Although rare mutations in the genes encoding low density lipoprotein (LDL) receptor (LDLR; 606945) and apolipoprotein B (APOB; 107730) account for a small proportion of variation in LDL cholesterol (LDLC), twin and adoption studies have indicated that at least 50% of the overall observed variation is genetically determined.
Clinical description All of them had hypercalciuria and low-molecular-weight (LMW) proteinuria. ... The presence of intellectual impairment and sub-clinical cataract were so mild as to dissuade the clinicians from considering a diagnosis of Lowe syndrome (see this term), which is characterized by congenital cataracts, delayed motor milestones, some degree of intellectual impairment in almost all affected males, growth retardation, rickets and renal proximal tubulopathy. Moreover, the patients with Dent disease type 2 and mild intellectual deficit were adults, who had not, over time, developed more overt features of Lowe syndrome. Etiology The reported patients share mutations in the OCRL1 gene with the oculocerebrorenal syndrome of Lowe.
"Dent's disease" is often used to describe an entire group of familial disorders, including X-linked recessive nephrolithiasis with kidney failure, X-linked recessive hypophosphatemic rickets , and both Japanese and idiopathic low-molecular-weight proteinuria. [2] About 60% of patients have mutations in the CLCN5 gene (Dent 1), which encodes a kidney-specific chloride/proton antiporter, and 15% of patients have mutations in the OCRL 1 gene (Dent 2). [3] Contents 1 Signs and symptoms 2 Genetics 2.1 Dent disease 1 2.2 Dent disease 2 3 Diagnosis 4 Treatment 5 History 6 References 7 External links Signs and symptoms [ edit ] Dent's disease often produces the following signs and symptoms: Extreme thirst combined with dehydration , which leads to frequent urination Nephrolithiasis (kidney stones) Hypercalciuria (high urine calcium - >300 mg/d or >4 mg/kg per d) with normal levels blood/serum calcium) Aminoaciduria ( amino acids in urine) Phosphaturia (phosphate in urine) Glycosuria (glucose in urine) Kaliuresis (potassium in urine) Hyperuricosuria (excessive amounts of uric acid in the urine) Impaired urinary acidification Rickets In a study of 25 patients with Dent's disease, [4] 9 of 15 men, and one of 10 women suffered end-stage kidney disease by the age of 47. [5] Genetics [ edit ] X-linked recessive inheritance Three-dimensional homology model of human CLC-5 based on the structure of ClC-ec1 (7) showing the locations of each mutated residue Dent disease 1 [ edit ] Dent's disease is a X-linked recessive disorder. ... The identification of additional CLCN5 mutations may help in these studies. [8] Dent disease 2 [ edit ] Dent disease 2 (nephrolithiasis type 2) is associated with the OCRL gene. [9] [10] Both Lowe syndrome ( oculocerebrorenal syndrome ) and Dent disease can be caused by truncating or missense mutations in OCRL . ... Friedman in 1964, when they reported two unrelated British boys with rickets associated with renal tubular damage characterized by hypercalciuria , hyperphosphaturia , proteinuria , and aminoaciduria . [14] This set of symptoms was not given a name until 30 years later, when the nephrologist Oliver Wrong more fully described the disease. [4] Wrong had studied with Dent and chose to name the disease after his mentor. [15] Dent's disease is a genetic disorder caused by mutations in the gene CLCN5 , which encodes a kidney-specific voltage-gated chloride channel , a 746-amino-acid protein (CLC-5) with 12 to 13 transmembrane domains. It manifests itself through low-molecular-weight proteinuria, hypercalciuria, aminoaciduria and hypophosphataemia. ... "Dent's disease; a familial proximal renal tubular syndrome with low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, metabolic bone disease, progressive kidney failure and a marked male predominance" .
