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Atelosteogenesis type I(AO1)

MedGen UID:
82701
Concept ID:
C0265283
Congenital Abnormality
Synonyms: Atelosteogenesis type 1; Giant cell chondrodysplasia; Spondylohumerofemoral hypoplasia
SNOMED CT: Atelosteogenesis type 1 (725141006); Atelosteogenesis type I (725141006); Giant cell chondrodysplasia (725141006)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): FLNB (3p14.3)
 
Monarch Initiative: MONDO:0007167
OMIM®: 108720
Orphanet: ORPHA1190

Disease characteristics

Excerpted from the GeneReview: FLNB Disorders
The FLNB disorders include a spectrum of phenotypes ranging from mild to severe. At the mild end are spondylocarpotarsal synostosis (SCT) syndrome and Larsen syndrome; at the severe end are the phenotypic continuum of atelosteogenesis types I (AOI) and III (AOIII) and Piepkorn osteochondrodysplasia (POCD). SCT syndrome is characterized by postnatal disproportionate short stature, scoliosis and lordosis, clubfeet, hearing loss, dental enamel hypoplasia, carpal and tarsal synostosis, and vertebral fusions. Larsen syndrome is characterized by congenital dislocations of the hip, knee, and elbow; clubfeet (equinovarus or equinovalgus foot deformities); scoliosis and cervical kyphosis, which can be associated with a cervical myelopathy; short, broad, spatulate distal phalanges; distinctive craniofacies (prominent forehead, depressed nasal bridge, malar flattening, and widely spaced eyes); vertebral anomalies; and supernumerary carpal and tarsal bone ossification centers. Individuals with SCT syndrome and Larsen syndrome can have midline cleft palate and hearing loss. AOI and AOIII are characterized by severe short-limbed dwarfism; dislocated hips, knees, and elbows; and clubfeet. AOI is lethal in the perinatal period. In individuals with AOIII, survival beyond the neonatal period is possible with intensive and invasive respiratory support. Piepkorn osteochondrodysplasia (POCD) is a perinatal-lethal micromelic dwarfism characterized by flipper-like limbs (polysyndactyly with complete syndactyly of all fingers and toes, hypoplastic or absent first digits, and duplicated intermediate and distal phalanges), macrobrachycephaly, prominant forehead, hypertelorism, and exophthalmos. Occasional features include cleft palate, omphalocele, and cardiac and genitourinary anomalies. The radiographic features at mid-gestation are characteristic. [from GeneReviews]
Authors:
Stephen Robertson   view full author information

Additional descriptions

From OMIM
Atelosteogenesis is the name given by Maroteaux et al. (1982) to a lethal chondrodysplasia characterized by distal hypoplasia of the humeri and femurs, hypoplasia of the midthoracic spine, occasionally complete lack of ossification of single hand bones, and the finding in cartilage of multiple degenerated chondrocytes encapsulated in fibrous tissue. Rimoin et al. (1980) termed it 'giant cell chondrodysplasia.' Patients with AO1 exhibit severe short-limbed dwarfism and dislocated elbows, hips, and knees (Jeon et al., 2014). Genetic Heterogeneity of Atelosteogenesis Atelosteogenesis type II (AO2; 256050) is caused by mutation in the SLC26A2 gene (606718) on chromosome 5q32. AO3 (108721) is also caused by mutation in the FLNB gene (603381).  http://www.omim.org/entry/108720
From MedlinePlus Genetics
Atelosteogenesis type 1 is a disorder that affects the development of bones throughout the body. Affected individuals are born with inward- and upward-turning feet (clubfeet) and dislocations of the hips, knees, and elbows. Bones in the spine, rib cage, pelvis, and limbs may be underdeveloped or in some cases absent. As a result of the limb bone abnormalities, individuals with this condition have very short arms and legs. Characteristic facial features include a prominent forehead, wide-set eyes (hypertelorism), an upturned nose with a grooved tip, and a very small lower jaw and chin (micrognathia). Affected individuals may also have an opening in the roof of the mouth (a cleft palate). Males with this condition can have undescended testes.

