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Muenke syndrome(MNKES)

MedGen UID:
355217
Concept ID:
C1864436
Disease or Syndrome
Synonyms: FGFR3-associated coronal synostosis; FGFR3-Related Craniosynostosis; MNKES; Muenke nonsyndromic coronal craniosynostosis; Syndrome of coronal craniosynostosis
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Autosomal dominant inheritance refers to genetic conditions that occur when a mutation is present in one copy of a given gene (i.e., the person is heterozygous).
SNOMED CT: Fibroblast growth factor receptor 3-related craniosynostosis (440350001); Muenke syndrome (440350001); Fibroblast growth factor receptor 3 (FGFR3) related craniosynostosis (440350001)
 
Gene: FGFR3
Cytogenetic location: 4p16.3
OMIM®: 602849
Orphanet: ORPHA53271

Definition

Muenke syndrome is defined by the presence of the specific FGFR3 pathogenic variant, c.749C>G, that results in the protein change p.Pro250Arg. Muenke syndrome is characterized by considerable phenotypic variability: features may include coronal synostosis (more often bilateral than unilateral); synostosis of other sutures, all sutures (pan synostosis), or no sutures; or macrocephaly. Bilateral coronal synostosis typically results in brachycephaly (reduced anteroposterior dimenstion of the skull), although turribrachycephaly (a "tower-shaped" skull) or a cloverleaf skull can be observed. Unilateral coronal synostosis results in anterior plagiocephaly (asymmetry of the skull and face). Other craniofacial findings typically include: temporal bossing; widely spaced eyes, ptosis or proptosis (usually mild); midface retrusion; and highly arched palate or cleft lip and palate. Strabismus is common. Other findings can include: hearing loss (in 33%-100% of affected individuals); developmental delay (~33%); epilepsy; intracranial anomalies; intellectual disability; carpal bone and/or tarsal bone fusions; brachydactyly, broad toes, broad thumbs, and/or clinodactyly; and radiographic findings of thimble-like (short and broad) middle phalanges and/or cone-shaped epiphyses. Phenotypic variability is considerable even within the same family. Of note, some individuals who have the p.Pro250Arg pathogenic variant may have no signs of Muenke syndrome on physical or radiographic examination. [from GeneReviews]

Additional descriptions

From OMIM
Muenke syndrome is an autosomal dominant disorder characterized by uni- or bicoronal synostosis, macrocephaly, midfacial hypoplasia, and developmental delay. Other more variable features include thimble-shaped middle phalanges, brachydactyly, carpal/tarsal fusion, and deafness. The phenotype is variable and can range from no detectable clinical manifestations to complex findings (summary by Abdel-Salam et al., 2011).  http://www.omim.org/entry/602849
From GHR
Muenke syndrome is a condition characterized by the premature closure of certain bones of the skull (craniosynostosis) during development, which affects the shape of the head and face. Many people with this disorder have a premature fusion of skull bones along the coronal suture, the growth line which goes over the head from ear to ear. Other parts of the skull may be malformed as well. These changes can result in an abnormally shaped head, wide-set eyes, and flattened cheekbones. About 5 percent of affected individuals have an enlarged head (macrocephaly). People with Muenke syndrome may also have mild abnormalities of the hands or feet, and hearing loss has been observed in some cases. Most people with this condition have normal intellect, but developmental delay and learning disabilities are possible. The signs and symptoms of Muenke syndrome vary among affected people, and some findings overlap with those seen in other craniosynostosis syndromes. Between 6 percent and 7 percent of people with the gene mutation associated with Muenke syndrome do not have any of the characteristic features of the disorder.  http://ghr.nlm.nih.gov/condition/muenke-syndrome

