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    Bone and Joints Related Growth Disorders


Autosomal recessive infantile malignant osteopetrosis

It is a generic name that represents a group of heritable conditions in which there is a defect in osteoclastic bone resorption. Patients with osteopetrosis display macrocephaly, progressive deafness and blindness, hepatosplenomegaly, and severe anemia beginning in early infancy or in fetal life. Deafness and blindness are generally thought to represent effects of pressure on nerves. Autosomal dominant osteopetrosis shows mild symptoms while autosomal recessive infantile malignant osteopetrosis is a more severe form. 5 forms of autosomal recessive infantile malignant osteopetrosis have been described: OPTB1 ( MIM: 259700) caused by the mutation in the TCIRG1 subunit of the vacuolar proton pump, OPTB4 ( MIM: 611490) which is caused by mutation in the CLCN7 gene, OPTB5 ( MIM: 259720) which is caused by mutation in the OSTM1 gene, a milder, osteoclast-poor form OPTB2 ( MIM: 259710) is caused by mutation in the TNFSF11 gene, an intermediate form OPTB6 ( MIM: 611497) is caused by mutation in the PLEKHM1 gene, and a severe osteoclast-poor form OPTB7 associated with hypogammaglobulinemia ( MIM: 612301) is caused by mutation in the TNFRSF11A gene and a form of autosomal recessive osteopetrosis associated with renal tubular acidosis, OPTB3 ( MIM: 259730) is caused by mutation in the gene encoding carbonic anhydrase II. The incidence of autosomal recessive osteopetrosis is estimated to be 1:200000.

Achondroplasia  ( MIM: 100800)

It is the most frequent form of short-limb dwarfism. It is characterised by short stature caused by rhizomelic shortening of the limbs, characteristic facies with frontal bossing and midface hypoplasia, exaggerated lumbar lordosis, limitation of elbow extension, genu varum, and trident hand. Achondroplasia is an autosomal dominant disorder. The gene for achondroplasia is fibroblast growth factor receptor-3 gene (FGFR3) located in the distal area of the short arm of chromosome 4 (4p16.3). Occurrence of this disease is about 1 in 26,000 (it affects all races and both genders).


Carbonic Anhydrase Deficiency ( MIM: 611492)

Carbonic anhydrase coded by Carbonic anhydrases genes (CAs) are a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide requied for cellular respiration, calcification, acid-base balance, bone resorption, and the formation of aqueous humor, cerebrospinal fluid, saliva, and gastric acid. CAs are encoded by members of 3 independent CA gene families, i.e., alpha-CA, beta-CA, and gamma-CA. Erythrocyte carbonic anhydrase has 2 isoenzymes CA I (or A) and CA II (or B). Most common form of Carbonic anhydrase deficiency is Carbonic anhydrase II (CA II) deficiency ( MIM: 611492), an extremely rare autosomal recessive disorder, characterised by a triad of osteopetrosis, renal tubular acidosis and cerebral calcifications.

            The database presently holds the relevant data for CA II.

  Papillon-Lefevre syndrome ( MIM: 245000 

 This disease is characterized by periodontitis and palmoplantar keratoderma, leading to early loss of both milk-teeth and permanent teeth, and associated hyperkeratosis of palms and soles of feet appearing in first few years of life. Papillon-Lefevre syndrome is caused by mutations in the cathepsin C gene (CTSC), the disorder being inherited in an autosomal recessive manner. The syndrome affects 1 to 4 persons per million.


  Haim Munk Syndrome ( MIM: 245010)

Haim-Munk syndrome (HMS), an autosomal recessive disorder, can be caused by mutations in the gene encoding cathepsin C. I fact, Haim-Munk Syndrome and Papillon-Lefevre syndrome are caused by allelic variants of the same gene. This is a rare syndrome of congenital palmoplantar keratosis, pes planus, onychogryphosis, periodontitis, arachnodactyly, and acroosteolysis (to some degree similar to the Papillon-Lefevre syndrome).

  Dyskeratosis congenita ( MIM: 305000)

The disease mainly affects the integumentary system with a major consequence being anomalies of the bone marrow. The disorder is characterised by premature aging with cutaneous pigmentation, dystrophy of the nails, leukoplakia of the oral mucosa, continuous lacrimation due to atresia of the lacrimal ducts, often thrombocytopenia, anemia, and in most cases testicular atrophy. Only males are affected in a pattern consistent with X-linked recessive inheritance as a result of one or more mutations in the long arm of the X chromosome in the gene DKC1. This may result in specific issues related to dysfunctional rRNA and perhaps a graver phenotype.

  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.

  Dyggve-Melchior-Clausen ( MIM: 223800 )

Dyggve-Melchior-Clausen (DMC) Disease is a part of a subgroup of osteochondroplasias known as spondylo-epi-metaphyseal dysplasias (SEMDs) characterized by malformations of the vertebra, with abnormal ossification of long bone epiphyses and metaphyses. DMC, an autosomal recessive disorder, is a progressive SEMD with additional clinical features that include short trunk dwarfism, microcephaly, facial dysmorphism, and variable mental retardation. The disease is caused by mutations in the Dymecilin (DMC) gene.

X-linked hypophosphatemic rickets ( MIM: 307800 )

X-linked hypophosphatemic rickets, although variable in its expressivity, is characterized by rickets with bone deformities, short stature and dental anomalies. Hypophosphatemia with low renal phosphate reabsorption, normal serum calcium level with hypocalciuria, normal or low serum level of vitamin D (1,25(OH)2D3, or calcitriol), normal serum level of PTH, and increased activity of serum alkaline phosphatases are also noticeable. Mutations in the PHEX gene cause this disease. The prevalence of the disease is 1:20000.

Hereditary Hypophosphatemic Ricket with Hypercalciuria ( MIM: 241530 )

Hereditary hypophosphatemic rickets is a disorder related to low levels of phosphate in the blood, the signs and symptoms beginning in early childhood. The features of the disorder vary widely, even among affected members of the same family. They develop bone abnormalities that can interfere with movement and cause bone pain, most noticeable being bowed legs or knock knees. The disease is caused by defects in SLC34A3 gene and is transmitted in an autosomal recessive mode.

Familial tumoral calcinosis ( MIM: 211900 )

Familial tumoral calcinosis is a rare autosomal recessive metabolic disorder characterized by hyperphosphatemia and progressive deposition of basic calcium phosphate crystals in periarticular spaces, soft tissues, and sometimes bone. Most cases are caused by mutation in the GALNT3 gene.