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Muenke syndrome(MNKES)

MedGen UID:
355217
Concept ID:
C1864436
Disease or Syndrome
Synonyms: FGFR3-Related Craniosynostosis; MNKES; Muenke nonsyndromic coronal craniosynostosis; Syndrome of coronal craniosynostosis
SNOMED CT: Fibroblast growth factor receptor 3-related craniosynostosis (440350001); Fibroblast growth factor receptor 3 (FGFR3) related craniosynostosis (440350001); Muenke syndrome (787407003)
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): FGFR3 (4p16.3)
 
Monarch Initiative: MONDO:0011274
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 dimension 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 (usually mild); 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 MedlinePlus Genetics
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 that goes over the head from ear to ear. Other parts of the skull may also be malformed. 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 problems are possible.

The signs and symptoms of Muenke syndrome vary among affected people, and some features overlap with those seen in other craniosynostosis syndromes. A small percentage of people with the gene mutation associated with Muenke syndrome do not have any of the characteristic features of the disorder.  https://medlineplus.gov/genetics/condition/muenke-syndrome

Clinical features

From HPO
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.
Broad thumb
MedGen UID:
140880
Concept ID:
C0426891
Finding
Increased thumb width without increased dorso-ventral dimension.
Radial deviation of finger
MedGen UID:
322852
Concept ID:
C1836189
Finding
Bending or curvature of a finger toward the radial side (i.e., towards the thumb). The deviation is at the metacarpal-phalangeal joint, and this finding is distinct from clinodactyly.
Short middle phalanx of finger
MedGen UID:
337690
Concept ID:
C1846950
Finding
Short (hypoplastic) middle phalanx of finger, affecting one or more fingers.
Broad hallux
MedGen UID:
401165
Concept ID:
C1867131
Finding
Visible increase in width of the hallux without an increase in the dorso-ventral dimension.
Short middle phalanx of toe
MedGen UID:
867359
Concept ID:
C4021723
Anatomical Abnormality
Developmental hypoplasia (shortening) of middle phalanx of toe.
Thimble-shaped middle phalanges of hand
MedGen UID:
870631
Concept ID:
C4025083
Anatomical Abnormality
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.
Clinodactyly
MedGen UID:
1644094
Concept ID:
C4551485
Congenital Abnormality
An angulation of a digit at an interphalangeal joint in the plane of the palm (finger) or sole (toe).
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Sensorineural hearing loss disorder
MedGen UID:
9164
Concept ID:
C0018784
Disease or Syndrome
A type of hearing impairment in one or both ears related to an abnormal functionality of the cochlear nerve.
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
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.
Attention deficit hyperactivity disorder
MedGen UID:
220387
Concept ID:
C1263846
Mental or Behavioral Dysfunction
Attention-deficit/hyperactivity disorder (ADHD) is a behavioral disorder that typically begins in childhood and is characterized by a short attention span (inattention), an inability to be calm and stay still (hyperactivity), and poor impulse control (impulsivity). Some people with ADHD have problems with only inattention or with hyperactivity and impulsivity, but most have problems related to all three features.\n\nIn people with ADHD, the characteristic behaviors are frequent and severe enough to interfere with the activities of daily living such as school, work, and relationships with others. Because of an inability to stay focused on tasks, people with inattention may be easily distracted, forgetful, avoid tasks that require sustained attention, have difficulty organizing tasks, or frequently lose items.\n\nHyperactivity is usually shown by frequent movement. Individuals with this feature often fidget or tap their foot when seated, leave their seat when it is inappropriate to do so (such as in the classroom), or talk a lot and interrupt others.\n\nIn most affected individuals, ADHD continues throughout life, but in about one-third of individuals, signs and symptoms of ADHD go away by adulthood.\n\nImpulsivity can result in hasty actions without thought for the consequences. Individuals with poor impulse control may have difficulty waiting for their turn, deferring to others, or considering their actions before acting.\n\nMore than two-thirds of all individuals with ADHD have additional conditions, including insomnia, mood or anxiety disorders, learning disorders, or substance use disorders. Affected individuals may also have autism spectrum disorder, which is characterized by impaired communication and social interaction, or Tourette syndrome, which is a disorder characterized by repetitive and involuntary movements or noises called tics.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Brachycephaly