Spermatogenesis was evident, though greatly reduced, with low numbers of spermatozoa. Valdes-Socin et al. (2004) designated the phenotype 'hypogonadotropic hypogonadism due to isolated LH deficiency.' ... All 3 sibs had undetectable LH levels; FSH was increased in the brothers, who also had low testosterone levels, whereas their sister had normal FSH, estradiol, and progesterone levels. ... Examination after 3 months off treatment showed virilization with normal masculine features, including normal penile length and low-normal testis volume. LH was undetectable and FSH levels were high, with very low serum testosterone. ... The 31-year-old brother had a 46,XY karyotype and presented with sexual infantilism, including micropenis, small testes, juvenile voice, scant pubic and axillary hair, and bilateral gynecomastia; he was azoospermic with low semen volume. LH was undetectable, FSH was normal, and testosterone was low. ... All heterozygotes were fertile and had normal basal gonadotropin and sex steroid levels for their ages, except for the 66-year-old mother who had unexpectedly low LH levels for her menopausal state.
. ^ McCullagh EP, Beck JC, Schaffenburg CA: A syndrome of eunuchoidism with spermatogenesis, normal urinary FSH and low or normal ICSH: (“Fertile eunuchs”).
Clinical description The clinical presentation and the severity of symptoms vary widely between patients. Although extremely low plasma HDL cholesterol may be detected fortuitously from birth, the most characteristic finding in children is large tonsils with a particular orange-yellow color due to carotene-enriched low-density lipoprotein (LDL) tissue-accumulation. ... Diagnostic methods The diagnosis is based on evidence of an abnormal lipoprotein profile characterized by isolated hypoalphalipoproteinemia, extremely low HDL cholesterol (<5 mg/dL) and apolipoprotein A-I (ApoA1) levels (< 5 mg/dL), with only pre beta-1 HDL found by bidimensional electrophoresis in the plasma. ... Differential diagnosis The differential diagnosis includes familial Apolipoprotein A-I deficiency, LCAT deficiency and secondary causes of extremely low HDL cholesterol levels that include medications (androgenic steroids, retinoids, paradoxical response to fibrates), liver failure or malignancies. ... Tonsillectomy may be required in case of significant tonsillar enlargement. A low-fat diet helps in reducing liver enlargement and preventing atherosclerosis. ... Prognosis Prognosis is usually good and depends mainly on the progression of peripheral neuropathy. TD patients with extremely low plasma HDL cholesterol (<20 mg/dL) have increased risk of coronary artery disease in adulthood and should be offered regular cardiovascular and neurological monitoring.
The diagnosis of Tangier disease is established in a proband with absent or extremely low HDL-cholesterol and apo A-I levels and biallelic pathogenic variants in ABCA1 identified by molecular genetic testing. ... Prevention of primary manifestations: Mitigation of cardiovascular risk factors, including improvement of plasma lipid profiles using statin therapy and a low-fat diet. Surveillance : Assessment for hepatosplenomegaly by physical examination and imaging at each visit; neurology and ophthalmology evaluations annually; cardiovascular risk assessment of atherosclerotic plaque burden annually beginning in adulthood; complete blood count with differential as clinically indicated. ... Clinical findings Enlarged tonsils that are yellow and/or orange in children and young adults Peripheral neuropathy Hepatomegaly and/or splenomegaly Corneal opacities Coronary artery disease Lymphadenopathy Blood disorders (especially thrombocytopenia) Supportive laboratory findings Major findings: Very low plasma HDL-cholesterol concentration, typically <5 mg/dL (0.125 mmol/L), rarely 5-10 mg/dL Very low or absent apo A-I concentration, usually <30 mg/dL (typically <5 mg/dL) Small or absent alpha band on lipoprotein electrophoresis Other laboratory findings: Low plasma total cholesterol concentration, typically <150 mg/dL (4 mmol/L) Mild-to-moderate hypertriglyceridemia, up to 400 mg/dL (4.5 mmol/L) Decreased LDL-cholesterol concentration Small beta or broad pre-beta band on lipoprotein electrophoresis Establishing the Diagnosis The diagnosis of Tangier disease is established in a proband with absent or extremely low HDL-cholesterol and apo A-I levels and biallelic pathogenic variants in ABCA1 identified on molecular genetic testing (see Table 1). ... Differential Diagnosis Artefactual and secondary causes of severe HDL deficiency. In the setting of an extremely low HDL-cholesterol in the absence of hypertriglyceridemia, artefactual causes (e.g., paraproteinemia) and secondary causes (e.g., androgenic anabolic steroids, paradoxic response to PPAR agonists, malaria, HIV infection, malignancy, liver disease) should be excluded [Rader & deGoma 2012]. ... Thrombocytopenia / Hemolytic anemia Standard treatment, if severe Prevention of Primary Manifestations Mitigation of cardiovascular risk factors (including LDL-cholesterol concentrations using statin therapy and a low-fat diet) is indicated. Surveillance Table 5.
