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  1. Home
  2. Health professionals
  3. Skeletal Rare Disorders
  4. Low bone resorption
  • Low Bone Resorption
  • High Bone Resorption
  • High Bone Formation
  • Decreased Bone Formation

ALTERED OSTEOCLAST, OSTEOBLAST OR OSTEOCYTE ACTIVITY

Low Bone Resorption

Osteopetrosis, Autosomal recessive 1 (OPTB1)

Craniometaphyseal dysplasia is a genetic syndrome involving cranial and tubular bone anomalies that commonly present at a young age, in particular with otolaryngologic manifestations. 

(OMIM phenotype number #259700)

Autosomal-recessive infantile malignant osteopetrosis is a severe , malignant, and heterogeneous genetic disorder. The autosomal-recessive infantile type is typically fatal during infancy or early childhood if untreated. The major therapeutical option is marrow transplantation. Osteoclasts number is usually normal or high, but their acidification function is defective. The main clinical features are: high bone density, recurrent infections, spontaneous bruising and bleeding, hypersplenism, haemolysis, anemia, delayed eruption of the dentition, blindness, deafness. Autosomal recessive osteopetrosis includes eight subtypes and incidence is estimated at 1/200.000 live births.
Osteopetrosis, Autosomal recessive 1 is a severe and genetically heterogeneous bone disorder with a fatal outcome (within the first decade of life). This disorder usually manifests in the first few months of life with macrocephaly and frontal bossing. The most severe complication, limiting survival, is bone marrow insufficiency. Osteoclasts are present in normal or elevated numbers.

Gene

TCIRG1 gene, 11q13.2 (OMIM gene/locus number *604592), encoding the alpha3 subunit of the vacuolar proton pump responsible for proton transport in the resorption lacunae, which mediates the acidification of the bone/osteoclast interface.

Phenotype

Severe form, macrocephaly, frontal bossing, nystagmus, optic atrophy, blindness, deafness, facial palsy, thick and dense skull, narrowness of neural and vascular foramina, genu valgum, dental defects (dental caries, distorted primary molars), loss of trabecular structure, poor/no definition between cortical and medullary bone, osteomyelitis, increased bone density (sclerosis) and generalized high bone mass, pathologic fractures, bone-within-bone appearance, sandwich appearance of vertebral bodies, coxa vara, splayed metaphyses, failure to thrive, hydrocephalus, seizures (tetany), hepato-splenomegaly, bone marrow insufficiency, pancytopenia, anemia.

Main biochemical alterations

Adult/intermediate forms: high CK-BB, high bone ALP. Infantile/severe forms: low Ca, high PTH, high 1,25(OH)2D, high CK-BB, high AP, anemia.

Images

Radiographies show: skull (a) and chest (b)
Radiographies show: skull (a) and chest (b) of the brother showing sclerotic changes in the base of the skull, dense mastoid and

Reproduced from J Bone Miner Metab, Novel mutation of TCIRG1 and clinical pictures of two infantile malignant osteopetrosis patients, 2011;29:251-6, Yuan P, Yue Z, Sun L, et al., with permission of Springer.

Other Resource:

  • Osteopetrosis Society (OPETS)
Osteopetrosis, Autosomal Recessive 2 (OPTB2)

Osteopetrosis, Autosomal recessive 2 is a genetic disease characterized by increased bone mass and density due to a failure in bone resorption. It is part of the group of autosomal recessive osteopetrosis, also called malignant infantile osteopetrosis (see OPTB1).

(OMIM #259710)

Osteopetrosis, Autosomal recessive 2 is a genetic disease characterized by increased bone mass and density due to a failure in bone resorption. It is part of the group of autosomal recessive osteopetrosis, also called malignant infantile osteopetrosis (see OPTB1). This disease is caused by loss-of-function mutations of TNFSF11 gene, causing lack of biologically active Receptor activator of nuclear factor-kappaB-ligand (RANKL) in the mesenchymal lineage, including osteoblasts and stromal cells, leading to osteoclast‐poor form of autosomal recessive osteopetrosis.