MedGen UID:
113165
Concept ID:
C0221356
Congenital Abnormality
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.
Coronal craniosynostosis
MedGen UID:
344694
Concept ID:
C1856266
Congenital Abnormality
Premature closure of the coronal suture of skull.
Capitate-hamate fusion
MedGen UID:
346488
Concept ID:
C1857002
Finding
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.
Cone-shaped epiphyses of the phalanges of the hand
MedGen UID:
347156
Concept ID:
C1859480
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.
Temporal bossing
MedGen UID:
395399
Concept ID:
C1860048
Anatomical Abnormality
Prominence (bulging) in the temple region, which is the part of the skull where the frontal, parietal, temporal, and sphenoid bones join on the side of the head.
Cloverleaf skull
MedGen UID:
348010
Concept ID:
C1860050
Congenital Abnormality
Trilobar skull configuration when viewed from the front or behind.
Plagiocephaly
MedGen UID:
1825944
Concept ID:
C2081594
Finding
Asymmetric head shape, which is usually a combination of unilateral occipital flattening with ipsilateral frontal prominence, leading to rhomboid cranial shape.
Macrocephaly
MedGen UID:
745757
Concept ID:
C2243051
Finding
Occipitofrontal (head) circumference greater than 97th centile compared to appropriate, age matched, sex-matched normal standards. Alternatively, a apparently increased size of the cranium.
Recurrent otitis media
MedGen UID:
155436
Concept ID:
C0747085
Disease or Syndrome
Increased susceptibility to otitis media, as manifested by recurrent episodes of otitis media.
Dental malocclusion
MedGen UID:
9869
Concept ID:
C0024636
Anatomical Abnormality
Dental malocclusion refers to an abnormality of the occlusion, or alignment, of the teeth and the way the upper and lower teeth fit together, resulting in overcrowding of teeth or in abnormal bite patterns.
High palate
MedGen UID:
66814
Concept ID:
C0240635
Congenital Abnormality
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).
Downslanted palpebral fissures
MedGen UID:
98391
Concept ID:
C0423110
Finding
The palpebral fissure inclination is more than two standard deviations below the mean.
Low anterior hairline
MedGen UID:
331280
Concept ID:
C1842366
Finding
Distance between the hairline (trichion) and the glabella (the most prominent point on the frontal bone above the root of the nose), in the midline, more than two SD below the mean. Alternatively, an apparently decreased distance between the hairline and the glabella.
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.
Amblyopia
MedGen UID:
8009
Concept ID:
C0002418
Disease or Syndrome
Reduced visual acuity that is uncorrectable by lenses in the absence of detectable anatomic defects in the eye or visual pathways.
Ptosis
MedGen UID:
2287
Concept ID:
C0005745
Disease or Syndrome
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).
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).
Strabismus
MedGen UID:
21337
Concept ID:
C0038379
Disease or Syndrome
A misalignment of the eyes so that the visual axes deviate from bifoveal fixation. The classification of strabismus may be based on a number of features including the relative position of the eyes, whether the deviation is latent or manifest, intermittent or constant, concomitant or otherwise and according to the age of onset and the relevance of any associated refractive error.

Professional guidelines

PubMed

Biamino E, Canale A, Lacilla M, Marinosci A, Dagna F, Genitori L, Peretta P, Silengo M, Albera R, Ferrero GB
Int J Pediatr Otorhinolaryngol 2016 Jun;85:95-8. Epub 2016 Apr 11 doi: 10.1016/j.ijporl.2016.03.038. PMID: 27240504

Recent clinical studies

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Bautista G
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Am J Med Genet A 2019 Aug;179(8):1442-1450. Epub 2019 May 20 doi: 10.1002/ajmg.a.61199. PMID: 31111620Free PMC Article
Samra F, Bauder AR, Swanson JW, Whitaker LA, Bartlett SP, Taylor JA
J Plast Reconstr Aesthet Surg 2016 Sep;69(9):1285-90. Epub 2016 Jul 16 doi: 10.1016/j.bjps.2016.06.017. PMID: 27449747
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

