Type A appears to be much more common in some Algonkian Indian tribes in eastern Canada. Causes Mutations in the PC gene cause pyruvate carboxylase deficiency. ... Pyruvate carboxylase also plays a role in the formation of the protective sheath that surrounds certain nerve cells (myelin) and the production of brain chemicals called neurotransmitters that allow nerve cells to communicate with one another. Mutations in the PC gene reduce the amount of pyruvate carboxylase in cells or disrupt the enzyme's activity. ... Learn more about the gene associated with Pyruvate carboxylase deficiency PC Inheritance Pattern This condition is inherited in an autosomal recessive pattern , which means both copies of the gene in each cell have mutations.

Epidemiology The overall prevalence of PC deficiency is not known and annual incidence has been reported to be 1/250,000 births. ... Clinical description Three clinical presentations of PC deficiency, probably constituting a continuum, have been described: infantile PC deficiency (type A); severe neonatal PC deficiency (type B); and intermittent/benign PC deficiency (type C). ... Type B has a very severe course with a fatal outcome in early infancy, and Type C involves only episodic metabolic acidosis. Etiology PC deficiency is caused by mutations in the PC gene (11q13.4-q13.5), involved in the conversion of pyruvate to oxaloacetate, an intermediate in the citric acid cycle and gluconeogenesis. ... Diagnostic methods PC deficiency may be suspected in patients with the non-specific clinical signs of the condition. Diagnosis is based on detection of characteristic laboratory test abnormalities in amino acid, organic acid, glucose, and ammonia serum concentrations. A PC enzyme activity assay demonstrating deficiency of the PC enzyme in fibroblasts is also diagnostic, along with mutations in the PC gene identified via molecular genetic testing.

In individuals with PC deficiency, fibroblast PC enzyme activity is usually less than 5% of that observed in controls. The diagnosis of PC deficiency can also be established in a proband by identification of biallelic pathogenic variants in PC on molecular genetic testing. ... In individuals with PC deficiency, fibroblast PC enzyme activity is usually less than 5% of that observed in controls [Wang et al 2008]. Note: Muscle PC activity is quite low in control tissue. Therefore, PC enzyme assay on muscle tissue is not recommended.

Benign pyruvate carboxylase (PC) deficiency (Type C) is a rare, very mild form of PC deficiency characterized by episodic metabolic acidosis and normal or mildly delayed neurological development. Epidemiology Benign PC deficiency is a very rare form of PC deficiency and has been described in fewer than 10 patients to date. ... Other signs include dystonia, episodic ataxia, dysarthria, transitory hemiparesis and seizures. Etiology Type C PC deficiency is caused by mutations in the PC gene (11q13.4-q13.5). ... The abnormal biochemical parameters found in severe forms of PC deficiency are absent in patients with Type C, although lysine, proline and alanine may be elevated, while citrulline is normal. PC enzyme activity assay demonstrating deficiency of the PC enzyme in fibroblasts is also diagnostic, along with mutations in the PC gene identified via molecular genetic testing.

Severe neonatal pyruvate carboxylase (PC) deficiency (Type B) is a rare, extremely severe form of PC deficiency characterized by severe, early-onset metabolic acidosis, and a generally fatal outcome in early infancy. ... Renal tubular acidosis has been reported. Etiology PC deficiency is caused by mutations in the PC gene (11q13.4-q13.5). ... Blood lactic acid levels are usually above 10 mmol/l. PC enzyme activity assay demonstrating deficiency of the PC enzyme in fibroblasts is also diagnostic, along with mutations in the PC gene identified via molecular genetic testing.

Infantile pyruvate carboxylase (PC) deficiency (Type A) is a rare, severe form of PC deficiency characterized by infantile-onset, mild to moderate lactic acidemia, and a generally severe course. ... Clinical description Patients with Type A PC deficiency usually first present with symptoms at the age of two to five months, often after normal early development. ... Renal tubular acidosis has also been reported. Etiology PC deficiency is caused by mutations in the PC gene (11q13.4-q13.5). ... Blood lactic acid levels are usually between 2 and 10 mmol/l. PC enzyme activity assay demonstrating deficiency of the PC enzyme in fibroblasts is also diagnostic, along with mutations in the PC gene identified via molecular genetic testing. Genetic counseling PC deficiency is inherited in an autosomal recessive manner.