Clinical features

Abnormality of body height
MedGen UID:
446329
Concept ID:
CN000003
Finding
Deviation from the norm of height with respect to that which is expected according to age and gender norms.
Low anterior hairline
MedGen UID:
331280
Concept ID:
C1842366
Finding
Midface retrusion
MedGen UID:
339938
Concept ID:
C1853242
Finding
Coronal craniosynostosis
MedGen UID:
344694
Concept ID:
C1856266
Finding
Malar flattening
MedGen UID:
347814
Concept ID:
C1859168
Finding
Proptosis
MedGen UID:
350667
Concept ID:
C1862425
Finding
Downslanted palpebral fissures
MedGen UID:
400661
Concept ID:
C1865016
Finding
Macrocephaly
MedGen UID:
745757
Concept ID:
C2243051
Finding
Abnormality of the palate
MedGen UID:
427798
Concept ID:
CN000169
Finding
Any abnormality of the palate, i.e., of roof of the mouth).
High palate
MedGen UID:
504397
Concept ID:
CN000211
Finding
Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).
Brachycephaly
MedGen UID:
504407
Concept ID:
CN000240
Finding
An abnormality of skull shape characterized by a decreased anterior-posterior diameter. That is, a cephalic index greater than 81%. Alternatively, an apparently shortened anteroposterior dimension (length) of the head compared to width.
Hypertelorism
MedGen UID:
504419
Concept ID:
CN000296
Finding
Interpupillary distance more than 2 SD above the mean (alternatively, the appearance of an increased interpupillary distance or widely spaced eyes).
Plagiocephaly
MedGen UID:
504812
Concept ID:
CN001243
Finding
Asymmetric head shape, which is usually a combination of unilateral occipital flattening with ipsilateral frontal prominence, leading to rhomboid cranial shape.
Proptosis
MedGen UID:
350667
Concept ID:
C1862425
Finding
Hypertelorism
MedGen UID:
504419
Concept ID:
CN000296
Finding
Interpupillary distance more than 2 SD above the mean (alternatively, the appearance of an increased interpupillary distance or widely spaced eyes).
Ptosis
MedGen UID:
504471
Concept ID:
CN000475
Finding
The upper eyelid margin is positioned 3 mm or more lower than usual and covers the superior portion of the iris (objective); or, the upper lid margin obscures at least part of the pupil (subjective).
Sensorineural hearing impairment
MedGen UID:
504436
Concept ID:
CN000380
Finding
A type of hearing impairment in one or both ears related to an abnormal functionality of the cochlear nerve.
Intellectual disability
MedGen UID:
334384
Concept ID:
C1843367
Finding
Cognitive impairment
MedGen UID:
383844
Concept ID:
C1856145
Finding
Hydrocephalus
MedGen UID:
369747
Concept ID:
C1963137
Finding
Increased intracranial pressure
MedGen UID:
776585
Concept ID:
C2364324
Finding
Global developmental delay
MedGen UID:
504774
Concept ID:
CN001157
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Coronal craniosynostosis
MedGen UID:
344694
Concept ID:
C1856266
Finding
Capitate-hamate fusion
MedGen UID:
346488
Concept ID:
C1857002
Finding
Malar flattening
MedGen UID:
347814
Concept ID:
C1859168
Finding
Cone-shaped epiphysis
MedGen UID:
351282
Concept ID:
C1865037
Finding
Radial deviation of finger
MedGen UID:
473540
Concept ID:
C2178410
Finding
Macrocephaly
MedGen UID:
745757
Concept ID:
C2243051
Finding
Brachycephaly
MedGen UID:
504407
Concept ID:
CN000240
Finding
An abnormality of skull shape characterized by a decreased anterior-posterior diameter. That is, a cephalic index greater than 81%. Alternatively, an apparently shortened anteroposterior dimension (length) of the head compared to width.
Brachydactyly syndrome
MedGen UID:
500899
Concept ID:
CN001088
Finding
Digits that appear disproportionately short compared to the hand/foot. The word brachydactyly is used to describe a series of Mendelian diseases characterized by distinct patterns of shortened digits (brachydactyly types A-E). This is the sense used here, however, it is preferable to described the observed phenotypic abnormalities precisely.
Plagiocephaly
MedGen UID:
504812
Concept ID:
CN001243
Finding
Asymmetric head shape, which is usually a combination of unilateral occipital flattening with ipsilateral frontal prominence, leading to rhomboid cranial shape.
Short toe
MedGen UID:
500911
Concept ID:
CN001658
Finding
A toe that appears disproportionately short compared to the foot.
Short middle phalanx of toe
MedGen UID:
500968
Concept ID:
CN003426
Finding
Developmental hypoplasia (shortening) of middle phalanx of toe.
Synostosis of carpal bones
MedGen UID:
505745
Concept ID:
CN004479
Finding
Short middle phalanx of finger
MedGen UID:
425789
Concept ID:
CN005134
Finding
Short (hypoplastic) middle phalanx of finger, affecting one or more fingers.
Thimble-shaped middle phalanges of hand
MedGen UID:
505895
Concept ID:
CN005414
Finding
The middle phalanx of finger resembles a thimble, a small metal cap to protect the finger while sewing that has a broad (proximal) base and narrower top, whereby both base and top are flat.
Tarsal synostosis
MedGen UID:
425983
Concept ID:
CN007362
Finding
Synostosis (bony fusion) involving one or more bones of the tarsus (calcaneus, talus, cuboid, navicular, cuneiiform bones).
Broad hallux
MedGen UID:
506344
Concept ID:
CN008889
Finding
Visible increase in width of the hallux without an increase in the dorso-ventral dimension.
Cone-shaped epiphyses of the phalanges of the hand
MedGen UID:
447221
Concept ID:
CN009062
Finding
A cone-shaped appearance of the epiphyses of the fingers of the hand, producing a 'ball-in-a-socket' appearance. The related entity 'angel-shaped' epiphysis refers to a pronounced cone-shaped epiphysis in combination with a pseudoepiphysis at the distal end of a phalanx.
Clinodactyly
MedGen UID:
807884
Concept ID:
CN220788
Finding
An angulation of a digit at an interphalangeal joint in the plane of the palm (finger) or sole (toe).
Low anterior hairline
MedGen UID:
331280
Concept ID:
C1842366
Finding
Capitate-hamate fusion
MedGen UID:
346488
Concept ID:
C1857002
Finding
Radial deviation of finger
MedGen UID:
473540
Concept ID:
C2178410
Finding
Brachydactyly syndrome
MedGen UID:
500899
Concept ID:
CN001088
Finding
Digits that appear disproportionately short compared to the hand/foot. The word brachydactyly is used to describe a series of Mendelian diseases characterized by distinct patterns of shortened digits (brachydactyly types A-E). This is the sense used here, however, it is preferable to described the observed phenotypic abnormalities precisely.
Short toe
MedGen UID:
500911
Concept ID:
CN001658
Finding
A toe that appears disproportionately short compared to the foot.
Short middle phalanx of toe
MedGen UID:
500968
Concept ID:
CN003426
Finding
Developmental hypoplasia (shortening) of middle phalanx of toe.
Synostosis of carpal bones
MedGen UID:
505745
Concept ID:
CN004479
Finding
Short middle phalanx of finger
MedGen UID:
425789
Concept ID:
CN005134
Finding
Short (hypoplastic) middle phalanx of finger, affecting one or more fingers.
Thimble-shaped middle phalanges of hand
MedGen UID:
505895
Concept ID:
CN005414
Finding
The middle phalanx of finger resembles a thimble, a small metal cap to protect the finger while sewing that has a broad (proximal) base and narrower top, whereby both base and top are flat.
Tarsal synostosis
MedGen UID:
425983
Concept ID:
CN007362
Finding
Synostosis (bony fusion) involving one or more bones of the tarsus (calcaneus, talus, cuboid, navicular, cuneiiform bones).
Broad hallux
MedGen UID:
506344
Concept ID:
CN008889
Finding
Visible increase in width of the hallux without an increase in the dorso-ventral dimension.
Cone-shaped epiphyses of the phalanges of the hand
MedGen UID:
447221
Concept ID:
CN009062
Finding
A cone-shaped appearance of the epiphyses of the fingers of the hand, producing a 'ball-in-a-socket' appearance. The related entity 'angel-shaped' epiphysis refers to a pronounced cone-shaped epiphysis in combination with a pseudoepiphysis at the distal end of a phalanx.
Clinodactyly
MedGen UID:
807884
Concept ID:
CN220788
Finding
An angulation of a digit at an interphalangeal joint in the plane of the palm (finger) or sole (toe).