The 2 hallmarks of the disease, enlarged lipid-laden tonsils and low serum HDL, were based on the initial description of the original kindred. ... Levels of apoA-I (107680) and HDL cholesterol were very low and triglycerides were high. Pressly et al. (1987) described a 66-year-old man with Tangier disease and discussed the ocular complications, including corneal clouding, decreased corneal sensation, cicatricial ectropion, and slowly progressive visual impairment. ... Cheung et al. (1993) described a 48-year-old Caucasian female of central European origin with very low apoprotein A-I and A-II (107670) and low HDL cholesterol. ... Sural nerve biopsy showed de- and remyelination, endoneurial fibrosis, and deposition of fat droplets in axons and Schwann cells. Relatively low levels of HDL were also found in the patient's mother and the 2 daughters, consistent with heterozygosity.
Therefore, the only current treatment modality for Tangier's disease is diet modification. A low-fat diet can reduce some of the symptoms, especially those involving neuropathies. [9] History [ edit ] In 1959, a five-year-old patient named Teddy Laird from Tangier Island, Virginia , presented with strikingly large and yellow-orange tonsils which were removed by armed forces physicians. ... During a second trip to the island, they found that the family had very low levels of HDL cholesterol, suggesting a genetic basis of the disease. [10] References [ edit ] ^ James, William D.; Berger, Timothy G.; et al. (2006).
Because people with Tangier disease have very low levels of HDL, they have a moderately increased risk of cardiovascular disease. ... In addition, the inability to transport cholesterol and phospholipids out of cells results in very low HDL levels, which increases the risk of cardiovascular disease.
Kraus-Ruppert (1958) described 3 brothers from a consanguineous mating. Syndactyly of the second to fourth toes and eunuchoidism were also present. The testes showed no spermatogenesis and the interstitium was occupied mainly by connective tissue. HEENT - Microcephaly Limbs - Syndactyly toes 2-4 Neuro - Mental retardation GU - Eunuchoidism - Aspermatogenesis Inheritance - Autosomal recessive ▲ Close
A number sign (#) is used with this entry because a transcription factor binding site for SORT1 (SORT1-TBS1; 602458) on chromosome 1p13 is responsible for the association of that locus with low density lipoprotein cholesterol (LDL-C) variability. ... With small interfering RNA knockdown and viral overexpression in mouse liver, Musunuru et al. (2010) demonstrated that Sort1 alters plasma LDL cholesterol and very low density lipoprotein (VLDL) particle levels by modulating hepatic VLDL secretion. ... INHERITANCE - Autosomal dominant LABORATORY ABNORMALITIES - Variable plasma LDL-C levels - Very low-density lipoprotein (VLDL) particle levels MOLECULAR BASIS - Susceptibility conferred by mutation in the sortilin gene (SORT1, 602458.0001 ) ▲ Close
They had brachydactyly and similar facial features, including a prominent forehead, low nasal bridge, midface hypoplasia, full lips, a small mouth, and small, low-set ears with overfolded helices. ... INHERITANCE - Autosomal recessive GROWTH Weight - Obesity HEAD & NECK Face - Prominent forehead - Midface hypoplasia Ears - Small ears - Low-set ears - Overfolded helices - Mixed hearing loss - Thick helices Eyes - Broad lateral eyebrows - Epicanthal folds - Ptosis Nose - Low nasal bridge - Anteverted nares Mouth - Full lips - Small mouth SKELETAL - Delayed bone age Hands - Brachydactyly SKIN, NAILS, & HAIR Hair - Coarse scalp hair - Broad lateral eyebrows NEUROLOGIC Central Nervous System - Hypotonia (neonatal) - Developmental delay METABOLIC FEATURES - Hypoglycemia (neonatal) MISCELLANEOUS - Sister of affected male siblings had mild learning disabilities and obesity ▲ Close
Serum succinic acid levels were greatly increased in both sibs and NADH-cytochrome c reductase activity was significantly low in both. In the fetal case, NADH-ferricyanide reductase activity was also low, suggesting a complex I deficiency of the electron transport system in the mitochondrial membrane. ... Resp - Respiratory distress Inheritance - Autosomal recessive Lab - Serum succinic acid levels greatly increased - Low NADH-cytochrome c reductase activity - Low NADH-ferricyanide reductase activity Metabolic - Succinicacidemia - Organic acidemia - Lactic acidosis ▲ Close
A rare autosomal trisomy, characterized by reduced fetal movements and intrauterine growth retardation, low birth weight, and multiple congenital anomalies. The latter include, amongst others, facial dysmorphism (like hypertelorism, cleft lip/palate, micrognathia, low hairline, and small, low-set, and posteriorly rotated ears), head circumference below average, deformities of the hands (campodactyly) and feet, marked hypertrichosis, and anomalies of the brain, heart, and lungs.