This condition is caused by mutations in the PC gene and inherited in an autosomal recessive pattern.

Diagnosis/testing. PC is diagnosed by clinical findings and/or by the identification of a heterozygous pathogenic variant in one of the five keratin genes known to cause PC: KRT6A , KRT6B , KRT6C , KRT16 , and KRT17 . ... Nomenclature Based on data from the International Pachyonychia Congenita Research Registry (IPCRR), the most recent classification for pachyonychia congenita is by mutated gene [McLean et al 2011, Wilson et al 2011]: PC-K6a (caused by pathogenic variants in KRT6A ) PC-K6b (caused by pathogenic variants in KRT6B ) PC-K6c (caused by pathogenic variants in KRT6C ) PC-K16 (caused by pathogenic variants in KRT16 ) PC-K17 (caused by pathogenic variants in KRT17 ) The classification suggested for PC prior to the identification of the genetic basis of the disease was based solely on clinical findings. Historically, the two major subtypes of PC were based on subtle variable phenotypic features (primarily on the presence or absence of pilosebaceous cysts and natal or prenatal teeth) [Leachman et al 2005, Liao et al 2007]: PC-1 (Jadassohn-Lewandowski syndrome) PC-2 (Jackson-Lawler syndrome) With detailed clinical histories and pathogenic variants identified in an increasing number of people with PC, it became clear that the older classification of PC-1 and PC-2 was not applicable to the broader population of individuals with PC. ... The International PC Research Registry has identified 774 individuals in 419 families with genetically confirmed PC. ... Familial onychogryphosis without the associated palmoplantar keratoderma or other features of PC can be confused with PC. Individuals who have nail findings only are unlikely to have a pathogenic variant in one of the PC-related genes.

Pachyonychia congenita (PC) is a rare genodermatosis predominantly featuring painful palmoplantar keratoderma, thickened nails, cysts and whitish oral mucosa. Epidemiology The prevalence is not known but approximately 1000 patients have been registered to date worldwide. Clinical description PC presents clinically as a spectrum of conditions. PC onset is variable with most cases manifesting soon after birth, others becoming clinically apparent only in late childhood and rarely in adulthood. ... Excessive sweating of palms and soles due to palmoplantar hyperhydrosis, widespread steatocystomas appearing during or after puberty, axillary and inguinal cysts, hoarseness in young children are other findings observed in some PC patients. Etiology Although historically two subtypes have been described, PC-1 and PC2, it is today recommended to classify PC patients into four subgroups based the underlying molecular etiology: PC-K6a, PC-K6b, PC-K16 and PC-K17, as PC is caused by dominant negative mutations in at least 4 genes [ KRT6A , KRT6B (12q13.13), KRT16 , KRT17 (17q21.2)] encoding keratins preferentially expressed in basal and suprabasal layers of palmoplantar skin, epidermal appendages and oral mucosa. ... Management and treatment There is no curative treatment for PC yet. Treatment of manifestations will focus primarily on grooming of nails and management of pain due to palmoplantar keratoderma: it includes the use of emollients to reduce hyperkeratosis and strategies to limit frictions and trauma of the feet.

Pachyonychia congenita (PC) is a rare inherited condition that primarily affects the nails and skin. ... Features may vary among affected people depending on their specific mutation. PC is divided into 5 types based on the specific keratin gene involved: PC- K6a , PC- K6b , PC- K6c , PC- K16 , and PC- K17 .

For a phenotypic description and a discussion of genetic heterogeneity of pachyonychia congenita, see 167200. Inheritance Chong-Hai and Rajagopalan (1977) suggested autosomal recessive inheritance of pachyonychia congenita in a 4-year-old Malaysian girl with first-cousin parents, although they recognized new dominant mutation as a possibility. See also Sivasundram et al. (1985). INHERITANCE - Autosomal recessive HEAD & NECK Mouth - No oral leukoplakia SKIN, NAILS, & HAIR Skin - Horny papules (face, leg, buttocks) - No palmoplantar hyperkeratosis - No hyperhidrosis Nails - Episodic inflammatory swelling of nail bed - Recurrent shedding of nails - Hard,thickened nails (pachyonychia) - Subungual hyperkeratosis MISCELLANEOUS - See also pachyonychia congenita, type 3 (PC1, 167200 ) ▲ Close