Recent clinical studies

Etiology

Agochukwu NB, Solomon BD, Gropman AL, Muenke M
Pediatr Neurol 2012 Nov;47(5):355-61. doi: 10.1016/j.pediatrneurol.2012.07.004. PMID: 23044018Free PMC Article
McGrath J, Gerety PA, Derderian CA, Steinbacher DM, Vossough A, Bartlett SP, Nah HD, Taylor JA
Plast Reconstr Surg 2012 Nov;130(5):681e-689e. doi: 10.1097/PRS.0b013e318267d4c0. PMID: 22777037
Agochukwu NB, Solomon BD, Doherty ES, Muenke M
J Craniofac Surg 2012 May;23(3):664-8. doi: 10.1097/SCS.0b013e31824db8bb. PMID: 22565872Free PMC Article
Yu JE, Park DH, Yoon SH
J Korean Med Sci 2010 Jul;25(7):1086-9. Epub 2010 Jun 17 doi: 10.3346/jkms.2010.25.7.1086. PMID: 20592905Free PMC Article
Mansour SL, Twigg SR, Freeland RM, Wall SA, Li C, Wilkie AO
Hum Mol Genet 2009 Jan 1;18(1):43-50. Epub 2008 Sep 25 doi: 10.1093/hmg/ddn311. [Epub ahead of print] PMID: 18818193Free PMC Article