Individuals with atelosteogenesis type 1 typically have an underdeveloped rib cage that affects the development and functioning of the lungs. As a result, affected individuals are usually stillborn or die shortly after birth from respiratory failure.  https://medlineplus.gov/genetics/condition/atelosteogenesis-type-1

Clinical features

From HPO
Cryptorchidism
MedGen UID:
8192
Concept ID:
C0010417
Congenital Abnormality
Cryptorchidism, or failure of testicular descent, is a common human congenital abnormality with a multifactorial etiology that likely reflects the involvement of endocrine, environmental, and hereditary factors. Cryptorchidism can result in infertility and increases risk for testicular tumors. Testicular descent from abdomen to scrotum occurs in 2 distinct phases: the transabdominal phase and the inguinoscrotal phase (summary by Gorlov et al., 2002).
Clubfoot
MedGen UID:
3130
Concept ID:
C0009081
Congenital Abnormality
Clubfoot is a congenital limb deformity defined as fixation of the foot in cavus, adductus, varus, and equinus (i.e., inclined inwards, axially rotated outwards, and pointing downwards) with concomitant soft tissue abnormalities (Cardy et al., 2007). Clubfoot may occur in isolation or as part of a syndrome (e.g., diastrophic dysplasia, 222600). Clubfoot has been reported with deficiency of long bones and mirror-image polydactyly (Gurnett et al., 2008; Klopocki et al., 2012).
Clubbing
MedGen UID:
57692
Concept ID:
C0149651
Anatomical Abnormality
Broadening of the soft tissues (non-edematous swelling of soft tissues) of the digital tips in all dimensions associated with an increased longitudinal and lateral curvature of the nails.
Knee dislocation
MedGen UID:
102364
Concept ID:
C0159970
Injury or Poisoning
Slippage of the FEMUR off the TIBIA.
Brachydactyly
MedGen UID:
67454
Concept ID:
C0221357
Congenital Abnormality
Digits that appear disproportionately short compared to the hand/foot. The word brachydactyly is used here to describe a series distinct patterns of shortened digits (brachydactyly types A-E). This is the sense used here.
Limb undergrowth
MedGen UID:
116086
Concept ID:
C0239399
Finding
Limb shortening because of underdevelopment of one or more bones of the extremities.
Short femur
MedGen UID:
87499
Concept ID:
C0345375
Congenital Abnormality
An abnormal shortening of the femur.
Talipes
MedGen UID:
220976
Concept ID:
C1301937
Congenital Abnormality
A deformity of foot and ankle that has different subtypes that are talipes equinovarus, talipes equinovalgus, talipes calcaneovarus and talipes calcaneovalgus.
Short humerus
MedGen UID:
316907
Concept ID:
C1832117
Congenital Abnormality
Underdevelopment of the humerus.
Fibular aplasia
MedGen UID:
373034
Concept ID:
C1836186
Finding
Absence of the fibula.
Tibial bowing
MedGen UID:
332360
Concept ID:
C1837081
Finding
A bending or abnormal curvature of the tibia.
Short metacarpal
MedGen UID:
323064
Concept ID:
C1837084
Anatomical Abnormality
Diminished length of one or more metacarpal bones in relation to the others of the same hand or to the contralateral metacarpal.
Short finger
MedGen UID:
334977
Concept ID:
C1844548
Anatomical Abnormality
Abnormally short finger associated with developmental hypoplasia.
Short metatarsal
MedGen UID:
341358
Concept ID:
C1849020
Finding
Diminished length of a metatarsal bone, with resultant proximal displacement of the associated toe.
Radial bowing
MedGen UID:
347136
Concept ID:
C1859399
Anatomical Abnormality
A bending or abnormal curvature of the radius.
Aplasia/Hypoplasia of the ulna
MedGen UID:
356032
Concept ID:
C1865571
Congenital Abnormality
Absence or underdevelopment of the ulna.
Rhizomelia
MedGen UID:
357122
Concept ID:
C1866730
Congenital Abnormality
Disproportionate shortening of the proximal segment of limbs (i.e. the femur and humerus).
Club-shaped proximal femur
MedGen UID:
368485
Concept ID:
C1968611
Finding
An abnormal conformation of the femur that becomes gradually enlarged towards the proximal end. This feature affects the proximal femoral metaphysis and epiphysis.
Distal tapering femur
MedGen UID:
870600
Concept ID:
C4025049
Anatomical Abnormality
Disproportionate short-limb short stature
MedGen UID:
342370
Concept ID:
C1849937
Finding
A type of disproportionate short stature characterized by a short limbs but an average-sized trunk.
Protuberant abdomen
MedGen UID:
340750
Concept ID:
C1854928
Finding
A thrusting or bulging out of the abdomen.
Low-set ears
MedGen UID:
65980
Concept ID:
C0239234
Congenital Abnormality
Upper insertion of the ear to the scalp below an imaginary horizontal line drawn between the inner canthi of the eye and extending posteriorly to the ear.