Although the condition had previously been subdivided clinically into Jadassohn-Lewandowsky PC type 1 and Jackson-Lawler PC type 2, patients with PC were later found to have a mixed constellation of both types, leading to a classification of PC based on genotype (summary by Sybert, 2010; Eliason et al., 2012; McLean et al., 2011). ... PC type 2, the Jackson-Lawler type, has natal teeth and epidermoid cysts (cylindromas), but no oral leukoplakia. Corneal dystrophy may be a feature exclusively of the Jackson-Lawler type. Smith et al. (1998) stated that PC type 2, in contrast to PC type 1, has minimal oral involvement and milder keratoderma, and multiple steatocystomas (184500) is a major clinical feature. ... Natal teeth are indicative of PC type 2, although their absence does not preclude the PC type 2 diagnosis. Nomenclature The form of PC caused by mutation in the KRT6A gene, here designated PC3, has also been designated PC-6a (Eliason et al., 2012) and PC-K6a (Shah et al., 2014).

Although the condition had previously been subdivided clinically into Jadassohn-Lewandowsky PC type 1 and Jackson-Lawler PC type 2, patients with PC were later found to have a mixed constellation of both types, leading to a classification of PC based on genotype (summary by Sybert, 2010; Eliason et al., 2012; McLean et al., 2011). ... PC type 2, the Jackson-Lawler type, has natal teeth and epidermoid cysts (cylindromas), but no oral leukoplakia. Corneal dystrophy may be a feature exclusively of the Jackson-Lawler type. Smith et al. (1998) stated that PC type 2, in contrast to PC type 1, has minimal oral involvement and milder keratoderma, and multiple steatocystomas (184500) is a major clinical feature. ... Natal teeth are indicative of PC type 2, although their absence does not preclude the PC type 2 diagnosis. Nomenclature The form of PC caused by mutation in the KRT17 gene, here designated PC2, has also been designated PC-17 (Eliason et al., 2012) and PC-K17 (Shah et al., 2014).

Although the condition had previously been subdivided clinically into Jadassohn-Lewandowsky PC type 1 and Jackson-Lawler PC type 2, patients with PC were later found to have a mixed constellation of both types, leading to a classification of PC based on genotype (summary by Sybert, 2010; Eliason et al., 2012; McLean et al., 2011). ... PC type 2, the Jackson-Lawler type, has natal teeth and epidermoid cysts (cylindromas), but no oral leukoplakia. Corneal dystrophy may be a feature exclusively of the Jackson-Lawler type. Smith et al. (1998) stated that PC type 2, in contrast to PC type 1, has minimal oral involvement and milder keratoderma, and multiple steatocystomas (184500) is a major clinical feature. ... Natal teeth are indicative of PC type 2, although their absence does not preclude the PC type 2 diagnosis. ... See 260130 for a possible autosomal recessive form of pachyonychia congenita. Nomenclature The form of PC caused by mutation in the KRT16 gene, here designated PC1, has also been designated PC-16 (Eliason et al., 2012) and PC-K16 (Shah et al., 2014).

A number sign (#) is used with this entry because mutations in a number of genes are associated with pancreatic carcinoma, familial or sporadic, germline or somatic. Description Pancreatic cancer shows among the highest mortality rates of any cancer, with a 5-year relative survival rate of less than 5%. By the time of initial diagnosis, metastatic disease is commonly present. Established risk factors include a family history of pancreatic cancer, a medical history of diabetes type 2, and cigarette smoking (summary by Amundadottir et al., 2009). Genetic Heterogeneity of Pancreatic Cancer Somatic mutations in pancreatic cancer occur in the KRAS (190070), CDKN2A (600160), MADH4 (600993), TP53 (191170), ARMET (601916), STK11 (602216), ACVR1B (601300), and RBBP8 (604124) genes.