Gene

TNFSF11 gene, 13q14.11 (OMIM gene/locus number *602642), encoding RANKL, the master osteoclastogenic cytokine produced mainly by osteoblasts and stromal cells in bone.

Phenotype

Intermediate form, osteoclast-poor, multiple fractures, increased bone density (sclerosis) and generalized high bone mass, diaphyseal sclerosis, genu valgum, dental defects (deciduous teeth retention, tooth crown malformation, dental caries), osteomyelitis of the mandible, mandibular prognathism, cranial hyperostosis, facial paralysis due to cranial nerve VII compression, normal intelligence, optic atrophy, early blindness, anemia, thrombocytopenia, pancytopenia, extramedullary hematopoiesis, hepatosplenomegaly.

Main biochemical alterations

Adult/intermediate forms: high CK-BB, high bone ALP. Infantile/severe forms: low Ca, high PTH, high 1,25(OH)2D, high CK-BB, high AP, anemia.

Other resource:

  • Osteopetrosis Society (OPETS)
Osteopetrosis, Autosomal Recessive 3 (OPTB3)

Osteopetrosis, Autosomal recessive 3, is a rare form of autosomal recessive osteopetrosis (see OPTB1) caused by homozygous or compound heterozygous mutation in the gene encoding carbonic anhydrase II (CA2 gene).

(OMIM phenotype number #259730)

Osteopetrosis, Autosomal recessive 3, is a rare form of autosomal recessive osteopetrosis (see OPTB1) caused by homozygous or compound heterozygous mutation in the gene encoding carbonic anhydrase II (CA2 gene). This disorder is characterized by a triad of osteopetrosis, renal tubular acidosis, and neurological disorders related to cerebral calcifications. Other clinical manifestations are: a high risk of fractures, dental abnormalities, cranial nerve compression, developmental delay and short stature. The radiographic exams can show cerebral calcifications by early childhood. The osteosclerosis and skeletal modeling defects may gradually resolve by adulthood. Renal tubular acidosis (proximal, distal, or combined type) can cause hyperchloremic metabolic acidosis, sometimes with hypokalemia. Nearly 100 cases have been described, predominantly from the Middle East and Mediterranean region, but cases have been documented worldwide.

Currently, there is no established medical therapy.

Gene

CA2 gene, 8q21.2 (OMIM gene/locus number #611492), enconding carbonic anhydrase, expressed at high levels in OCs during bone resorption. Several different mutations within the CA2 gene have been identified.

Phenotype

Intermediate form, renal tubular acidosis (typical sign), basal ganglion calcification (typical sign), early fractures, short stature, dental malocclusion, increased bone density (sclerosis) and generalized high bone mass, diaphyseal sclerosis, cranial hyperostosis, normal intelligence or mental retardation, visual impairment, hepatosplenomegaly, anemia (not usual), extramedullary hematopoiesis.

Main biochemical alterations

Adult/intermediate forms: high CK-BB, high bone ALP. Infantile/severe forms: low Ca, high PTH, high 1,25(OH)2D, high CK-BB, high AP, anemia, metabolic acidosis.

Other resource:

  • Osteopetrosis Society (OPETS)
Osteopetrosis, Autosomal Recessive 4 (OPTB4)

Osteopetrosis, Autosomal recessive 4, is a form of autosomal recessive osteopetrosis (see OPTB1) caused by homozygous or compound heterozygous mutation in the Chloride Channel 7 (CLCN7 gene). CLCN7-dependent OPTB4 is diagnosed at birth or early in infancy due to generalized osteosclerosis and severe haematological deficits.

(OMIM phenotype number #611490)

Osteopetrosis, Autosomal recessive 4, is a form of autosomal recessive osteopetrosis (see OPTB1) caused by homozygous or compound heterozygous mutation in the Chloride Channel 7 (CLCN7 gene). CLCN7-dependent OPTB4 is diagnosed at birth or early in infancy due to generalized osteosclerosis and severe haematological deficits. Other clinical manifestations include primary neurological defects, such as cerebral and retinal atrophy. This disease is frequently lethal in early life, despite haematological reconstitution by haematopoietic stem cell transplantation.