A replication study in postmenopausal Danish women, in one group with persistently low BMD and another with osteoporotic fracture, showed a significant association for haplotype 'C' (p = 0.0038) for low BMD, whereas S37A and haplotype 'B' were nominally significant for osteoporotic fractures and low BMD, respectively. Kung et al. (2010) performed a genomewide association study in 800 unrelated Southern Chinese women with extreme BMD (high or low), followed by replication studies in 6 independent study populations of European descent and Asian populations involving 18,098 individuals. In the metaanalysis, a SNP (rs2273061) in intron 3 of the JAG1 gene (601920) was associated with high BMD (p = 5.27 x 10(-8) and p = 4.15 x 10(-5) for lumbar spine and femoral neck, respectively) and was further found to be associated with low risk of osteoporotic fracture (p = 0.009; odds ratio, 0.7).
Clinical Features Kuijpers et al. (2010) reported a Turkish girl, born of consanguineous parents, who developed recurrent respiratory infections and bronchopneumonia at age 2 years. At onset, she had low IgG and low IgA levels. During a follow-up of 4 years, she showed normal IgM and IgA levels, but low IgG levels. ... INHERITANCE - Autosomal recessive RESPIRATORY - Respiratory infections, recurrent IMMUNOLOGY - Recurrent bacterial infections - Normal numbers of B cells - Reduced numbers of memory B cells - B cells lack surface CD20 expression - Normal numbers of T cells - Defective antibody production, particularly T-cell-independent LABORATORY ABNORMALITIES - Hypogammaglobulinemia - Low serum IgG and IgA - Low or normal serum IgM MISCELLANEOUS - Onset in early childhood - One patient has been reported (as of July 2010) MOLECULAR BASIS - Caused by mutation in the membrane-spanning 4 domains, subfamily A, member 1 gene (MS4A1, 112210.0001 ) ▲ Close
Laboratory studies showed hypogammaglobulinemia with decreased IgG, low to normal IgA, and normal IgM. There was no antibody response to either tetanus or pneumococcal antigens. ... INHERITANCE - Autosomal recessive RESPIRATORY - Respiratory infections, recurrent GENITOURINARY Kidneys - Glomerulonephritis, autoimmune SKIN, NAILS, & HAIR Skin - Purpura HEMATOLOGY - Thrombocytopenia, autoimmune IMMUNOLOGY - Recurrent bacterial infections - Hypogammaglobulinemia - Normal numbers of B cells - Reduced numbers of memory B cells - B cells lack surface CD19 and CD81 expression - Defective antibody production - Normal numbers of T cells LABORATORY ABNORMALITIES - Low serum IgG and IgA - Low or normal serum IgM MISCELLANEOUS - Onset in early childhood - One patient has been reported (as of July 2010) MOLECULAR BASIS - Caused by mutation in the CD81 antigen gene (CD81, 186845.0001 ) ▲ Close
Overview Common variable immunodeficiency (CVID) is an immune system disorder that causes you to have low levels of the proteins that help fight infections.
A number sign (#) is used with this entry because of evidence that autosomal dominant common variable immunodeficiency-12 (CVID12) is caused by heterozygous mutation in the NFKB1 gene (164011) on chromosome 4q24. Description Common variable immunodeficiency-12 is an autosomal dominant primary immunodeficiency characterized by recurrent infections, mainly respiratory, associated with hypogammaglobulinemia. The disorder shows a highly variable age at onset and highly variable disease severity, even within the same family. Some patients have features of autoimmunity (summary by Fliegauf et al., 2015). For a general description and a discussion of genetic heterogeneity of common variable immunodeficiency, see CVID1 (607594).