Diagnosis

Agochukwu NB, Solomon BD, Gropman AL, Muenke M
Pediatr Neurol 2012 Nov;47(5):355-61. doi: 10.1016/j.pediatrneurol.2012.07.004. PMID: 23044018Free PMC Article
Nah HD, Koyama E, Agochukwu NB, Bartlett SP, Muenke M
Childs Nerv Syst 2012 Sep;28(9):1483-93. Epub 2012 Aug 8 doi: 10.1007/s00381-012-1778-9. [Epub ahead of print] PMID: 22872265Free PMC Article
Talbot SG, Upton J, Rogers GF
J Craniofac Surg 2012 Mar;23(2):e115-7. doi: 10.1097/SCS.0b013e31824cd9f6. PMID: 22446440
de Jong T, Mathijssen IM, Hoogeboom AJ
J Craniofac Surg 2011 Mar;22(2):571-5. doi: 10.1097/SCS.0b013e318207b761. PMID: 21403557
Ranger A, Chaudhary N, Rau J, Matir D, Goobie S
J Craniofac Surg 2011 Jan;22(1):187-90. doi: 10.1097/SCS.0b013e3181f75412. PMID: 21233754

Therapy

Bayazit YA, Abaday A, Dogulu F, Göksu N
ORL J Otorhinolaryngol Relat Spec 2011;73(2):72-5. Epub 2011 Jan 27 doi: 10.1159/000323438. [Epub ahead of print] PMID: 21273799
Escobar LF, Hiett AK, Marnocha A
Am J Med Genet A 2009 Jun;149A(6):1273-6. doi: 10.1002/ajmg.a.32841. PMID: 19449410

Prognosis

Roscioli T, Elakis G, Cox TC, Moon DJ, Venselaar H, Turner AM, Le T, Hackett E, Haan E, Colley A, Mowat D, Worgan L, Kirk EP, Sachdev R, Thompson E, Gabbett M, McGaughran J, Gibson K, Gattas M, Freckmann ML, Dixon J, Hoefsloot L, Field M, Hackett A, Kamien B, Edwards M, Adès LC, Collins FA, Wilson MJ, Savarirayan R, Tan TY, Amor DJ, McGillivray G, White SM, Glass IA, David DJ, Anderson PJ, Gianoutsos M, Buckley MF
Am J Med Genet C Semin Med Genet 2013 Nov;163C(4):259-70. Epub 2013 Oct 11 doi: 10.1002/ajmg.c.31378. [Epub ahead of print] PMID: 24127277
Agochukwu NB, Solomon BD, Doherty ES, Muenke M
J Craniofac Surg 2012 May;23(3):664-8. doi: 10.1097/SCS.0b013e31824db8bb. PMID: 22565872Free PMC Article
Barroso E, Pérez-Carrizosa V, García-Recuero I, Glucksman MJ, Wilkie AO, García-Minaur S, Heath KE
Am J Med Genet A 2011 Dec;155A(12):3050-3. Epub 2011 Oct 28 doi: 10.1002/ajmg.a.34199. [Epub ahead of print] PMID: 22038757

Clinical prediction guides

Maliepaard M, Mathijssen IM, Oosterlaan J, Okkerse JM
Pediatrics 2014 Jun;133(6):e1608-15. doi: 10.1542/peds.2013-3077. PMID: 24864183
de Jong T, Mathijssen IM, Hoogeboom AJ
J Craniofac Surg 2011 Mar;22(2):571-5. doi: 10.1097/SCS.0b013e318207b761. PMID: 21403557
Didolkar MM, Vinson EN, Gaca AM
Skeletal Radiol 2009 Oct;38(10):1011-4. Epub 2009 May 16 doi: 10.1007/s00256-009-0716-8. [Epub ahead of print] PMID: 19449001
van der Meulen J, van den Ouweland A, Hoogeboom J
Am J Med Genet A 2006 Nov 15;140(22):2493-4. doi: 10.1002/ajmg.a.31460. PMID: 17036334
Grosso S, Farnetani MA, Berardi R, Bartalini G, Carpentieri M, Galluzzi P, Mostardini R, Morgese G, Balestri P
Am J Med Genet A 2003 Jul 1;120A(1):88-91. doi: 10.1002/ajmg.a.10171. PMID: 12794698

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