Gene

CLCN7 gene, 16p13.3 (OMIM gene/locus number #602727), encoding chloride channel 7 responsible for Cl-transport. It is expressed in different cell types in vesicles of the endocytotic-lysosomal pathway. In osteoclasts, ClC-7 is localized also in the ruffled border and is involved in the acidification of the resorption lacuna.

Phenotype

Severe form, increased bone density (sclerosis) and generalized high bone mass, loss of trabecular structure, poor/no definition between cortical and medullary bone, fractures, hepatosplenomegaly, mild optic nerve atrophy, cerebral and retinal atrophy.

Main biochemical alterations

Adult/intermediate forms: high CK-BB, high bone ALP. Infantile/severe forms: low Ca, high PTH, high 1,25(OH)2D, high CK-BB, high AP, anemia.

Other resource:

  • Osteopetrosis Society (OPETS)
Osteopetrosis, Autosomal Recessive 5 (OPTB5)

Osteopetrosis, Autosomal recessive 5, is a form of autosomal recessive osteopetrosis (see OPTB1) caused by mutation in the gene encoding osteopetrosis-associated transmembrane protein-1 (OSTM1 gene).

(OMIM phenotype number #259720)

Osteopetrosis, Autosomal recessive 5, is a form of autosomal recessive osteopetrosis (see OPTB1) caused by mutation in the gene encoding osteopetrosis-associated transmembrane protein-1 (OSTM1 gene). Mutations in OSTM1 entail the most severe form of autosomal recessive osteopetrosis. This disease is characterized by a very severe clinical presentation poor prognosis, with a severe central nervous system involvement, whose predominant symptoms are marked cerebral atrophy and a decreased myelinization, in addition to the classical severe bone sclerosis.

Gene

OSTM1 gene, 6q21 (OMIM gene/locus number #607649), encoding Osteopetrosis-associated transmembrane protein 1, required for osteoclasts maturation and function.

Phenotype

Severe form, loss of trabecular structure, poor/no definition between cortical and medullary bone, fractures, increased bone density (sclerosis) and generalized high bone mass, in utero fractures, and skeletal hyperdensity, hepatosplenomegaly, hydrocephaly, microcephaly, cerebral atrophy, visual impairment, and bone marrow insufficiency.

Main biochemical alterations

Adult/intermediate forms: high CK-BB, high bone ALP. Infantile/severe forms: low Ca, high PTH, high 1,25(OH)2D, high CK-BB, high AP, anemia.

Images

Radiographies shows:
Fig. Radiographies show: (a) femur and tibia lack bone marrow cavities and the translucent growth plate at the distal femur seems irregular, (b) typical sandwich appearance of vertebrae due to endplate sclerosis.

Reproduced from Bone, Vol 55, Ott CE, Fischer B, Schröter P, et al. Severe neuronopathic autosomal recessive osteopetrosis due to homozygous deletions affecting OSTM1, Pages 292-7, Copyright 2013, with permission from Elsevier.

Other resource:

  • http://www.osteopetrosis.org/
Osteopetrosis, Autosomal Recessive 6 (OPTB6)

Osteopetrosis, Autosomal recessive 6, is a form of autosomal recessive osteopetrosis (see OPTB1) caused by mutation in the PLEKHM1 (Pleckstrin homology domain-containing protein, family M, member 1) gene. The loss of function mutations in the PLEKHM1 gene underlie an intermediate form of human osteopetrosis.

(OMIM #611497)

Osteopetrosis, Autosomal recessive 6, is a form of autosomal recessive osteopetrosis (see OPTB1) caused by mutation in the PLEKHM1 (Pleckstrin homology domain-containing protein, family M, member 1) gene. The loss of function mutations in the PLEKHM1 gene underlies an intermediate form of human osteopetrosis.

Gene

PLEKHM1 gene, 17q21.31 (OMIM gene/locus number *611466), encoding a nonsecretory adaptor protein that localizes to endosomal vesicles. A highly truncated Plekhm1 protein has been previously found in a patient with intermediate autosomal recessive osteopetrosis. The exact function of Plekhm1 remains to be determined.

