptoms occur, they may include skin ulcers, purple skin spots ( purpura ), numbness in the fingers and toes ( Raynaud's phenomenon ), joint pain, and kidney problems. The underlying cause is unknown. Simple cryoglobulinemia is typically associated with immune system cancers, such as multiple myeloma or non-Hodgkin lymphoma.

A number sign (#) is used with this entry because susceptibility to the development of atypical hemolytic uremic syndrome-5 (AHUS5) can be conferred by mutation in the gene encoding complement component-3 (C3; 120700). For a general phenotypic description and a discussion of genetic heterogeneity of aHUS, see AHUS1 (235400). Clinical Features Fremeaux-Bacchi et al. (2008) reported 11 probands with atypical HUS. Further pedigree analysis showed that 1 proband had 2 additional affected family members and another had 1 additional affected family member. Age at onset ranged from 8 months to 40 years. Most developed end-stage renal disease, and all had decreased serum C3.

A number sign (#) is used with this entry because susceptibility to the development of atypical hemolytic uremic syndrome-2 (AHUS2) can be conferred by variation in the gene encoding membrane cofactor protein (CD46, MCP; 120920) on chromosome 1q32. For a general phenotypic description and a discussion of genetic heterogeneity of aHUS, see AHUS1 (235400), which is caused by mutation in the CFH gene (134370). Some patients with aHUS may have mutations in multiple genes involved in the complement pathway (Esparza-Gordillo et al., 2006). Clinical Features Pirson et al. (1987) described 3 Belgian brothers who developed atypical HUS at ages 27, 31, and 35 years. C3 levels at presentation were normal and there was no recovery of renal function.

A number sign (#) is used with this entry because susceptibility to the development of atypical hemolytic uremic syndrome-3 (AHUS3) can be conferred by heterozygous mutation in the gene encoding complement factor I (CFI; 217030) on chromosome 4q25. For a general phenotypic description and a discussion of genetic heterogeneity of aHUS, see AHUS1 (235400). Clinical Features Fremeaux-Bacchi et al. (2004) reported 3 unrelated patients with aHUS. The first patient was a 32-year-old woman who developed aHUS after pregnancy. Renal biopsy showed thrombotic microangiopathy. She had decreased serum factor I, factor B (CFB; 138470), and C3, indicating consumptive depletion of these complement proteins.

A rare thrombotic microangiopathy disorder characterized by mechanical hemolytic anemia, thrombocytopenia, and renal dysfunction.

Including subsequent relapses, a total of approximately two-thirds (65%) of patients died, required dialysis, or had permanent renal damage within the first year after diagnosis despite plasma exchange or plasma infusion (PE/PI). [6] Contents 1 Signs and symptoms 1.1 Comorbidities 2 Mechanisms 3 Diagnosis 4 Treatment 4.1 Plasma exchange/infusion 4.2 Monoclonal antibody therapy 4.3 Dialysis 4.4 Kidney transplantation 5 Prognosis 6 Epidemiology 7 Society and culture 7.1 Naming 7.2 Research directions 8 References 9 External links Signs and symptoms [ edit ] Clinical signs and symptoms of complement-mediated TMA can include abdominal pain, [8] confusion, [8] fatigue, [5] edema (swelling), [9] nausea/vomiting [10] and diarrhea. [11] aHUS often presents with malaise and fatigue, as well as microangiopathic anemia. [7] : 1931 However, severe abdominal pain and bloody diarrhea are unusual. [7] : 1931 Laboratory tests may also reveal low levels of platelets (cells in the blood that aid in clotting), [1] elevated lactate dehydrogenase (LDH, a chemical released from damaged cells, and which is therefore a marker of cellular damage), [6] decreased haptoglobin (indicative of the breakdown of red blood cells), [6] anemia (low red blood cell count)/schistocytes (damaged red blood cells), [1] [6] elevated creatinine (indicative of kidney dysfunction), [12] and proteinuria (indicative of kidney injury). [13] Patients with aHUS often present with an abrupt onset of systemic signs and symptoms such as acute kidney failure, [1] hypertension (high blood pressure), [5] myocardial infarction (heart attack), [14] stroke, [8] lung complications, [14] pancreatitis (inflammation of the pancreas), [10] liver necrosis (death of liver cells or tissue), [5] encephalopathy (brain dysfunction), [5] seizure, [15] or coma. [16] Failure of neurologic, cardiac, kidney, and gastrointestinal (GI) organs, as well as death, can occur unpredictably at any time, either very quickly or following prolonged symptomatic or asymptomatic disease progression. [1] [13] [17] [18] [19] For example, approximately 1 in 6 patients with aHUS initially will present with proteinuria or hematuria without acute kidney failure. [13] Patients who survive the presenting signs and symptoms endure a chronic thrombotic and inflammatory state, which puts many of them at lifelong elevated risk of sudden blood clotting, kidney failure, other severe complications and premature death. [9] [20] Comorbidities [ edit ] Although many patients experience aHUS as a single disease, comorbidities are common. ... In addition, there are other conditions that can cause TMA as a secondary manifestation; these entities include systemic lupus erythematosus (SLE), malignant hypertension, progressive systemic sclerosis (PSS, also known as scleroderma), the pregnancy-associated HELLP (hemolysis, liver dysfunction, and low platelets) syndrome, and toxic drug reaction (e.g., to cocaine, cyclosporine, or tacrolimus). ... PE/PI is associated with significant safety risks, including risk of infection, allergic reactions, thrombosis, loss of vascular access, and poor quality of life. [22] [26] Importantly, terminal complement activation has been shown to be chronically present on the surface of platelets in patients with aHUS who appear to be clinically well while receiving chronic PE/PI. [9] [27] Guidelines issued by the European Paediatric Study Group for HUS recommend rapid administration of plasma exchange or plasma infusion (PE/PI), intensively administered daily for 5 days and then with reducing frequency. [22] However, the American Society for Apheresis offers a "weak" recommendation for plasma exchange to treat aHUS, due to the "low" or "very low" quality of evidence supporting its use.

