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Craniofrontonasal syndrome(CFNS)

MedGen UID:
65095
Concept ID:
C0220767
Disease or Syndrome
Synonyms: CFNS; Craniofrontonasal dysostosis; Craniofrontonasal dysplasia
SNOMED CT: Craniofrontonasal dysplasia (715421009); Craniofrontonasal syndrome (715421009)
Modes of inheritance:
X-linked dominant inheritance
MedGen UID:
376232
Concept ID:
C1847879
Finding
Source: Orphanet
A mode of inheritance that is observed for dominant traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked dominant disorders tend to manifest very severely in affected males. The severity of manifestation in females may depend on the degree of skewed X inactivation.
 
Gene (location): EFNB1 (Xq13.1)
 
Monarch Initiative: MONDO:0010570
OMIM®: 304110
Orphanet: ORPHA1520

Definition

Craniofrontonasal syndrome is an X-linked developmental disorder that shows paradoxically greater severity in heterozygous females than in hemizygous males. Females have frontonasal dysplasia, craniofacial asymmetry, craniosynostosis, bifid nasal tip, grooved nails, wiry hair, and abnormalities of the thoracic skeleton, whereas males typically show only hypertelorism (Twigg et al., 2004; Wieland et al., 2004). [from OMIM]

Additional description

From MedlinePlus Genetics
Craniofrontonasal syndrome is a rare condition characterized by the premature closure of certain bones of the skull (craniosynostosis) during development, which affects the shape of the head and face. The condition is named for the areas of the body that are typically affected: the skull (cranio-), face (fronto-), and nose (nasal).

In people with craniofrontonasal syndrome, the skull bones along the coronal suture, which is the growth line that goes over the head from ear to ear, closes early. These changes can result in an abnormally shaped head and distinctive facial features. The size and shape of facial structures may differ between the right and left sides of the face (facial asymmetry) in individuals with craniofrontonasal syndrome. Affected individuals may also have wide-set eyes (ocular hypertelorism), eyes that do not point in the same direction (strabismus), involuntary eye movements (nystagmus), a slit (cleft) in the tip of the nose, a wide nasal bridge, an upper lip that points outward (called a tented lip), or a cleft in the upper lip with or without a cleft in roof of the mouth (palate). Some affected individuals have brain abnormalities, such as absent or underdeveloped tissue connecting the left and right halves of the brain (agenesis or dysgenesis of the corpus callosum). However, intelligence is usually unaffected in people with this condition. Females with craniofrontonasal syndrome typically have more severe signs and symptoms than affected males, who often have hypertelorism and rarely, cleft lip.

Other common features of craniofrontonasal syndrome include extra folds of skin on the neck (webbed neck), ridged nails, unusual curving of the fingers or toes (clinodactyly), extra fingers (polydactyly) or fingers that are fused together (syndactyly), low-set breasts, a sunken chest (pectus excavatum), a spine that curves to the side (scoliosis), or narrow and sloped shoulders with reduced range of motion. People with this condition may also have eyebrows that grow together in the middle (synophrys), a widow's peak hairline with a low hairline in the back, or wiry hair.  https://medlineplus.gov/genetics/condition/craniofrontonasal-syndrome