Laboratory studies showed hypogammaglobulinemia, poor antibody response to antigens, and decreased numbers of memory and marginal zone B cells. All patients also had low ACTH and cortisol levels that did not response to synthetic ACTH, indicating central adrenal insufficiency. ... INHERITANCE - Autosomal dominant RESPIRATORY - Recurrent respiratory infections - Asthma SKIN, NAILS, & HAIR Skin - Psoriasiform dermatitis (in some patients) Nails - Trachyonychia (in some patients) - Onychodystrophy (in some patients) Hair - Alopecia (in some patients) NEUROLOGIC Central Nervous System - Developmental delay (1 patient) - Hypoplastic anterior pituitary (in some patients) ENDOCRINE FEATURES - Central adrenal insufficiency - Growth hormone deficiency (1 patient) IMMUNOLOGY - Recurrent infections - Hypogammaglobulinemia - Low levels of memory B cells - Autoimmune features (in some patients) - Autoantibodies (in some patients) - Thyroid hormone deficiency (1 patient) LABORATORY ABNORMALITIES - Low serum cortisol - Low serum ACTH - Hypoglycemia, intermittent MISCELLANEOUS - Onset in childhood - Variable severity - Variable manifestations MOLECULAR BASIS - Caused by mutation in the nuclear factor kappa-beta, subunit 2 gene (NFKB2, 164012.0001 ) ▲ Close
Common variable immunodeficiency (CVID) is a group of disorders characterized by low levels of a type of protein known as immunoglobulins (Ig). Because of low level of Ig, the immune system cannot make antibodies that fight bacteria, viruses or other toxins in the body.
All affected individuals had hypogammaglobulinemia with low serum IgG, IgM, and IgA, and recurrent infections, including otitis media, respiratory tract infections, and gastrointestinal tract infections. ... All presented with recurrent sinopulmonary infections requiring intravenous Ig therapy. Serum IgG and IgA were low, and serum antibody response to immunization with pneumococcal vaccine was decreased, although T cell-dependent response to tetanus toxin was normal.
Common variable immunodeficiency (CVID) comprises a heterogeneous group of diseases characterized by a significant hypogammaglobulinemia of unknown cause, failure to produce specific antibodies after immunizations and susceptibility to bacterial infections, predominantly caused by encapsulated bacteria. Epidemiology Prevalence is estimated at 1/25,000 among Caucasians and CVID affects men and women equally. Clinical description While some patients are diagnosed with CVID in early childhood, the major peak of onset lies between the second and third decade of life, frequently with several years delay between onset and diagnosis. Over 98% of patients present with recurrent bronchitis, sinusitis, otitis and pneumonia, and chronic pulmonary damage is the major complication. About 25% of patients develop autoimmune phenomena; immune thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia (AIHA) are the most common (see these terms).