Atypical hemolytic uremic syndrome (aHUS) is a disease that causes abnormal blood clots to form in small blood vessels in the kidneys. These clots can cause serious medical problems if they restrict or block blood flow, including hemolytic anemia, thrombocytopenia, and kidney failure. It can occur at any age and is often caused by a combination of environmental and genetic factors. Genetic factors involve genes that code for proteins that help control the complement system (part of your body’s immune system). Environmental factors include certain medications (such as anticancer drugs), chronic diseases (e.g., systemic sclerosis and malignant hypertension), viral or bacterial infections, cancers, organ transplantation, and pregnancy.

Thompson and Winterborn (1981) reported an 8-month-old Asian boy with very low levels of plasma factor H who presented with the hemolytic uremic syndrome. ... In total, 8 patients died at ages 3 weeks to 10 months. Factor H levels were low to undetectable in all 4 patients studied, and C3 levels were decreased in 9 of 10 infants tested. ... Pathogenesis Atypical Hemolytic Uremic Syndrome Low levels of factor H in patients with aHUS were reported by Roodhooft et al. (1990), Pichette et al. (1994), and others. ... All cases with factor H abnormalities had low C3 serum concentrations. Noris et al. (1999) concluded that reduced C3 in familial HUS is likely related to a genetically determined deficiency of factor H. ... Plasma from a 54-year-old woman with HUS had a low capacity to stimulate PGI2 production by rat aortic rings.

., 1981), Goicoechea de Jorge et al. (2007) identified a heterozygous mutation in the CFB gene (F286L; 138470.0005) that segregated with low levels of C3. Functional expression studies showed that the mutant CFB resulted in increased formation of the C3bB complex, indicating a gain-of-function effect that enhanced the generation of C3b.

Meier-Gorlin syndrome (MGS) is a very rare inherited condition characterized by very small ears and ear canals, short stature, and absent or very small kneecaps (patellae). Other signs and symptoms can include hearing loss, feeding problems, respiratory tract abnormalities, small chin, and small head size. People with MGS may also have characteristic facial features including a small mouth, full lips and a narrow nose. Females with MGS may have underdeveloped breasts. Most people with this syndrome have normal intelligence. There are many forms of MGS and it can be caused by mutations in any of eight different genes: ORC1 , ORC4 , ORC6 , CDT1 , CDC6 , CDC45L , MCM5 and GMNN .

INHERITANCE - Autosomal recessive GROWTH Height - Short stature - Birth length less than 3rd percentile Weight - Birth weight less than 3rd percentile Other - Intrauterine growth retardation (IUGR) - Failure to thrive HEAD & NECK Head - Microcephaly Ears - Microtia - Low-set ears - Abnormally formed ears Mouth - Small mouth - Full lips - Maxillary hypoplasia - Mandibular hypoplasia RESPIRATORY - Respiratory problems Lung - Emphysema, congenital CHEST Ribs Sternum Clavicles & Scapulae - Hook-shaped clavicles - Abnormal glenoid fossa Breasts - Breast hypoplasia ABDOMEN Gastrointestinal - Feeding difficulties in early infancy GENITOURINARY External Genitalia (Male) - Cryptorchidism SKELETAL - Delayed bone age Limbs - Slender long bones - Absent patellae - Genu recurvatum NEUROLOGIC Central Nervous System - No mental retardation - Intellect high (in some patients) MOLECULAR BASIS - Caused by mutation in the chromatin licensing and DNA replication factor 1 gene (CDT1, 605525.0001 ) ▲ Close

