GCLEB
MCID: GRC002
MIFTS: 32

Gracile Bone Dysplasia (GCLEB)

Categories: Bone diseases, Fetal diseases, Genetic diseases, Rare diseases

Aliases & Classifications for Gracile Bone Dysplasia

MalaCards integrated aliases for Gracile Bone Dysplasia:

Name: Gracile Bone Dysplasia 57 20 58 72 39 70
Osteocraniostenosis 57 20 58 72 36 29 6
Osteocraniosplenic Syndrome 57 20 58 72
Habrodysplasia 57 20 72
Gcleb 57 72
Skeletal Dysplasia, Lethal, with Gracile Bones 57
Skeletal Dysplasia Lethal with Gracile Bones 20
Lethal Skeletal Dysplasia with Gracile Bones 72

Characteristics:

Orphanet epidemiological data:

58
osteocraniostenosis
Inheritance: Autosomal dominant; Prevalence: <1/1000000 (Worldwide); Age of onset: Antenatal,Neonatal; Age of death: infantile,stillbirth;

OMIM®:

57 (Updated 05-Apr-2021)
Inheritance:
autosomal dominant

Miscellaneous:
death in utero or in early infancy is common


HPO:

31
gracile bone dysplasia:
Inheritance autosomal dominant inheritance


Classifications:

Orphanet: 58  
Rare bone diseases
Developmental anomalies during embryogenesis


Summaries for Gracile Bone Dysplasia

GARD : 20 The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs. Orpha Number: 2763 Definition Osteocraniostenosis is a lethal skeletal dysplasia characterized by a cloverleaf skull anomaly, facial dysmorphism, limb shortness, splenic hypo/aplasia and radiological anomalies including thin tubular bones with flared metaphyses and deficient calvarial mineralization. Epidemiology First described in 1989, less than 30 cases have been reported so far. Clinical description 'This multiple congenital anomalies syndrome is characterized by dysmorphic features of the fetus and the newborn: the skull is misshapen, combining acrocephaly and cloverleaf deformity, fontanelles are very large; facial dysmorphism includes midface hypoplasia with telecanthus, short upturned nose, short philtrum, small inverted V-shaped mouth and low-set ears; limbs are also affected with bowed forearms, micromelia and acromicria with brachydactyly.' Etiology Etiology of osteocraniostenosis is not well known, but some histological findings report growth plate disorganization and adjacent diaphyseal ossification. Recently, heterozygous mutations of the FAM111A gene, encoding a protein of unknown function and responsible of some autosomal dominant forms of Kenny-Caffey syndrome (see this term) with hypothyroidism and slender and dense bone, have been identified in patients with osteocraniostenosis. A clinical and genetic heterogeneity remains likely. Diagnostic methods Diagnosis is based mainly on radiological and pathological examination. Radiological examination reveals hypomineralisation of the skull, flat and dense vertebral bodies, thin tubular bones with flared and dense metaphyses, brachymetacarpia and brachyphalangy with ''diabolo appearance'' (very thin tubular bones with abrupt metaphyseal flare) and lack of ossification of the distal phalanges. The spleen is hypoplasic or even absent. Diaphyseal fractures are frequent at birth. Differential diagnosis Differential diagnosis includes the hypo/akinesia sequence, Hallermann-Streiff-FranAois syndrome, Kenny-Caffey syndrome and other slender bone dysplasias, and some cases of osteogenesis imperfecta with slender bones (see these terms). Antenatal diagnosis Prenatal ultrasound observation reveals micromelic dwarfism, cranial deformity, mild intra-uterine growth retardation and sometimes fractures. Genetic counseling Cases with FAM111A gene mutations show an autosomal dominant mode of inheritance with a majority of de novo mutations. Management and treatment There is no treatment for osteocraniostenosis. Prognosis Prognosis is very poor as most cases are stillborn or die in their first days of life.