Encephalocele
MedGen UID:
1646412
Concept ID:
C4551722
Congenital Abnormality
A neural tube defect characterized by sac-like protrusions of the brain and the membranes that cover it through openings in the skull.
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
Developmental hypoplasia of the mandible.
Frontal bossing
MedGen UID:
67453
Concept ID:
C0221354
Congenital Abnormality
Bilateral bulging of the lateral frontal bone prominences with relative sparing of the midline.
Vertebral hypoplasia
MedGen UID:
87502
Concept ID:
C0345394
Congenital Abnormality
Small, underdeveloped vertebral bodies.
Narrow chest
MedGen UID:
96528
Concept ID:
C0426790
Finding
Reduced width of the chest from side to side, associated with a reduced distance from the sternal notch to the tip of the shoulder.
Long clavicles
MedGen UID:
96530
Concept ID:
C0426808
Finding
Increased length of the clavicles.
Coronal cleft vertebrae
MedGen UID:
320483
Concept ID:
C1834954
Finding
Frontal schisis (cleft or cleavage) of vertebral bodies.
Thoracic hypoplasia
MedGen UID:
373339
Concept ID:
C1837482
Congenital Abnormality
11 pairs of ribs
MedGen UID:
326950
Concept ID:
C1839731
Finding
Presence of only 11 pairs of ribs.
Malar flattening
MedGen UID:
347616
Concept ID:
C1858085
Finding
Underdevelopment of the malar prominence of the jugal bone (zygomatic bone in mammals), appreciated in profile, frontal view, and/or by palpation.
Thoracic platyspondyly
MedGen UID:
400049
Concept ID:
C1862428
Finding
A flattened vertebral body shape with reduced distance beween the vertebral endplates affecting the thoracic spine.
Bell-shaped thorax
MedGen UID:
351320
Concept ID:
C1865186
Finding
The rib cage has the shape of a wide mouthed bell. That is, the superior portion of the rib cage is constricted, followed by a convex region, and the inferior portion of the rib cage expands again to have a large diameter.
Elbow dislocation
MedGen UID:
404765
Concept ID:
C2720437
Injury or Poisoning
Dislocation of the distal humerus out of the elbow joint, where the radius, ulna, and humerus meet.
Fused cervical vertebrae
MedGen UID:
854386
Concept ID:
C3887527
Congenital Abnormality
A congenital anomaly characterized by a joining (fusion) of two or more cervical vertebral bodies with one another.
Multinucleated giant chondrocytes in epiphyseal cartilage
MedGen UID:
868115
Concept ID:
C4022506
Finding
The presence of cartilage cells (chondrocytes) that are substantially increased in size and contain more than one nucleus and are located within the resting zone of the epiphyseal cartilage.
Laryngeal stenosis
MedGen UID:
7274
Concept ID:
C0023075
Pathologic Function
Stricture or narrowing of the larynx that may be associated with symptoms of respiratory difficulty depending on the degree of laryngeal narrowing.
Short neck
MedGen UID:
99267
Concept ID:
C0521525
Finding
Diminished length of the neck.
Depressed nasal bridge
MedGen UID:
373112
Concept ID:
C1836542
Finding
Posterior positioning of the nasal root in relation to the overall facial profile for age.
Midface retrusion
MedGen UID:
339938
Concept ID:
C1853242
Anatomical Abnormality
Posterior positions and/or vertical shortening of the infraorbital and perialar regions, or increased concavity of the face and/or reduced nasolabial angle.
Short nose
MedGen UID:
343052
Concept ID:
C1854114
Finding
Distance from nasion to subnasale more than two standard deviations below the mean, or alternatively, an apparently decreased length from the nasal root to the nasal tip.
Cleft palate
MedGen UID:
756015
Concept ID:
C2981150
Congenital Abnormality
Cleft palate is a developmental defect of the palate resulting from a failure of fusion of the palatine processes and manifesting as a separation of the roof of the mouth (soft and hard palate).
Polyhydramnios
MedGen UID:
6936
Concept ID:
C0020224
Pathologic Function
The presence of excess amniotic fluid in the uterus during pregnancy.
Premature birth
MedGen UID:
57721
Concept ID:
C0151526
Pathologic Function
The birth of a baby of less than 37 weeks of gestational age.
Proptosis
MedGen UID:
41917
Concept ID:
C0015300
Disease or Syndrome
An eye that is protruding anterior to the plane of the face to a greater extent than is typical.
Hypertelorism
MedGen UID:
9373
Concept ID:
C0020534
Finding
Although hypertelorism means an excessive distance between any paired organs (e.g., the nipples), the use of the word has come to be confined to ocular hypertelorism. Hypertelorism occurs as an isolated feature and is also a feature of many syndromes, e.g., Opitz G syndrome (see 300000), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  