Phenotype

Intermediate form, bone deformities, increased bone density (sclerosis) and generalized high bone mass, pain, chondrolysis, dense metaphyseal bands.

Main biochemical alterations

Adult/intermediate forms: high CK-BB, high bone ALP.

Infantile/severe forms: low Ca, high PTH, high 1,25(OH)2D, high CK-BB, high AP, anemia.

Fig a)

cortical sclerosis of the pelvic bones

Fig b)

right femur
Fig. Radiographies show: (a) cortical sclerosis of the pelvic bones, particularly at the iliac wings. Note the band-like sclerosis of the vertebral endplates (rugger jersey spine) and the inhomo- geneous sclerosis at the metadiaphyses of the distal femora, tibiae and fibulae, and proximal fibulae and tibiae. Also note the broadening of the involved segments of the long bones (“Erlenmeyer flask” deformity). (b) Radiograph of the right femur showing the presence of a dense metaphyseal band at the distal metaphysis.

Reproduced from Van Wesenbeeck L, Odgren PR, Coxon FP, et al., Involvement of PLEKHM1 in osteoclastic vesicular transport and osteopetrosis in incisors absent rats and humans. J Clin Invest 2007;117:919-30.

Other resource:

  • Osteopetrosis Society (OPETS)
Osteopetrosis, Autosomal Recessive 7 (OPTB7)

Osteopetrosis, Autosomal recessive 7, is a form of osteoclast-poor autosomal recessive osteopetrosis (see OPTB1), and it can be caused by a mutation in the tumor necrosis factor receptor superfamily, member 11a (TNFRSF11A) gene.

(OMIM phenotype number #612301)

Osteopetrosis, Autosomal recessive 7, is a form of osteoclast-poor autosomal recessive osteopetrosis (see OPTB1), and it can be caused by mutation in the tumor necrosis factor receptor superfamily, member 11a (TNFRSF11A) gene. As opposed to TNFSF11 deficiency, osteopetrosis in TNFRSF11A-deficient patients could be rescued by hematopoietic stem cell transplantation.

Gene

TNFRSF11A gene, 18q21.33 (OMIM gene/locus number #603499), encoding receptor activator of NF kappa B (RANK). RANKL, the protein coded for by the TNFSF11 gene, binds to RANK, a membrane-anchored receptor, and RANKL signaling through RANK is fundamental for osteoclast maturation.

Phenotype

Severe form, osteoclast-poor, increased bone density (sclerosis) and generalized high bone mass, hypogammaglobulinemia.

Main biochemical alterations

Adult/intermediate forms: high CK-BB, high bone ALP. Infantile/severe forms: low Ca, high PTH, high 1,25(OH)2D, high CK-BB, high AP.

Image

Bone thickening of vertebrae and ribs is evident
Fig. Radiographies show: (a,b) Bone thickening of vertebrae and ribs is evident, revealing classical osteopetrotic phenotype.

Reproduced from Am J Hum Genet, Vol 83, Guerrini MM, Sobacchi C, Cassani B, et al. Human osteoclast-poor osteopetrosis with hypogammaglobulinemia due to TNFRSF11A (RANK) mutations, Pages 64-76, Copyright 2008, with permission from Elsevier.

Other resource:
  • http://www.osteopetrosis.org/
Osteopetrosis, Autosomal Recessive 8 (OPTB8)

Osteopetrosis, Autosomal recessive 8, is a form of osteoclast-poor autosomal recessive osteopetrosis (see OPTB1), and it is caused by homozygous mutation in the sorting nexin 10 (SNX10) gene.

(OMIM phenotype number #615085)

Osteopetrosis, Autosomal recessive 8, is a form of osteoclast-poor autosomal recessive osteopetrosis (see OPTB1), and it is caused by homozygous mutation in the sorting nexin 10 (SNX10) gene. This gene has been shown to be involved in the process of osteoclast differentiation and function upon RANKL-stimulation.