She had delayed bone age (-3.5 SD from mean for age) with low IGF1 (147440) and normal IGFBP3 (146732). ... INHERITANCE - Autosomal dominant GROWTH Height - Short stature - Small for gestational age Weight - Low birthweight for gestational age Other - Failure to thrive HEAD & NECK Head - Microcephaly Face - Frontal bossing - High forehead - Midface hypoplasia - Micrognathia - Retrognathia Ears - Microtia - Posteriorly rotated ears - Hearing loss, conductive Eyes - Strabismus - Downslanting palpebral fissures - Entropion Nose - Short nose - Upturned nose - Hypoplastic nares - Anteverted nares - Depressed nasal bridge Mouth - Full lips - Cleft palate RESPIRATORY - Recurrent respiratory infections Larynx - Laryngomalacia Airways - Bronchomalacia - Tracheomalacia Lung - Emphysema ABDOMEN External Features - Umbilical hernia Gastrointestinal - Gastroesophageal reflux - Feeding problems in infancy GENITOURINARY External Genitalia (Female) - Hypoplastic labia majora Internal Genitalia (Male) - Cryptorchidism SKELETAL - Delayed bone age Spine - Lumbar lordosis, excessive Pelvis - Hip dysplasia Limbs - Aplastic patellae Hands - Midphalangeal hypoplasia of the 5th fingers (bilateral) - Palmar crease Feet - Planovalgus - Sandal gap NEUROLOGIC Central Nervous System - Speech delay - Motor delay - Intellectual disability - Delayed myelination - Simplified gyral pattern, mild - Speech delay Peripheral Nervous System - 'Onion bulb' formations seen on nerve biopsy ENDOCRINE FEATURES - Delayed puberty - Growth hormone deficiency MOLECULAR BASIS - Caused by mutation in the geminin gene (GMNN, 602842.0001 ) ▲ Close

A number sign (#) is used with this entry because of evidence that Meier-Gorlin syndrome-2 (MGORS2) is caused by homozygous or compound heterozygous mutation in the ORC4 gene (603056) on chromosome 2q23. For a general phenotypic description and a discussion of genetic heterogeneity of Meier-Gorlin syndrome, see 224690. Clinical Features Bongers et al. (2001) reported 5.25-year-old monozygotic twin sisters, born of consanguineous American parents of Acadian/French Creole ancestry, who had intrauterine growth retardation and were noted to be microcephalic at birth. Examination at 5 years of age showed height and weight below the 3rd centile for both girls, with head circumferences at the 3rd centile. Both had dolichocephaly, mild micrognathia, flat philtrum with small mouth, and slight hypoplasia of the nasal alae.

INHERITANCE - Autosomal recessive GROWTH Height - Short stature - Birth length less than 3rd percentile Weight - Birth weight less than 3rd percentile Other - Failure to thrive - Intrauterine growth retardation (IUGR) HEAD & NECK Head - Microcephaly Face - Triangular face - Maxillary hypoplasia - Mandibular hypoplasia - Microretrognathia Ears - Microtia, bilateral - Ears abnormally formed - Low-set ears - Posteriorly rotated ears Eyes - Downslanting palpebral fissures Nose - Convex nasal profile - High nasal bridge Mouth - Full lips - Small mouth RESPIRATORY Larynx - Laryngomalacia Airways - Tracheomalacia - Bronchomalacia Lung - Pulmonary infections, recurrent - Dyspnea secondary to thorax morphology CHEST Ribs Sternum Clavicles & Scapulae - Narrow chest - Short thorax - Short ribs - Lack of sternal ossification Breasts - Breast hypoplasia ABDOMEN Gastrointestinal - Gastroesophageal reflux - Feeding problems in early infancy GENITOURINARY External Genitalia (Male) - Cryptorchidism - Hypoplastic scrotum - Micropenis - Hypospadias External Genitalia (Female) - Hypertrophic clitoris - Hypoplastic labia minora/majora SKELETAL - Delayed bone age Skull - Frontal circular lacuna Limbs - Slender long bones - Abnormal humeral epiphyses with flat metaphyses - Abnormal femoral epiphyses with flat metaphyses - Abnormal tibial epiphyses - Coxa vara - Absent or hypoplastic patellae - Genu varum Hands - Clinodactyly, fifth finger Feet - Club feet SKIN, NAILS, & HAIR Hair - Absent or sparse axillary hair - Absent or sparse pubic hair NEUROLOGIC Central Nervous System - Delayed motor development (in some patients) - Delayed speech development (in some patients) MOLECULAR BASIS - Caused by mutation in origin recognition complex, subunit 6, gene (ORC6, 607213.0001 ) ▲ Close