A number sign (#) is used with this entry because of evidence that the form of familial pancreatic cancer that maps to 4q32-q34 is determined by mutation in the gene encoding palladin (PALLD; 608092). Clinical Features Familial pancreatic cancer (260350) occurs as part of several familial cancer syndromes and as part of hereditary pancreatitis. In addition, families with isolated pancreatic cancer have been identified, most notably the family of former President of the United States Jimmy Carter (Lynch et al., 1990; Brentnall et al., 1999; Banke et al., 2000; Hruban et al., 2001). Affected members of these families inherit pancreatic cancer in the absence of other types of cancer and in the absence of chronic pancreatitis. A striking example of autosomal dominant pancreatic cancer is 'family X' described by Brentnall et al. (1999) and Meckler et al. (2001).

Familial pancreatic cancer (FPC) is the occurrence of pancreatic cancer in two or more first-degree relatives (parent and child, or two siblings). It is sometimes referred to as FPC only when there is not a known hereditary cancer syndrome in an affected family. In familial cases, pancreatic cancer often occurs before age 50 (earlier than other forms of pancreatic cancer). In 60% of cases it occurs within the head of the pancreas. Symptoms of pancreatic cancer are generally non-specific and may include pain in the upper abdomen that radiates to the back; loss of appetite; significant weight loss; and jaundice due to bile duct obstruction . Pancreatic cancer often goes undetected until the advanced stages of the disease, and rapid tumor growth and metastasis are common.

A number sign (#) is used with this entry because susceptibility to pancreatic cancer is conferred by heterozygous mutation in the BRCA2 gene (600185) on chromosome 13q13. For background, phenotypic description, and a discussion of genetic heterogeneity of pancreatic carcinoma, see 260350. Mapping Schutte et al. (1995) observed that, although pancreatic adenocarcinoma is relatively frequent, description of the genetic alterations has been hampered for several reasons. Because of the aggressive clinical course, the number of resected specimens, especially at early stages of the cancer, have been somewhat limited. Furthermore, pancreatic adenocarcinomas characteristically exhibit an exuberant host desmoplastic response, resulting in a high mixture of nonneoplastic cells and hampering the molecular genetic analysis of primary tumor samples.

A number sign (#) is used with this entry because this form of susceptibility to pancreatic cancer is caused by heterozygous mutation in the BRCA1 gene (113705). For background, phenotypic description, and a discussion of genetic heterogeneity of pancreatic cancer, see 260350. Mapping This form of susceptibility to pancreatic cancer is caused by mutations in the BRCA1 gene, which Miki et al. (1994) mapped to chromosome 17q21. Molecular Genetics Al-Sukhni et al. (2008) found loss of heterozygosity at the BRCA1 locus in pancreatic tumor DNA from 5 (71%) of 7 patients with pancreatic cancer who carried a heterozygous germline BRCA1 mutation (see, e.g., 113705.0003 and 113705.0018). Pancreatic tumor DNA was available for sequencing in 4 cases, and 3 demonstrated loss of the wildtype allele.

A number sign (#) is used with this entry because heterozygous mutation in the PALB2 gene (610355) on chromosome 16p12 confers susceptibility to pancreatic cancer. For background, phenotypic description, and a discussion of genetic heterogeneity of pancreatic carcinoma, see 260350. Molecular Genetics To explore the utility of personal genome sequencing, Jones et al. (2009) screened 20,661 coding genes for germline mutations in a patient with pancreatic cancer whose tumor DNA had previously been sequenced. They detected 15,461 germline variants. Three genes, including PALB2, carried variants in both germline and tumor DNA. PALB2 was considered the best candidate for a pancreatic cancer susceptibility gene because of the rarity of terminating PALB2 mutations in healthy individuals and because PALB2 had previously been implicated in breast cancer and Fanconi anemia.

A number sign (#) is used with this entry because mosaic variegated aneuploidy syndrome-2 (MVA2) is caused by homozygous or compound heterozygous mutation in the CEP57 gene (607951) on chromosome 11q21. Description Mosaic variegated aneuploidy syndrome is an autosomal recessive disorder characterized by poor growth and variable phenotypic manifestations, such as facial dysmorphism and congenital heart defects, associated with mosaic aneuploidies resulting from defects in cell division (summary by Snape et al., 2011). See also MVA1 (257300), caused by mutation in the BUB1B gene (602860) on chromosome 15q15. Clinical Features Lane et al. (2002) reported a 12-year-old boy with poor growth, short stature, microcephaly, mild cognitive defects, and mildly dysmorphic facial features. Cytogenetic analysis found 24% hyperdiploid chromosome numbers during metaphase, consistent with MVA.