Laboratory studies showed hypogammaglobulinemia affecting mainly IgG; IgA values were slightly reduced and IgM levels were low-normal. Antibodies against recall antigens, such as measles, mumps, and varicella, were normal, and he had antibodies against EBV. ... INHERITANCE - Autosomal recessive RESPIRATORY - Respiratory infections, recurrent ABDOMEN Gastrointestinal - Diarrhea, recurrent IMMUNOLOGY - Recurrent infections - Hypogammaglobulinemia LABORATORY ABNORMALITIES - Deceased IgG - Decreased IgA - Low-normal IgM - Decreased switched memory B cells - Proper antibody response to protein vaccinations MISCELLANEOUS - Onset in childhood - One patient has been reported (last curated July 2012) MOLECULAR BASIS - Caused by mutation in the complement component receptor 2 gene (CR2, 120650.0002 ) ▲ Close
Rosen and Bougas (1963) reported the case of a woman with recurrent infection, marked elevation of 19S gamma globulin, and virtual absence of 7S. Feldman et al. (1975) found that 12 relatives had a variable immunodeficiency. Ten had elevation of IgM, combined with deficiency of IgG and IgA in 3 and deficiency of one or the other in 2. Five had only elevated IgM and 2 had normal IgM but deficiency of IgG and IgA. No male-to-male transmission was observed. Immunology - Variable immunodeficiency - Increased IgM - IgG deficiency - IgA deficiency Misc - Recurrent infection Inheritance - Autosomal dominant ▲ Close
Immune disorder Common variable immunodeficiency Specialty Immunology Common variable immunodeficiency ( CVID ) is an immune disorder characterized by recurrent infections and low antibody levels, specifically in immunoglobulin (Ig) types IgG, IgM and IgA. [1] Generally symptoms include high susceptibility to foreign invaders, chronic lung disease , and inflammation and infection of the gastrointestinal tract. [1] However, symptoms vary greatly between people. ... CVID is formally diagnosed by levels of IgG and IgA more than two standard deviations below the norm, and no other cause for hypogammaglobulinemia , an abnormally low level of immunoglobulins in the blood. ... Hypogammaglobulinemia manifests as a significant decrease in the levels of IgG antibodies, usually alongside IgA antibodies; IgM antibody levels are also decreased in about half of people. [6] Infections are a direct result of the low antibody levels in the circulation, which do not adequately protect them against pathogens. ... Affected individuals typically present with low frequencies of CD4 + , a T-cell marker, and decreased circulation of regulatory T cells and iNKT cell .
INHERITANCE - Autosomal recessive HEAD & NECK Head - Sinusitis, recurrent Ears - Otitis media, recurrent Eyes - Conjunctivitis, recurrent RESPIRATORY - Respiratory infections, recurrent GENITOURINARY Kidneys - Glomerulonephritis, postinfectious (1 patient) IMMUNOLOGY - Bacterial infections, recurrent - Hypogammaglobulinemia - Defective antibody production - Normal numbers of B cells - Reduced numbers of memory B cells - B cells lack surface CD19 expression - Normal numbers of T cells LABORATORY ABNORMALITIES - Low serum IgG and IgA - Low or normal serum IgM MISCELLANEOUS - Onset in early childhood MOLECULAR BASIS - Caused by mutation in the CD19 antigen gene (CD191, 107265.0001 ) ▲ Close
One of the patients was female, suggesting autosomal recessive inheritance. Laboratory studies showed low peripheral blood B-cell counts ranging from 0.7 to 1.3% in 1 family and 2.8 to 3.3% in the other. ... All patients had decreased switched memory B cells and decreased levels of serum IgG and IgA; IgM was low-normal or low. The T-cell compartment appeared normal. ... Pathogenesis Kirkpatrick and Schimke (1967) focused on low IgM as a 'marker' in familial hypogammaglobulinemia. In patients with low serum gammaglobulin, Cooper et al. (1971) found normal numbers of B lymphocytes bearing membrane-bound immunoglobulins; germinal centers were normally formed in antigen-stimulated lymph nodes. ... In addition, CVID plasmacytoid dendritic cells, which expressed normal amounts of intracytoplasmic TLR9, produced only low amounts of IFNA (147660). No TLR9 mutations or polymorphisms were detected.
Distal arthrogryposis type 4 is an inherited developmental defect syndrome characterized by multiple congenital contractures of limbs, without primary neurologic and/or muscle disease that affects limb function, and a mild to severe scoliosis. Intelligence is normal.