INHERITANCE - Autosomal recessive GROWTH Height - Short stature - Birth length less than 3rd percentile Weight - Birth weight less than 3rd percentile Other - Failure to thrive - Intrauterine growth retardation HEAD & NECK Head - Microcephaly - Small anterior fontanel Face - Micrognathia - Maxillary hypoplasia - Mandibular hypoplasia - Frontal bossing Ears - Bilateral microtia - Hearing loss - Mondini malformation - Low-set ears - Atretic auditory canal Eyes - Strabismus - Long eyelashes - Short palpebral fissures Mouth - Small mouth - Full lips - Cleft palate - High-arched palate Teeth - Small teeth RESPIRATORY - Respiratory distress (neonate) Lung - Emphysema, congenital (in some patients) CHEST External Features - Chest asymmetry Ribs Sternum Clavicles & Scapulae - Pectus carinatum - Lack of sternal ossification - Slender ribs - Flat or absent glenoid fossae - Hooked clavicles - Short ribs Breasts - Breast hypoplasia ABDOMEN Gastrointestinal - Feeding problems - Gastroesophageal reflux GENITOURINARY External Genitalia (Male) - Shawl scrotum - Micropenis External Genitalia (Female) - Clitoromegaly - Hypoplastic labia minora - Hypoplastic labia majora Internal Genitalia (Male) - Cryptorchidism SKELETAL - Delayed bone age - Joint laxity - Joint contractures Spine - Hemivertebrae Pelvis - Blount osteochondritis dissecans - Aseptic femoral necrosis - Coxa valga/vara Limbs - Aplastic or hypoplastic patellae - Elbow dislocation - Epiphyseal flattening - Slender long bones - Genu valgum - Genu varum Hands - Fifth finger clinodactyly - Small hands - Camptodactyly Feet - Cutaneous syndactyly (2nd-3rd, 4th-5th) - Talipes equinovarus SKIN, NAILS, & HAIR Skin - Thin skin - Prominent vasculature (nose and forehead) Nails - Hyperconvex nails Hair - Long eyelashes NEUROLOGIC Central Nervous System - Mental retardation PRENATAL MANIFESTATIONS Delivery - Breech presentation MISCELLANEOUS - Genetic heterogeneity MOLECULAR BASIS - Caused by mutation in the origin recognition complex, subunit 1, gene (ORC1, 601902.0001 ) ▲ Close

Ear-patella-short stature syndrome is an association of malformations including bilateral microtia (severe hypoplasia of ear pinnae), absent patellae, short stature, poor weight gain, and characteristic facial features such as high forehead, micrognathism with full lips and small mouth, and accentuated nasolabial folds (smile wrinkles linking the nostrils to the labial commissure). Epidemiology Ear-patella-short stature syndrome is a rare condition, with less than 50 cases reported in the literature. Clinical description Other skeletal anomalies include dislocation of the elbow, slender ribs and long bones, abnormal modelling of the glenoid fossas with hooked clavicles, and clinodactyly. Bone age is significantly delayed and long bone epiphyses are flattened. Hypoplastic genitalia have been reported in affected boys and girls. Some patients have severe deafness, which may impair neuromotor and mental development, and cognitive ability may be subnormal.

INHERITANCE - Autosomal recessive GROWTH Height - Short stature - Birth length less than 3rd percentile Weight - Birth weight less than 3rd percentile Other - Intrauterine growth retardation (IUGR) - Failure to thrive HEAD & NECK Head - Microcephaly Face - Triangular face - Long philtrum - Maxillary hypoplasia - Mandibular hypoplasia - Micrognathia Ears - Microtia, bilateral - Low-set ears - Absent helices, bilaterally - Hypoplastic lobules - Small external auditory meatus Mouth - Lips full - Palate cleft, submucous Teeth - Teeth small CHEST Ribs Sternum Clavicles & Scapulae - Shoulder hypermobility ABDOMEN Gastrointestinal - Gastroesophageal reflux in early infancy - Feeding problems in early infancy GENITOURINARY External Genitalia (Male) - Micropenis - Cryptorchidism SKELETAL - Delayed bone age Skull - Prominent metopic suture Limbs - Slender long bones - Absent patellae - Elbow hypermobility - Elbow dislocation - Knee hypermobility - Hypoplastic and irregular femoral epiphyses - Hypoplastic and irregular tibial epiphyses Hands - Clinodactyly, fifth fingers - Finger hypermobility Feet - Clinodactyly, fifth toes NEUROLOGIC Central Nervous System - Psychomotor retardation, mild MOLECULAR BASIS - Caused by mutation in the cell division cycle 6 gene (CDC6, 602627.0001 ) ▲ Close