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    Multisystem Disorders


Cystic Fibrosis ( MIM: 219700)

Cystic Fibrosis (CF) is a common autosomal recessive disorder, which affects the entire body, causing progressive disability and often early death. The hallmark symptoms of cystic fibrosis are salty tasting skin, poor growth and poor weight gain despite a normal food intake, accumulation of thick, sticky mucus, frequent chest infections and coughing or shortness of breath. CF is caused by a mutation in the gene for the protein cystic fibrosis transmembrane conductance regulator (CFTR). This gene is required to regulate the components of sweat, digestive juices, and mucus. The most common mutation, ?F508, is a deletion (?) of three nucleotides that results in a loss of the amino acid phenylalanine (F) at the 508th position on the protein. This mutation accounts for two-thirds (66-70%) of CF cases worldwide CF is most common among Caucasians and Ashkenazi Jews; one in 25 people of European descent carry one mutant copy of CFTR. The estimated prevalence of CF is 1/43,321 to 1/100,323 in Indian population. The carrier frequency of F508del mutation in the Indian population has been estimated to be 1/238 (0.42%). Frequency of CF patients homozygous for F508del mutation is 1/228,006.


Porphyrias are a group of inherited or acquired disorders of certain enzymes in the heme bio-synthetic pathway, manifesting with either neurological complications or skin problems (or occasionally both). They are broadly classified as acute (hepatic) porphyrias and cutaneous (erythropoietic) porphyrias according to the site of accumulation or overproduction of porphyrins. Acute intermittent porphyria (AIP), one of the most common form of porphyria ( MIM: 176000) is rare autosomal dominant metabolic disorder (very rarely homozygous) characterized by a deficiency of the enzyme porphobilinogen deaminase, the responsible gene being PBGD.

            The database currently holds the relevant data of PBGD gene only pertaining to intermittent porphyria.

Rhizomelic Chondrodysplasia Punctata type 1 ( MIM: 215100)

Rhizomelic chondrodysplasia punctata (also known as "Autosomal recessive chondrodysplasia punctata type 1), is a rare, multisystem developmental disorder characterized by dwarfism due to systemic shortening of the proximal bones (i.e. rhizomelia), specific radiologic abnormalities, joint contractures, congential cataracts, ichthyosis, and severe mental retardation. It is caused by mutations in the PEX7 gene, which encodes the peroxisomal type 2 targeting signal (PTS2) receptor.

H syndrome ( MIM: 612391

H syndrome is a recently reported autosomal-recessive disorder characterized by cutaneous hyperpigmentation, hypertrichosis, hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism, short stature, hallux valgus, and fixed flexion contractures of the toe joints and the proximal interphalangeal joints. It is caused by mutations in the SLC29A3 gene, which encodes the equilibrative nucleoside transporter hENT3.

Biotidinase Deficiency ( MIM: 253260 )

Biotinidase deficiency is an autosomal recessive metabolic disorder where the body is unable to reuse and recycle biotin. This disorder is classified as a multiple carboxylase deficiency, a group of disorders characterized by impaired activity of certain enzymes that depend on biotin. The signs and symptoms appear within the first few months of life, but the age of onset varies. Sverely affected sunjects often have seizures, weak muscle tone (hypotonia), breathing problems, and delayed development. If left untreated, the disorder can lead to hearing loss, eye abnormalities and loss of vision, problems with movement and balance (ataxia), skin rashes, hair loss (alopecia), and a fungal infection called candidiasis. Mutations in the BTD gene cause biotinidase deficiency.

Costello Syndrome ( MIM: 218040 )

Costello syndrome, also called faciocutaneoskeletal syndrome or FCS syndrome, is a rare multisystem genetic disorder characterized by delayed development and mental retardation, distinctive facial features, unusually flexible joints, and loose folds of extra skin, especially on the hands and feet, heart abnormalities, structural heart defects, and overgrowth of the heart muscle etc. Infants with Costello syndrome may be large at birth, but grow more slowly than other children and have difficulty feeding. Later in life, people with this condition have relatively short stature and many have reduced levels of growth hormones.  This is caused by mutations in the HRAs gene and the disease is inherited in autosomal dominant mode.