Gene

SNX10 gene, 7p15.2 (OMIM gene/locus number #614780). SNX10 has been recently shown to interact with vacuolar type H(+)-ATPase (V-ATPase) which pumps protons at the osteoclast-bone interface. A mutation in SNX10 may therefore result in 'secondary V-ATPase deficiency' with a failure to acidify the resorption lacuna.

Phenotype

Severe form, loss of trabecular structure, poor/no definition between cortical and medullary bone, macrocephaly, failure to thrive, macrocephaly, frontal bossing, facial nerve palsy, optic nerve atrophy, nasal stuffiness due to fully ossified sinuses, narrowed medullary space due to encroachment of cortical bone, narrowed auditory canal, sclerosis of semicircular canals, narrow optic canal, narrow auditory canal, sclerosis of semicircular canals, fully ossified ethmoid air cells, fully ossified sphenoid sinuses, anemia, thrombocytopenia, bone marrow insufficiency, hepatosplenomegaly.

Main biochemical alterations

Adult/intermediate forms: high CK-BB, high bone ALP. Infantile/severe forms: low Ca, high PTH, high 1,25(OH)2D, high CK-BB, high AP, anemia.

Other resource:

  • Osteopetrosis Society (OPETS)
Osteopetrosis, Autosomal Dominant 2 (OPTA2) / Albers-Schonberg Disease

The autosomal-dominant adult type od Osteopetrosis, so-called ‘Albers-Schonberg disease’, is a benign form and it is associated with few symptoms. The disease is characterized by increased bone density, secondary to a bone resorption defect caused by abnormal osteoclasts. The onset occurs in adolescence or adulthood with variable penetrance.

(OMIM phenotype number #166600)

Osteopetrosis is a heterogeneous group of sclerosing bone dysplasias, marked by the inability of osteoclast to resorb bone due to defects in the osteoclastogenesis or the acidification of the extracellular compartment. The hallmark of osteopetrosis is an increased bone density within the medullary portion of the bone and relative sparing of the cortices. Patients with osteopetrosis have decreased osteoclastic activity, increased bone mass, leading to decreased elasticity of the bone or impaired repair capabilities and, therefore, increased risk of fracture. This bone disorder include both autosomal-dominant and autosomal-recessive subtypes.

The autosomal-dominant adult type, so-called ‘Albers-Schonberg disease’, is a benign form and it is associated with few symptoms. The disease is characterized by increased bone density, secondary to a bone resorption defect caused by abnormal osteoclasts. The onset occurs in adolescence or adulthood with variable penetrance. The severity of the clinical manifestation is quite variable, even in the same familiy. Prevalence has been estimated to be 5/100.000. Orthopaedic treatment can be necessary in case of fractures and arthritis, but, until now, any effective medical treatment exists for osteopetrosis.

Gene

OPTA2 is caused by loss of chloride channel 7 activity, as a result of deactivating mutations in one allele of the CLCN7 gene, 16p13.3 (OMIM gene/locus number *602727). This disorder is transmitted in an autosomal dominant manner.

Phenotype

Most patients are asymptomatic, although some may have mild anemia due to narrowed medullary. Phenotypic features include: increased bone density (sclerosis) and generalized high bone mass, fractures (80% of cases, often in any long bones and in the posterior arch of the vertebrae, inducing dylolisthesis), scoliosis, hip osteoarthritis, dental abscesses, osteomyelitis of the mandible, cranial nerve compression of the skull base, and hearing and visual loss. Radiological features include: "sandwich vertebra" appearance (dense bands of sclerosis parallel to the vertebral endplates), bone-within-bone pattern mainly at the iliac wings and at some other epiphysis, alternating sclerotic and lucent bands in the iliac wings and near the ends of the long bones, and increased skull base density.

Main biochemical alterations

Adult/intermediate forms: high CK-BB, high bone ALP.

Infantile/severe forms: low Ca, high PTH, high 1,25(OH)2D, high CK-BB, high AP, anemia.