MalaCards based summary : Gracile Bone Dysplasia, also known as osteocraniostenosis, is related to odontochondrodysplasia and brachydactyly, and has symptoms including seizures An important gene associated with Gracile Bone Dysplasia is FAM111A (FAM111 Trypsin Like Peptidase A). Affiliated tissues include bone and spleen, and related phenotypes are asplenia and decreased skull ossification

OMIM® : 57 Gracile bone dysplasia is a perinatally lethal condition characterized by gracile bones with thin diaphyses, premature closure of basal cranial sutures, and microphthalmia (summary by Unger et al., 2013). (602361) (Updated 05-Apr-2021)

KEGG : 36 Osteocraniostenosis, also known as gracile bone dysplasia (GCLEB), is a perinatally lethal condition characterized by gracile bones with thin diaphyses, premature closure of basal cranial sutures, and microphthalmia. It has been reported that individuals with GCLEB had mutations in FAM111A.

UniProtKB/Swiss-Prot : 72 Gracile bone dysplasia: A perinatally lethal condition characterized by narrowing of the medullary cavity of the long bones and of the skull, gracile bones with thin diaphyses, premature closure of basal cranial sutures, and microphthalmia. Most affected individuals who survive beyond the perinatal period develop hypocalcemia with low parathyroid hormone levels.

Related Diseases for Gracile Bone Dysplasia

Diseases related to Gracile Bone Dysplasia via text searches within MalaCards or GeneCards Suite gene sharing:

(show all 13)
# Related Disease Score Top Affiliating Genes
1 odontochondrodysplasia 10.0
2 brachydactyly 10.0
3 dwarfism 10.0
4 aniridia 1 9.9
5 cleft palate, isolated 9.9
6 craniosynostosis 1 9.9
7 hallermann-streiff syndrome 9.9
8 microphthalmia 9.9
9 hypospadias 9.9
10 microcephaly 9.9
11 craniosynostosis 9.9
12 angiomatosis 9.9
13 hypotonia 9.9

Graphical network of the top 20 diseases related to Gracile Bone Dysplasia:



Diseases related to Gracile Bone Dysplasia

Symptoms & Phenotypes for Gracile Bone Dysplasia

Human phenotypes related to Gracile Bone Dysplasia:

31 (show all 19)
# Description HPO Frequency HPO Source Accession
1 asplenia 31 occasional (7.5%) HP:0001746
2 decreased skull ossification 31 occasional (7.5%) HP:0004331
3 failure to thrive 31 HP:0001508
4 hydrocephalus 31 HP:0000238
5 global developmental delay 31 HP:0001263
6 short stature 31 HP:0004322
7 prominent forehead 31 HP:0011220
8 ascites 31 HP:0001541
9 slender long bone 31 HP:0003100
10 brachydactyly 31 HP:0001156
11 micropenis 31 HP:0000054
12 microphthalmia 31 HP:0000568
13 hypocalcemia 31 HP:0002901
14 aniridia 31 HP:0000526
15 thin ribs 31 HP:0000883
16 ankyloglossia 31 HP:0010296
17 flared metaphysis 31 HP:0003015
18 hypoplastic spleen 31 HP:0006270
19 seizure 31 HP:0001250

Symptoms via clinical synopsis from OMIM®:

57 (Updated 05-Apr-2021)
Neurologic Central Nervous System:
seizures
hydrocephalus
developmental delay

Head And Neck Face:
prominent forehead

Skeletal Hands:
brachydactyly

Head And Neck Eyes:
microphthalmia
aniridia

Head And Neck Mouth:
ankyloglossia

Growth Other:
failure to thrive, severe

Skeletal:
bones dense but thin
obliteration of medullary cavity seen on radiography

Skeletal Limbs:
micromelic short limbs
flared metaphyses
long bone fractures prenatally

Growth Height:
short stature

Abdomen:
ascites

Genitourinary External Genitalia Male:
micropenis

Laboratory Abnormalities:
hypocalcemia

Abdomen Spleen:
hypoplastic spleen
asplenia (rare)

Chest Ribs Sternum Clavicles And Scapulae:
thin ribs and clavicles

Skeletal Skull:
cloverleaf-shaped skull
hypoplastic cranial bones
decreased mineralization of skull (in some patients)

Clinical features from OMIM®:

602361 (Updated 05-Apr-2021)

UMLS symptoms related to Gracile Bone Dysplasia:


seizures

Drugs & Therapeutics for Gracile Bone Dysplasia

Search Clinical Trials , NIH Clinical Center for Gracile Bone Dysplasia

Genetic Tests for Gracile Bone Dysplasia

Genetic tests related to Gracile Bone Dysplasia:

# Genetic test Affiliating Genes
1 Osteocraniostenosis 29 FAM111A

Anatomical Context for Gracile Bone Dysplasia

MalaCards organs/tissues related to Gracile Bone Dysplasia:

40
Bone, Spleen

Publications for Gracile Bone Dysplasia

Articles related to Gracile Bone Dysplasia:

(show all 23)
# Title Authors PMID Year
1
FAM111A mutations result in hypoparathyroidism and impaired skeletal development. 57 6 61
23684011 2013
2
Osteocraniostenosis: a further case report documenting the antenatal findings. 57 61
17351358 2007
3
Parietal bone agenesis with gracile bones and splenic hypoplasia/aplasia: clinico-pathologic report and differential diagnosis with review of cranio-gracile bone syndromes, "osteocraniostenosis" and Kleeblattschädel. 61 57
17036309 2006
4
Osteocraniostenosis-hypomineralized skull with gracile long bones and splenic hypoplasia. Four new cases with distinctive chondro-osseous morphology. 61 57
16770805 2006
5
Gracile bones, periostal appositions, hypomineralization of the cranial vault, and mental retardation in brothers: milder variant of osteocraniostenosis or new syndrome? 61 57
16086393 2005
6
Two familial cases with a lethal gracile bone dysplasia and intrauterine growth retardation. 61 57
12687665 2003
7
Gracile bone dysplasias. 57 61
12195301 2002
8
Osteocraniostenosis in a fetus with a 46,XX/46,XY karyotype. 61 57
11822707 2002
9
Skeletal dysplasias with gracile bones: three new cases, including two offspring of a mother with a dwarfing condition. 61 57
9511974 1998
10
Gracile bone dysplasia. 61 57
9450865 1998
11
Osteocraniostenosis. 57 61
7837254 1994
12
Slender bone dysplasia (gracile). 57
19006220 2008
13
[Lethal syndromes with thin bones]. 57
3060039 1988
14
Report of a novel variant in the FAM111A gene in a fetus with multiple anomalies including gracile bones, hypoplastic spleen, and hypomineralized skull. 61
33750016 2021
15
FAM111A induces nuclear dysfunction in disease and viral restriction. 61
33369867 2021
16
FAM111 protease activity undermines cellular fitness and is amplified by gain-of-function mutations in human disease. 61
32776417 2020
17
Case report: targeted whole exome sequencing enables the first prenatal diagnosis of the lethal skeletal dysplasia Osteocraniostenosis. 61
31910817 2020
18
Contribution of DNA Replication to the FAM111A-Mediated Simian Virus 40 Host Range Phenotype. 61
30333173 2019
19
Osteocraniosplenic Syndrome-Hypomineralized Skull with Gracile Long Bones and Splenic Hypoplasia: A Case Report and Literature Review. 61
29485259 2016
20
[Kenny-Caffey syndrome and its related syndromes]. 61
26619675 2015
21
Splenopancreatic field abnormality is not unique to trisomy 13. 61
15255041 2004
22
[Gracile bone dysplasia]. 61
11462676 2001
23
Osteocraniostenosis vs. severe Hallermann-Streiff-François syndrome. 61
8986288 1997

Variations for Gracile Bone Dysplasia

ClinVar genetic disease variations for Gracile Bone Dysplasia:

6 (show all 13)
# Gene Name Type Significance ClinVarId dbSNP ID Position
1 FAM111A NM_001312909.2(FAM111A):c.1020_1022TTC[2] (p.Ser343del) Microsatellite Pathogenic 56811 rs1565206032 GRCh37: 11:58920161-58920163
GRCh38: 11:59152688-59152690
2 FAM111A NM_001312909.2(FAM111A):c.782_791dup (p.Phe264fs) Duplication Pathogenic 770974 rs533676902 GRCh37: 11:58919922-58919923
GRCh38: 11:59152449-59152450
3 FAM111A NM_001312909.2(FAM111A):c.97C>T (p.Gln33Ter) SNV Pathogenic 998261 GRCh37: 11:58919238-58919238
GRCh38: 11:59151765-59151765
4 FAM111A NM_001312909.2(FAM111A):c.1706G>A (p.Arg569His) SNV Pathogenic 56810 rs587777011 GRCh37: 11:58920847-58920847
GRCh38: 11:59153374-59153374
5 FAM111A NM_001312909.2(FAM111A):c.1477C>T (p.Arg493Ter) SNV Pathogenic 1033999 GRCh37: 11:58920618-58920618
GRCh38: 11:59153145-59153145
6 FAM111A NM_001312909.2(FAM111A):c.1583A>G (p.Asp528Gly) SNV Pathogenic/Likely pathogenic 56813 rs587777013 GRCh37: 11:58920724-58920724
GRCh38: 11:59153251-59153251
7 FAM111A NM_001312909.2(FAM111A):c.1012A>G (p.Thr338Ala) SNV Pathogenic/Likely pathogenic 56814 rs587777014 GRCh37: 11:58920153-58920153
GRCh38: 11:59152680-59152680
8 FAM111A NM_001312909.2(FAM111A):c.1579C>A (p.Pro527Thr) SNV Pathogenic/Likely pathogenic 56815 rs587777015 GRCh37: 11:58920720-58920720
GRCh38: 11:59153247-59153247
9 FAM111A NM_001312909.2(FAM111A):c.931A>T (p.Ile311Phe) SNV Likely pathogenic 982416 GRCh37: 11:58920072-58920072
GRCh38: 11:59152599-59152599
10 FAM111A NM_001312909.2(FAM111A):c.1138A>G (p.Ile380Val) SNV Uncertain significance 930855 GRCh37: 11:58920279-58920279
GRCh38: 11:59152806-59152806
11 FAM111A NM_001312909.2(FAM111A):c.1818G>A (p.Met606Ile) SNV Uncertain significance 1031325 GRCh37: 11:58920959-58920959
GRCh38: 11:59153486-59153486
12 FAM111A NM_001312909.2(FAM111A):c.533C>T (p.Ser178Leu) SNV Uncertain significance 1031326 GRCh37: 11:58919674-58919674
GRCh38: 11:59152201-59152201
13 FAM111A NM_001312909.2(FAM111A):c.1706G>A (p.Arg569His) SNV not provided 56810 rs587777011 GRCh37: 11:58920847-58920847
GRCh38: 11:59153374-59153374

UniProtKB/Swiss-Prot genetic disease variations for Gracile Bone Dysplasia:

72
# Symbol AA change Variation ID SNP ID
1 FAM111A p.Thr338Ala VAR_069513 rs587777014
2 FAM111A p.Pro527Thr VAR_069516 rs587777015
3 FAM111A p.Asp528Gly VAR_069517 rs587777013

Expression for Gracile Bone Dysplasia

Search GEO for disease gene expression data for Gracile Bone Dysplasia.

Pathways for Gracile Bone Dysplasia

GO Terms for Gracile Bone Dysplasia

Sources for Gracile Bone Dysplasia

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 EFO
18 ExPASy
19 FMA
20 GARD
28 GO
29 GTR
30 HMDB
31 HPO
32 ICD10
33 ICD10 via Orphanet
34 ICD9CM
35 IUPHAR
36 KEGG
37 LifeMap
39 LOVD
41 MedGen
44 MeSH
45 MESH via Orphanet
46 MGI
49 NCI
50 NCIt
51 NDF-RT
53 NINDS
54 Novoseek
56 OMIM via Orphanet
57 OMIM® (Updated 05-Apr-2021)
61 PubMed
63 QIAGEN
68 SNOMED-CT via HPO
69 Tocris
70 UMLS
71 UMLS via Orphanet
Content
Loading form....