Nance-Horan Syndrome  ( MIM: 303250 )

Nance-Horan syndrome (NHS) is a rare but probably underdiagnosed disorder characterized by the association in male patients of congenital cataracts with microcornea, dental anomalies and facial dysmorphism. Intellectual impairment is observed in about 30% of cases with inter- and intrafamilial variability. NHS is caused by mutations in the NHS gene and is transmitted in an X-linked dominant mode.

Frasier syndrome ( MIM: 136680 )

Frasier syndrome is a rare disorder characterized by genital (normal female external genitalia, streak gonads, XY karyotype and frequently gonadoblastoma) and renal manifestations (childhood proteinuria and nephritic syndrome, characterized by nonspecific focal and segmental glomerular sclerosis, progressing to end-stage renal failure in adolescence or early adulthood).

Renal Cysts and Diabetes (RCAD) Syndrome  ( MIM: 137920 )

Renal Cysts and Diabetes (RCAD) Syndrome is caused by mutation in the gene encoding hepatocyte nuclear factor-1-beta (TCF2, or HNF1B). It is an autosomal dominant disorder comprising nondiabetic renal disease resulting from abnormal renal development, and diabetes, which in some cases occurs earlier than age 25 years (MODY). The renal disease is highly variable and may also accompany different abnormalities of the genital tract.

Neurodegeneration with Brain Iron Accumulation, Type 1  

Neurodegeneration with Brain Iron Accumulation type 1, NBIA 1 ( MIM: 234200 ) , is an autosomal recessive neurological/metabolicdisorder characterized by progressive iron accumulation within the basal ganglia leading to motor disabilities, speechdisorders, intellectual impairments, psychiatric problems, depression and vision loss.Motor disabilities gains severity with increasing age and the condition of the patient worsens. Mutations in the PANK2is the gene responsible for this disorder and is mapped to chromosome 20p. The mutations in the PANK2 gene cause paucity in the production of coenzyme A, which causes iron accumulation in the basal ganglia of brain that leads to neurodegeneration. It is estimated to affect 1 to 3 per million people worldwide.

Terminal 4q deletion syndrome 

Terminal 4q deletion (4q31->qter) syndrome is a rare chromosomal abnormality, often arises de novo. Patients are severely affected with the characteristic facial, skeletal, and developmental anomalies; many patients die at infancy.

Chronic infantile neurological cutaneous articular (CINCA) syndrome ( MIM: 607115)

Chronic infantile neurological cutaneous articular (CINCA) syndrome is a rare congenital auto inflammatory disorder characterized by persistent cutaneous symptoms, meningitis, joint deformities with recurrent fever and inflammation. It is caused by mutations in the CIAS1gene, mapped to chromosome 1q44.

Congenital Generalized Lipodystrophy, Type 2 ( MIM: 269700)

Congenital Generalized Lipodystrophy, type 2, also known as Berardinelli-Seip syndrome, is a rare form of autosomal recessive metabolic disorder characterized by lack of overall adipose tissuein the body along with extreme insulin resistance, hypertriglyceridemia, hepatic steatosis, early onset of diabetesand mental and intellectual impairment. The estimated prevalence of CGL Type 2 is 1 in 10 million people worldwide. BSCL2 ( MIM: 606158), the gene responsible for this disorder, has been reported that is mapped to chromosome 11q. BSCL2 mutants in general exhibit premature mortality with a range of 4 months to 35 years of age.

Allgrove syndrome ( MIM: 231550)

Allgrove syndrome is a rare autosomal recessive congenital disease. The candidate gene is AAAS, which is mapped to chromosome 12q13.13 (AAAS; MIM: 605378). The clinical manifestations include achalasia, alacrima, autonomic neuropathy and addisonianism, with significant impairment of the central nervous system, ACTH-resistant adrenal insufficiency, altered skin pigmentation, iron deficiencies, abnormal peristalsis of the intestine, delay in motor and speech developments, ataxia, anisocoria and progressive loss of cholinergic functions. Only 4 individuals with no specified ethnicity have been studied in India from South Indian population. The disease is prevalent in consanguineous communities.