Images

Fig. Radiographies show “sandwich vertebrae” and “bone within a bone”
Fig. Radiographies show “sandwich vertebrae” and “bone within a bone” appearance (a: lower thoracic spine frontal view; b: lumba

Reproduced from Kirkland JD, O'Brien WT, Osteopetrosis - Classic Imaging Findings in the Spine. J Clin Diagn Res 2015;9:TJ01-2. 

Other resource:

  • Osteopetrosis Society (OPETS)
Osteopetrosis and infantile neuroaxonal dystrophy

Osteopetrosis and infantile neuroaxonal dystrophy is characterized by osteopetrosis, agenesis of the corpus callosum, cerebral atrophy and a small hippocampus. There are rare cases reported with the association of neuroaxonal dystrophy and osteopetrosis.

(OMIM phenotype number #600329)

Osteopetrosis and infantile neuroaxonal dystrophy is characterized by osteopetrosis, agenesis of the corpus callosum, cerebral atrophy and a small hippocampus. There are rare cases reported with the association of neuroaxonal dystrophy and osteopetrosis. Autosomal recessive inheritance has been suggested and the etiology remains unclear.

Phenotype

Severe form, see OPTB1 phenotype, infantile osteopetrosis, infantile death, infantile neuroaxonal dystrophy, agenesis of corpus callosum, cerebral atrophy, and small hippocampus.

Other resource:

  • Osteopetrosis Society (OPETS)
Pycnodysostosis

Pyknodysostosis is an autosomal recessive osteochondrodysplasia, first described in 1962 by Maroteaux and Lamy (Greek: pycnos = dense; dys = defective; osteon = bone). This disease is also called "Toulouse-Lautrec syndrome" after the famous French artist Henri de Toulouse-Lautrec, who was thought to be afflicted with the disorder.

(OMIM phenotype number #265800)

Pyknodysostosis is an autosomal recessive osteochondrodysplasia, first described in 1962 by Maroteaux and Lamy (Greek: pycnos = dense; dys = defective; osteon = bone). This disease is also called "Toulouse-Lautrec syndrome" after the famous French artist Henri de Toulouse-Lautrec, who was thought to be afflicted with the disorder. It is generally diagnosed during infancy or early childhood. Sometimes, the diagnosis is late and after a bone fracture, given the severe bone fragility resulting from increased bone density. More than 100 cases have been described since 1962. The prevalence of PYCD is estimated to be 1 to 1.7 per million with equal sex distribution. It is transmitted as an autosomal recessive trait and with a mutation in the Cathepsin K (CTSK) gene (nonsense, missense, and stop codon mutations have been described). Cathepsin K is a lysosomal cysteine proteinase that is highly expressed in osteoclasts, localized to the pycnodysostosis region, and is required for the degradation of collagen. Therefore, PYCD is due to an impaired degradation of the organic matrix of bone by osteoclast, caused by loss-of-function mutations of the CTSK gene.

The differential diagnosis is established with osteopetrosis, cleidocranial dysplasia and idiopathic acro-osteolysis.

Gene

CTSK gene, 1q21.3 (OMIM gene/locus number *601105)

Phenotype

Generalized high bone mass, bone fragility, disproportionate short stature, dwarfism, large cranium, dysmorphic features of the face, obtuse angle of mandible, clavicular dysplasia, fingers are short and clubbed from acro-osteolysis or aplasia of the terminal phalanges, hypoplastic fingernails, small and square hands, narrow thorax, pectus excavatum, kyphoscoliosis, increased lumbar lordosis, recurrent fractures typically involve the lower limbs and cause genu valgum deformity, long bones manifest hyperostosis and narrow medullary canals. The calvarium and base of the skull are sclerotic, and the orbital ridges are radiodense. Hypoplasia of facial bones and sinuses are characteristic of this disorder. Vertebrae are dense, yet their transverse processes are not involved. Lumbosacral spondylolisthesis is not uncommon.

Main biochemical alterations

Low GH, low IGF1.