Mosaic variegated aneuploidy (MVA) syndrome is a rare disorder in which some cells in the body have an abnormal number of chromosomes instead of the usual 46 chromosomes , a situation known as aneuploidy. Most commonly, cells have an extra chromosome, which is called trisomy, or are missing a chromosome, which is known as monosomy. In MVA syndrome, some cells are aneuploid and others have the normal number of chromosomes, which is a phenomenon known as mosaicism . Typically, at least one-quarter of cells in affected individuals have an abnormal number of chromosomes. Because the additional or missing chromosomes vary among the abnormal cells, the aneuploidy is described as variegated.

A number sign (#) is used with this entry because of evidence that mosaic variegated aneuploidy syndrome-3 (MVA3; 617598) is caused by homozygous mutation in the TRIP13 gene (604507) on chromosome 5p15. Description MVA3 is an autosomal recessive disorder resulting from errors in chromosome segregation. Most affected individuals develop early-onset Wilms tumor and show either aneuploidy or premature chromatid separation in cells. Some patients may have additional developmental features, such as microcephaly, growth retardation, or developmental delay (summary by Yost et al., 2017). For a discussion of genetic heterogeneity of MVA, see MVA1 (257300). Clinical Features Yost et al. (2017) reported 6 probands with onset of Wilms tumor in early childhood.

Mosaic variegated aneuploidy (MVA) syndrome is a very rare condition characterized by problems with cell division (specifically during mitosis) that results in a high number of cells with missing (monosomy) or extra (trisomy) genetic material in multiple chromosomes and tissues (mosaic aneuploidies). Only about 50 cases have been described in the medical literature. Features include severe microcephaly, growth deficiency and short stature, mild physical abnormalities, eye abnormalities, problems with the brain and central nervous system, seizures, developmental delay, and intellectual disability. The risk for cancer is increased, with rhabdomyosarcoma , Wilm's tumor , and leukemia reported in several cases. MVA syndrome is an autosomal recessive condition. It can be caused by changes (mutations) in the BUB1B gene or the CEP57 gene. The BUB1B gene encodes BubR1, a key protein in mitotic spindle checkpoint function.

Mosaic variegated aneuploidy (MVA) syndrome is a chromosomal anomaly characterized by multiple mosaic aneuploidies that leads to a variety of phenotypic abnormalities and cancer predisposition. Epidemiology To date, 41 cases of MVA have been described in the literature. Clinical description The most common clinical features are growth retardation of prenatal onset, microcephaly, developmental delay, structural central nervous system and ophthalmological anomalies (e.g. cataract, corneal opacities, microphthalmia and glaucoma), and mild dysmorphic features, including triangular facies, micrognathia, and epicanthic folds. Additional features include oligohydramnios, ventricular dilatation, Dandy-Walker malformation, fetal ascites, and increased nuchal translucency. Cancer occurs in approximately 1/3 of individuals. Wilms tumor, rhabdomyosarcoma, acute lymphoblastic leukemia, and granulosa cell malignant tumor of the ovary (see these terms) all occur before the age of 5 years.

A number sign (#) is used with this entry because paramyotonia congenita is caused by heterozygous mutation in the voltage-gated sodium channel alpha-subunit gene (SCN4A; 603967) on chromosome 17q23. Allelic disorders with overlapping phenotypes include hyperkalemic periodic paralysis (HYPP; 170500) and the potassium-aggravated myotonias (608390). See also autosomal dominant myotonia congenita (160800), which is caused by mutation in the CLCN1 gene (118425). Clinical Features The characteristics of paramyotonia congenita, first described by von Eulenburg (1886), are (1) inheritance as a dominant with high penetrance; (2) myotonia, increased by exposure to cold; (3) intermittent flaccid paresis, not necessarily dependent on cold or myotonia; (4) lability of serum potassium; (5) nonprogressive nature; and (6) lack of atrophy or hypertrophy of muscles. Lajoie (1961) described a family with many affected members. The condition, which was already evident in infancy, was manifested mainly by paralysis of muscles exposed to cold; it was not progressive, did not interfere with a reasonably normal social and economic life, and did not affect longevity.