Serum electrolyte analysis revealed increased Mg(2+) levels, and abnormal renal reabsorption of cations was reflected in urine spot samples that showed low concentrations of Mg(2+) and Ca(2+). ... These observations suggested secondary hyperparathyroidism and renal damage, further supported by an estimated glomerular filtration rate (eGFR) in the low normal range. Serum creatinine, urea, and bicarbonate were normal, as were CT scans of the kidneys. ... All 6 patients had high plasma renin levels with normal to high plasma aldosterone and normal to low blood pressure. Plasma potassium was low in adults but normal in children, and 5 of the 6 patients had elevated plasma magnesium levels. ... INHERITANCE - Autosomal recessive HEAD & NECK Eyes - Alacrima Mouth - Xerostomia Teeth - Enamel wear, severe CARDIOVASCULAR Vascular - Low to low-normal blood pressure ABDOMEN Gastrointestinal - Polydipsia GENITOURINARY Kidneys - Polyuria - Renal NaCl wasting - Renal failure, mild - Nephrolithiasis (in some patients) - Extensive nonspecific fibrosis seen on renal biopsy (in 1 patient) - Estimated glomerular filtration rate (eGFR) in low-normal range - Decreased eGFR in the oldest patient SKIN, NAILS, & HAIR Skin - Generalized hypohidrosis or anhidrosis - Heat intolerance - Dry skin - Fine scaling (predominantly on arms and knees) Skin Histology - Slightly thickened stratum corneum - Follicular ostial dilation - Basket-weave keratin - Increased number of dilated eccrine sweat glands - Acantholytic appearance of epithelial cells of eccrine sweat glands ENDOCRINE FEATURES - Normal to high plasma aldosterone - Elevated plasma renin levels - Elevated parathyroid hormone levels LABORATORY ABNORMALITIES - Hypokalemia (in adults) - Hypermagnesemia - Low urinary magnesium - Hypocalciuria - Reduced 25-hydroxy vitamin D levels MOLECULAR BASIS - Caused by mutation in the claudin 10 gene (CLDN10, 617579.0001 ) ▲ Close
A rare genetic disease characterized by abnormalities in renal ion transport, ectodermal gland homeostasis, and epidermal integrity, resulting in generalized hypohidrosis, heat intolerance, salt-losing nephropathy, electrolyte imbalance, lacrimal gland dysfunction, ichthyosis, and xerostomia. Development of nephrolithiasis and severe enamel wear have also been described. Laboratory findings include hypermagnesemia, hypokalemia, hypercalcemia, and hypocalciuria.
Some heart conditions that can lead to low blood pressure include extremely low heart rate (bradycardia), heart valve problems, heart attack and heart failure. ... These can provide information about overall health, including low blood sugar (hypoglycemia) or low red blood cell levels (anemia). Both can cause low blood pressure Electrocardiogram (ECG or EKG). ... If blood pressure drops after eating, having small, low-carbohydrate meals might help. Exercising. ... How often should I be screened for low blood pressure? Should I measure it at home?
A shortage of red blood cells (anemia ) can cause pale skin (pallor), weakness, shortness of breath, and extreme tiredness (fatigue). Low numbers of white blood cells (neutropenia) can lead to frequent and potentially life-threatening infections. ... The TPMT gene can be classified as either low-activity or high-activity. When the gene is altered in a way that impairs the activity of the TPMT enzyme, it is described as low-activity. ... Because two copies of the gene are present in each cell, each person can have two low-activity copies, one low-activity copy and one high-activity copy, or two high-activity copies. People with two low-activity copies of the TPMT gene in each cell have TPMT deficiency and are at the greatest risk of developing hematopoietic toxicity when treated with thiopurine drugs unless they are given much less than the usual dose. People with one high-activity copy and one low-activity copy have moderately reduced enzyme activity and are also at increased risk of this complication unless given a significantly lower dose of the drug.
Two of 3 adult patients with very high TGN concentrations and 6MP-induced leukopenia had no detectable TPMT activity, presumed to be an inherited deficiency of the enzyme (Lennard et al., 1987). Children with low concentrations of TGNs had higher TPMT activity and a higher subsequent relapse rate (Lennard et al., 1990). Lennard et al. (1987, 1990) concluded that individuals with inherited low TPMT activity may be at risk for increased TGNs and acute myelosuppression when treated with standard doses of thiopurine drugs. ... Compared to control patients who did not develop myelosuppression, the 5 patients had very low TPMT activities and abnormally high levels of cytotoxic thioguanine nucleotides, consistent with inherited low TPMT activity. ... Five of the 6 patients discontinued treatment within 1 month because of low leukocyte levels. The authors concluded that TPMT heterozygotes taking AZA are at increased risk for adverse side effects.
Thiopurine S-methyltransferase deficiency is an autosomal recessive disorder that affects the body's ability to metabolize thiopurine drugs. Thiopurine S-methyltransferase (TPMT) is an enzyme that the body uses to break down thiopurine drugs. Thiopurine S-methyltransferase deficiency patients have a mutation in either one or both copies of the TPMT gene that causes reduced enzyme activity and difficulties breaking down thiopurine drugs. Affected individuals are at a high risk of experiencing bone marrow damage if they take thiopurine drugs. Many patients recover from the bone marrow damage once thiopurine drug use is stopped.