Image

Pycnodysostosis
Fig. The radiograph shows thin mandible, obtuse mandibular angle, malposed teeth, elongation of the condyle and coronoid process

Reproduced from Int J Clin Exp Med 201;7:492-6 under the terms of the Creative Commons Attribution License (CC BY).

Other resources:

  • The UK Lysosomal Storage Disorder (LSD) Patient Collaborative
  • Vaincre les Maladies Lysosomales
  • Lysosuisse
Dysosteosclerosis (DSS)

Dysosteosclerosis is an extremely rare form of osteopetrosis, presents in infancy or early childhood, with a poor prognosis. The disease is characterized by diffuse osteosclerosis, red-violet macular atrophy, platyspondyly and metaphyseal osteosclerosis with relative radiolucency of widened diaphyses.

(OMIM phenotype number %224300)

Dysosteosclerosis is an extremely rare form of osteopetrosis, presents in infancy or early childhood, with a poor prognosis. The disease is characterized by diffuse osteosclerosis, red-violet macular atrophy, platyspondyly and metaphyseal osteosclerosis with relative radiolucency of widened diaphyses. Bone histology during childhood shows unresorbed primary spongiosa and a paucity of osteoclasts when the disease presents. Most cases of DSS appear to be inherited in an autosomal recessive fashion, though X-linked recessive inheritance has been proposed in one family. Fewer than 25 cases have been reported since the first description by Ellis in 1934.

Gene

SLC29A3 gene, 10q22.1 (OMIM gene/locus number #612373). This gene encodes a nucleoside transporter.

Phenotype

Platyspondyly and metaphyseal osteosclerosis with relative radiolucency of widened diaphyses, dense but brittle skeleton, short stature and fractures, optic atrophy and sometimes cranial nerve palsy, failure of tooth eruption, developmental delay, seizures, skin findings such as red-violet macular atrophy, and at the histopathological level paucity of osteoclasts.

Main biochemical alterations

Low total and bone ALP, low TRAP5b, low Ur DPD/Cr.

Ectodermal dysplasia, anhidrotic, immunodeficiency, osteopetrosis, lymphedema (OLEDAID)

Ectodermal dysplasia, anhidrotic, immunodeficiency, osteopetrosis, lymphedema is a rare disease characterized by anhidrotic ectodermal dysplasia, severe immunodeficiency, osteopetrosis and lymphedema.

(OMIM phenotype number #300301)

Ectodermal dysplasia, anhidrotic, immunodeficiency, osteopetrosis, lymphedema is a rare disease characterized by anhidrotic ectodermal dysplasia, severe immunodeficiency, osteopetrosis and lymphedema. This disorder has been described in a few unrelated male patients born to mothers with mild incontinentia pigmenti. It is classified as a X-linked osteopetrosis, and is caused by mutations (stop codon mutations) in the IKBKG (inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma). IKBKG encodes NEMO (NF-B essential modulator), the regulatory subunit of the IKK (IkappaB kinase) complex, which is essential for NF-kappaB signaling. Germline loss-of-function mutations in IKBKG are lethal in male fetuses.

Gene

IKBKG gene, Xq28 (OMIM gene/locus number #300248)

Phenotype

Lymphedema, anhidrotic ectodermal dysplasia, immunologic alterations (benign or severe infections), and osteopetrosis.

Image

Skeletal radiograph of iliac wings
Fig. Skeletal radiograph of iliac wings demonstrating a “bone-within- bone” appearance. Reproduced from Pediatrics. 2002,109:e97

Other resources:

  • Ectodermal Dysplasia Society
  • National Foundation for Ectodermal Dysplasias (NFED)
  • Canadian Ectodermal Dysplasia Syndromes Association
  • Selbsthilfegruppe Ectodermal Dysplasia
  • Association Francaise ED
  • Associazione Nazionale Displasia Ectodermica
  • Svenska Ed-foereningen
  • AADE Asociacion de Afectados por Displasia Ectodermica
  • Ektodermal Displazi Tyrkiye

REFERENCES

1.

Frattini A, Orchard PJ, Sobacchi C, et al. Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis.Nat Genet. 2000 Jul;25(3):343-6.

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