Recent clinical studies

Etiology

Wessels A, Wainwright HC, Beighton P
Pediatr Dev Pathol 2011 Nov-Dec;14(6):496-500. Epub 2011 Oct 10 doi: 10.2350/11-01-0969-CR.1. PMID: 21985323
Sillence D, Worthington S, Dixon J, Osborn R, Kozlowski K
Pediatr Radiol 1997 May;27(5):388-96. doi: 10.1007/s002470050154. PMID: 9133349

Diagnosis

Meira JGC, Sarno MAC, Faria ÁCO, Yamamoto GL, Bertola DR, Scheibler GG, Tavares DF, Acosta AX
Rev Bras Ginecol Obstet 2018 Sep;40(9):570-576. Epub 2018 Sep 19 doi: 10.1055/s-0038-1670684. PMID: 30231296Free PMC Article
Wessels A, Wainwright HC, Beighton P
Pediatr Dev Pathol 2011 Nov-Dec;14(6):496-500. Epub 2011 Oct 10 doi: 10.2350/11-01-0969-CR.1. PMID: 21985323
Ueno K, Tanaka M, Miyakoshi K, Zhao C, Shinmoto H, Nishimura G, Yoshimura Y
Prenat Diagn 2002 Dec;22(12):1071-5. doi: 10.1002/pd.470. PMID: 12454961
Nishimura G, Horiuchi T, Kim OH, Sasamoto Y
Am J Med Genet 1997 Dec 12;73(2):132-8. PMID: 9409862
Schrander-Stumpel C, Havenith M, Linden EV, Maertzdorf W, Offermans J, van der Harten J
Clin Dysmorphol 1994 Oct;3(4):318-27. PMID: 7632220

Prognosis

S UK, Sankar S, Younes S, D TK, Ahmad MN, Okashah SS, Kamaraj B, Al-Subaie AM, C GPD, Zayed H
Molecules 2020 Nov 26;25(23) doi: 10.3390/molecules25235543. PMID: 33255942Free PMC Article
Li BC, Hogue J, Eilers M, Mehrotra P, Hyland J, Holm T, Prosen T, Slavotinek AM
Am J Med Genet A 2013 Mar;161A(3):619-25. Epub 2013 Feb 11 doi: 10.1002/ajmg.a.35792. PMID: 23401428
Wessels A, Wainwright HC, Beighton P
Pediatr Dev Pathol 2011 Nov-Dec;14(6):496-500. Epub 2011 Oct 10 doi: 10.2350/11-01-0969-CR.1. PMID: 21985323
Ueno K, Tanaka M, Miyakoshi K, Zhao C, Shinmoto H, Nishimura G, Yoshimura Y
Prenat Diagn 2002 Dec;22(12):1071-5. doi: 10.1002/pd.470. PMID: 12454961
Schrander-Stumpel C, Havenith M, Linden EV, Maertzdorf W, Offermans J, van der Harten J
Clin Dysmorphol 1994 Oct;3(4):318-27. PMID: 7632220

Clinical prediction guides

S UK, Sankar S, Younes S, D TK, Ahmad MN, Okashah SS, Kamaraj B, Al-Subaie AM, C GPD, Zayed H
Molecules 2020 Nov 26;25(23) doi: 10.3390/molecules25235543. PMID: 33255942Free PMC Article
Li BC, Hogue J, Eilers M, Mehrotra P, Hyland J, Holm T, Prosen T, Slavotinek AM
Am J Med Genet A 2013 Mar;161A(3):619-25. Epub 2013 Feb 11 doi: 10.1002/ajmg.a.35792. PMID: 23401428
Wessels A, Wainwright HC, Beighton P
Pediatr Dev Pathol 2011 Nov-Dec;14(6):496-500. Epub 2011 Oct 10 doi: 10.2350/11-01-0969-CR.1. PMID: 21985323
Takamine Y, Lachman RS, Field FM, Rimoin DL
Pediatr Radiol 2004 Jul;34(7):530-4. Epub 2004 Apr 24 doi: 10.1007/s00247-004-1191-y. PMID: 15107965
Sillence D, Worthington S, Dixon J, Osborn R, Kozlowski K
Pediatr Radiol 1997 May;27(5):388-96. doi: 10.1007/s002470050154. PMID: 9133349