Description Multiple types of congenital heart defects-3 (CHTD3) is an autosomal dominant condition characterized by various types of congenital heart defects and low atrial rhythm (van de Meerakker et al., 2011). ... All affected individuals exhibited 'low atrial rhythm' on electrocardiography (ECG), consisting of a p-wave frontal axis oriented in a superior direction, reflecting atrial pacemaker tissue located in the lower part of the atrium. ... MRI demonstrated normal situs of the lungs and abdominal organs, and ECG consistently showed left QRS axis deviation and low atrial rhythm. Her asymptomatic sister and father both had normal echocardiography but low atrial rhythm on ECG; the father had bradycardia. ... Her daughter was born with a large incomplete AVSD and secundum-type atrial septal defect (ASD II), and at the time of surgical correction was also found to have absence of the coronary sinus and a persistent left superior vena cava (LSVC); situs of lungs and abdominal organs was normal. ECG consistently showed low atrial rhythm. Cardiac defects present in other family members included tetralogy of Fallot with LSVC, aortic hypoplasia, LSVC with aberrant right subclavian artery, and secundum ASD. ECG abnormalities in addition to low atrial rhythm included bradycardia, incomplete or complete right bundle branch block, atrial fibrillation, and paroxysmal supraventricular tachycardia.
In the first family, 2 sisters had hypergonadotropic primary amenorrhea, short stature, low weight, and a normal 46,XX karyotype. Estradiol levels were low, whereas luteinizing hormone (LH; see 152780) and follicle-stimulating hormone (FSH; see 136530) levels were high. ... In the second family, a 16-year-old girl had primary amenorrhea, lack of breast development, short stature, low weight, and a normal 46,XX karyotype. ... Pelvic ultrasound showed an infantile uterus and no visible ovaries. Basal estradiol level was low, with high LH and FSH and normal PRL levels. ... Both had vaginal bleeding after hormonal replacement. Estradiol levels were low, while LH and FSH levels were high.
A rare, genetic disorder of sex development characterized by primary amenorrhea, short stature, delayed bone age, decreased levels of estradiol, elevated levels of follicle-stimulating hormone and luteinizing hormone, absent or underdeveloped uterus and ovaries, delayed development of pubic and axillary hair, and normal 46,XX karyotype.
Etiology Gamma-glutamylcysteine synthetase catalyses the first and rate-limiting step in the synthesis of glutathione. Its deficiency results in low cellular levels of glutathione and gamma-glutamylcysteine. ... Diagnostic methods The diagnosis consists of the following stages: clinical findings, the finding of low cellular levels of glutathione, low activity of gamma-glutamylcysteine synthetase, and mutation analysis of the gamma-glutamylcysteine synthetase genes. Differential diagnosis The differential diagnosis should include glutathione synthetase deficiency (see this term), which is also associated with low levels of glutathione. Antenatal diagnosis Antenatal diagnosis could be performed by measurement of gamma-glutamylcysteine synthetase activity or mutational analysis (if the mutation in the family is known) of chorionic villi samples or cultured amniocytes.
A number sign (#) is used with this entry because the disorder is caused by mutation in the gene encoding gamma-glutamylcysteine synthetase (GCLC; 606857), the first rate-limiting enzyme in glutathione biosynthesis. Description Gamma-glutamylcysteine synthetase deficiency is 1 of 4 diseases involving enzymes in the gamma-glutamyl cycle (Meister, 1974). The other 3 disorders are glutathione synthetase deficiency (231900), 5-oxoprolinuria, which is a severe or generalized form of glutathione synthetase deficiency (266130), and gamma-glutamyl transpeptidase deficiency (231950). All except gamma-glutamyl transpeptidase deficiency are accompanied by hemolytic anemia (Larsson and Anderson, 2001). Clinical Features Konrad et al. (1972) described a brother and sister of German descent with hemolytic anemia due to deficiency of the first enzyme of glutathione synthesis, gamma-glutamylcysteine synthetase.