Paramyotonia congenita is a disorder that affects muscles used for movement (skeletal muscles). Beginning in infancy or early childhood, people with this condition experience bouts of sustained muscle tensing (myotonia) that prevent muscles from relaxing normally. Myotonia causes muscle stiffness that typically appears after exercise and can be induced by muscle cooling. This stiffness chiefly affects muscles in the face, neck, arms, and hands, although it can also affect muscles used for breathing and muscles in the lower body. Unlike many other forms of myotonia, the muscle stiffness associated with paramyotonia congenita tends to worsen with repeated movements.

Paramyotonia congenita of Von Eulenburg is characterised by exercise- or cold-induced myotonia and muscle weakness. Prevalence is unknown. The syndrome is nonprogressive and is transmitted as an autosomal dominant trait. It is caused by mutations in the gene encoding the alpha subunit of the type IV voltage-gated sodium channel (SCN4A; 17q23.3).

Paramyotonia congenita is an inherited condition that affects muscles used for movement ( skeletal muscles ), mainly in the face, neck, arms, and hands. Symptoms begin in infancy or early childhood and include episodes of sustained muscle tensing ( myotonia ) that prevent muscles from relaxing normally and lead to muscle weakness. Symptoms in paramyotonia congenita worsen during exposure to cold temperatures, and unlike many other forms of myotonia, worsen with exercise and repeated movements. This condition is caused by mutations in the SCN4A gene and is inherited in an autosomal dominant pattern.

Roberts syndrome (RBS) is characterized by pre- and postnatal growth retardation, severe symmetric limb reduction defects, craniofacial anomalies and severe intellectual deficit. SC phocomelia is a milder form of RBS. Epidemiology The prevalence and incidence are not known. Less than 150 cases have been described in the literature. Clinical description Upper limbs are more frequently and severely affected than lower limbs. The defect is mostly mesomelic with the radius being the most affected in the upper limbs, and the fibula in the lower limbs. The most severe defects result in phocomelia. Aplastic or hypoplastic thumbs, oligodactyly, clinodactyly or syndactyly can also occur.

The first chromosomal abnormality is called premature centromere separation (PCS) and is the most likely pathogenic mechanism for Roberts syndrome. Chromosomes that have PCS will have their centromeres separate during metaphase rather than anaphase (one phase earlier than normal chromosomes). ... Confirmation of a Roberts syndrome diagnosis requires detection of the characteristic chromosomal abnormalities (PCS and HR) or the identification of two ESCO2 mutations that have been linked to Roberts syndrome. [6] Carrier testing and prenatal diagnosis [ edit ] Carrier testing for Roberts syndrome requires prior identification of the disease-causing mutation in the family. ... The following are observations that have been made in individuals with cytogenetic findings of PCS/HR or ESCO2 mutations: The symptom of prenatal growth retardation is the most common finding and can be moderate to severe.

Roberts syndrome is a genetic disorder characterized by limb and facial abnormalities. Affected individuals also grow slowly before and after birth. Mild to severe intellectual impairment occurs in about half of all people with Roberts syndrome. Children with Roberts syndrome are born with abnormalities of all four limbs. They have shortened arm and leg bones (hypomelia), particularly the bones in their forearms and lower legs. In severe cases, the limbs may be so short that the hands and feet are located very close to the body (phocomelia).

Tumor cells and cultured lymphocytes and fibroblasts of both patients showed premature separation of centromeric heterochromatin (PCS). Holmes-Siedle et al. (1990) described what they called the Roberts/SC phocomelia syndrome in 3 sibs of second-cousin parents.

Roberts syndrome is a genetic disorder characterized by limb and facial abnormalities. Affected individuals are born with abnormalities of all four limbs and typically have shortened arm and leg bones (hypomelia). They may also have phocomelia (in severe cases); abnormal or missing fingers and toes; joint deformities (contractures); and numerous facial abnormalities including cleft lip with or without cleft palate ; micrognathia; ear abnormalities; hypertelorism ; down-slanting palpebral fissures ; small nostrils; and a beaked nose. Microcephaly, intellectual disability, and heart, kidney or genital abnormalities may also be present. Infants with a severe form of Roberts syndrome are often stillborn or die shortly after birth, while mildly affected individuals may live into adulthood.