Diagnosis

Couloigner V, Ayari Khalfallah S
Neurochirurgie 2019 Nov;65(5):318-321. Epub 2019 Sep 27 doi: 10.1016/j.neuchi.2019.09.015. PMID: 31568777
Murali CN, McDonald-McGinn DM, Wenger TL, McDougall C, Stroup BM, Sheppard SE, Taylor J, Bartlett SP, Bhoj EJ, Zackai EH, Santani A
Am J Med Genet A 2019 Aug;179(8):1442-1450. Epub 2019 May 20 doi: 10.1002/ajmg.a.61199. PMID: 31111620Free PMC Article
Wang JC, Nagy L, Demke JC
Facial Plast Surg Clin North Am 2016 Nov;24(4):531-543. doi: 10.1016/j.fsc.2016.06.008. PMID: 27712819
Samra F, Bauder AR, Swanson JW, Whitaker LA, Bartlett SP, Taylor JA
J Plast Reconstr Aesthet Surg 2016 Sep;69(9):1285-90. Epub 2016 Jul 16 doi: 10.1016/j.bjps.2016.06.017. PMID: 27449747
Agochukwu NB, Solomon BD, Muenke M
Am J Audiol 2014 Jun;23(2):135-41. doi: 10.1044/2014_AJA-13-0036. PMID: 24686979Free PMC Article

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. 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

Pickrell BB, Meaike JD, Cañadas KT, Chandy BM, Buchanan EP
J Craniofac Surg 2017 May;28(3):696-699. doi: 10.1097/SCS.0000000000003489. PMID: 28468151
Yarnell CM, Addissie YA, Hadley DW, Guillen Sacoto MJ, Agochukwu NB, Hart RA, Wiggs EA, Platte P, Paelecke Y, Collmann H, Schweitzer T, Kruszka P, Muenke M
J Pediatr 2015 Aug;167(2):428-34. Epub 2015 May 28 doi: 10.1016/j.jpeds.2015.04.080. PMID: 26028288Free PMC Article
Rijken BF, Lequin MH, van der Lijn F, van Veelen-Vincent ML, de Rooi J, Hoogendam YY, Niessen WJ, Mathijssen IM
J Craniomaxillofac Surg 2015 Jul;43(6):813-9. Epub 2015 Apr 14 doi: 10.1016/j.jcms.2015.04.001. PMID: 25979575
Thomas GP, Wall SA, Jayamohan J, Magdum SA, Richards PG, Wiberg A, Johnson D
J Craniofac Surg 2014 Sep;25(5):1721-7. doi: 10.1097/SCS.0000000000000995. PMID: 25162545
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

Clinical prediction guides

Perrot A, Rickert-Sperling S
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Childs Nerv Syst 2023 Dec;39(12):3491-3499. Epub 2023 Jun 15 doi: 10.1007/s00381-023-06005-z. PMID: 37322357
Leinonen S, Rice D, Leikola J, Heliövaara A
Cleft Palate Craniofac J 2021 Mar;58(3):290-298. Epub 2020 Aug 20 doi: 10.1177/1055665620950145. PMID: 32815397
Couloigner V, Ayari Khalfallah S
Neurochirurgie 2019 Nov;65(5):318-321. Epub 2019 Sep 27 doi: 10.1016/j.neuchi.2019.09.015. PMID: 31568777
Yarnell CM, Addissie YA, Hadley DW, Guillen Sacoto MJ, Agochukwu NB, Hart RA, Wiggs EA, Platte P, Paelecke Y, Collmann H, Schweitzer T, Kruszka P, Muenke M
J Pediatr 2015 Aug;167(2):428-34. Epub 2015 May 28 doi: 10.1016/j.jpeds.2015.04.080. PMID: 26028288Free PMC Article

Recent systematic reviews

Tcherbbis Testa V, Jaimovich S, Argañaraz R, Mantese B
Acta Neurochir (Wien) 2021 Nov;163(11):3083-3091. Epub 2021 Sep 27 doi: 10.1007/s00701-021-04980-3. PMID: 34570275

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