Glycogen storage disease Ia  ( MIM: 232200)

Glycogen storage disorder Ia, caused by mutations in G6PC gene, is an autosomal recessive disorder causing accumulation of glycogen in different organs. It typically manifests during the first year of life with severe hypoglycemia and hepatomegaly. The disorder is characterized by growth retardation, delayed puberty, lactic acidemia, hyperlipidemia, hyperuricemia and other features.

Hypohidrotic-Hair-Tooth type Ectodermal Dysplasia 10B ( MIM: 224900)

Hypohidrotic-Hair-Tooth type Ectodermal Dysplasia 10B is an autosomal recessive congenital disorder caused by mutations in the EDAR/Ectodysplasin Anhidrotic Receptor gene. The disease is characterized by a triad of signs comprising sparse hair (hypotrichosis), abnormal or missing teeth (anodontia or hypodontia) and inability to sweat (anhidrosis or hypohidrosis).

X-linked hypohidrotic ectodermal dysplasia 1 ( MIM: 305100)

X-linked hypohidrotic ectodermal dysplasia 1 caused by mutations in the ED1 gene, is the most frequent form of hypohidrotic ectodermal dysplasia. It is an X-linked recessive congenital disorder manifesting only in males. The disorder is characterized by a triad of signs comprising sparse hair (hypotrichosis), abnormal or missing teeth (anodontia or hypodontia) and inability to sweat (anhidrosis or hypohidrosis). Dryness of the skin, eyes, airways, mucous membranes and various dysmorphic features may also be present in the patients.

Chronic Pancreatitis MIM: 167800)

Chronic pancreatitis is a disorder characterized by recurrent episodes of inflammation of the pancreas (pancreatitis) manifesting as occasional or frequent abdominal pain of varying severity, fever, pancreatic insufficiency, diabetes mellitus and pancreatic calculi.Chronic pancreatitis may be caused by mutations in the cationic trypsinogen gene PRSS1 ( MIM: 276000) and the SPINK1 gene ( MIM: 167790), and can also be associated with mutations in the cystic fibrosis gene (CFTR; MIM: 602421) and CTRC gene ( MIM: 601405). Mutations in the Calcium-Sensing Receptor gene (CASR; MIM: 601199) have also been reported in association with chronic pancreatitis.

The database presently holds the data for SPINK1, CFTR, CTRC and CASR mutations.

Congenital erythropoietic porphyria (Gunther disease) ( MIM: 263700)

Congenital erythropoietic porphyria (Gunther disease) is an autosomal recessive disease caused by mutation in the uroporphyrinogen III synthase gene (UROS, MIM: 606938). The porphyrias are group of diseases characterized by defects in heme synthesis, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. They manifest as light-sensitization and severe skin damage, hemolytic anemia, jaundice, hepatosplenomegaly, bleeding and thrombocytopenia.

Dilated cardiomyopathy with woolly hair and keratoderma (Carvajal syndrome) ( MIM: 605676)

Dilated cardiomyopathy with woolly hair and keratoderma (Carvajal syndrome) is an autosomal recessive disease caused by mutation in the DSP gene ( MIM: 125647). Patients have wooly hair since birth and keratoderma appears a little later. Dilation of cardiac chambers and other cardiac changes might lead to congestive heart failure and death.

Focal dermal hypoplasia (Goltz syndrome) ( MIM: 305600)

Focal dermal hypoplasia is an X-linked dominantdisease caused by mutations in the PORCN gene ( MIM: 300651 ), causing in utero lethality in males. It is characterized by atrophy and linear pigmentation of the skin, herniation of fat through the dermal defects, and multiple papillomas of the mucous membranes or skin. Various digital, oral and ocular anomalies along with striated bones are also common manifestations.