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).
Hypospadias
MedGen UID:
163083
Concept ID:
C0848558
Congenital Abnormality
Abnormal position of urethral meatus on the ventral penile shaft (underside) characterized by displacement of the urethral meatus from the tip of the glans penis to the ventral surface of the penis, scrotum, or perineum.
Shawl scrotum
MedGen UID:
388088
Concept ID:
C1858539
Congenital Abnormality
Superior margin of the scrotum superior to the base of the penis.
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.
Toe syndactyly
MedGen UID:
75581
Concept ID:
C0265660
Congenital Abnormality
Webbing or fusion of the toes, involving soft parts only or including bone structure. Bony fusions are referred to as "bony" Syndactyly if the fusion occurs in a radio-ulnar axis. Fusions of bones of the toes in a proximo-distal axis are referred to as "Symphalangism".
Clinodactyly of the 5th finger
MedGen UID:
340456
Concept ID:
C1850049
Congenital Abnormality
Clinodactyly refers to a bending or curvature of the fifth finger in the radial direction (i.e., towards the 4th finger).
3-4 finger syndactyly
MedGen UID:
346463
Concept ID:
C1856889
Finding
Syndactyly with fusion of fingers three and four.
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 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).
Hemihypotrophy of lower limb
MedGen UID:
375494
Concept ID:
C1844734
Finding
Shortening of a leg affecting only one side.
Corpus callosum, agenesis of
MedGen UID:
104498
Concept ID:
C0175754
Congenital Abnormality
The corpus callosum is the largest fiber tract in the central nervous system and the major interhemispheric fiber bundle in the brain. Formation of the corpus callosum begins as early as 6 weeks' gestation, with the first fibers crossing the midline at 11 to 12 weeks' gestation, and completion of the basic shape by age 18 to 20 weeks (Schell-Apacik et al., 2008). Agenesis of the corpus callosum (ACC) is one of the most frequent malformations in brain with a reported incidence ranging between 0.5 and 70 in 10,000 births. ACC is a clinically and genetically heterogeneous condition, which can be observed either as an isolated condition or as a manifestation in the context of a congenital syndrome (see MOLECULAR GENETICS and Dobyns, 1996). Also see mirror movements-1 and/or agenesis of the corpus callosum (MRMV1; 157600). Schell-Apacik et al. (2008) noted that there is confusion in the literature regarding radiologic terminology concerning partial absence of the corpus callosum, where various designations have been used, including hypogenesis, hypoplasia, partial agenesis, or dysgenesis.
Hypoplasia of the corpus callosum
MedGen UID:
138005
Concept ID:
C0344482
Congenital Abnormality
Underdevelopment of the corpus callosum.
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.
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.
Umbilical hernia
MedGen UID:
9232
Concept ID:
C0019322
Anatomical Abnormality
Protrusion of abdominal contents through a defect in the abdominal wall musculature around the umbilicus. Skin and subcutaneous tissue overlie the defect.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Congenital elevation of scapula
MedGen UID:
56291
Concept ID:
C0152438
Congenital Abnormality
A congenital skeletal deformity characterized by the elevation of one scapula (thus, one scapula is located superior to the other).
Frontal bossing
MedGen UID:
67453
Concept ID:
C0221354
Congenital Abnormality
Bilateral bulging of the lateral frontal bone prominences with relative sparing of the midline.
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.
Congenital diaphragmatic hernia
MedGen UID:
68625
Concept ID:
C0235833
Congenital Abnormality
The presence of a hernia of the diaphragm present at birth.
Congenital pseudoarthrosis of clavicle
MedGen UID:
75577
Concept ID:
C0265565
Congenital Abnormality
The two portions of the clavicle (corresponding to the two primary ossification centers of the clavicle) are connected by a fibrous bridge that is contiguous with the periosteum, and a synovial membrane develops, resulting in a clavicle with a bipartite appearance radiographically. Congenital pseudarthrosis of the clavicle generally presents as a painless mass or swelling over the clavicle.
Joint hypermobility
MedGen UID:
336793
Concept ID:
C1844820
Finding
The capability that a joint (or a group of joints) has to move, passively and/or actively, beyond normal limits along physiological axes.
Coronal craniosynostosis
MedGen UID:
344694
Concept ID:
C1856266
Congenital Abnormality
Premature closure of the coronal suture of skull.
Down-sloping shoulders
MedGen UID:
346461
Concept ID:
C1856872
Finding
Low set, steeply sloping shoulders.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Pectus excavatum
MedGen UID:
781174
Concept ID:
C2051831
Finding
A defect of the chest wall characterized by a depression of the sternum, giving the chest ("pectus") a caved-in ("excavatum") appearance.
Abnormal rib cage morphology
MedGen UID:
871275
Concept ID:
C4025763
Anatomical Abnormality
A morphological anomaly of the rib cage.
Cleft upper lip
MedGen UID:
40327
Concept ID:
C0008924
Congenital Abnormality
A gap or groove in the upper lip. This is a congenital defect resulting from nonfusion of tissues of the lip during embryonal development.
Webbed neck
MedGen UID:
113154
Concept ID:
C0221217
Congenital Abnormality
Pterygium colli is a congenital skin fold that runs along the sides of the neck down to the shoulders. It involves an ectopic fibrotic facial band superficial to the trapezius muscle. Excess hair-bearing skin is also present and extends down the cervical region well beyond the normal hairline.
Abnormality of the dentition
MedGen UID:
78084
Concept ID:
C0262444
Finding
Any abnormality of the teeth.
Downslanted palpebral fissures
MedGen UID:
98391
Concept ID:
C0423110
Finding
The palpebral fissure inclination is more than two standard deviations below the mean.
Telecanthus
MedGen UID:
140836
Concept ID:
C0423113
Finding
Distance between the inner canthi more than two standard deviations above the mean (objective); or, apparently increased distance between the inner canthi.
Bifid nasal tip
MedGen UID:
140870
Concept ID:
C0426428
Finding
A splitting of the nasal tip. Visually assessable vertical indentation, cleft, or depression of the nasal tip.
Short neck
MedGen UID:
99267
Concept ID:
C0521525
Finding
Diminished length of the neck.
Facial asymmetry
MedGen UID:
266298
Concept ID:
C1306710
Finding
An abnormal difference between the left and right sides of the face.
Hypoplastic nasal tip
MedGen UID:
336765
Concept ID:
C1844731
Finding
Wide nasal bridge
MedGen UID:
341441
Concept ID:
C1849367
Finding
Increased breadth of the nasal bridge (and with it, the nasal root).
Widow peak
MedGen UID:
342891
Concept ID:
C1853486
Finding
Frontal hairline with bilateral arcs to a low point in the midline of the forehead.
Low posterior hairline
MedGen UID:
383755
Concept ID:
C1855728
Finding
Hair on the neck extends more inferiorly than usual.
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).
Split nail
MedGen UID:
120482
Concept ID:
C0263530
Finding
A nail plate that has a longitudinal separation and the two sections of the nail share the same lateral radius of curvature.
Ridged nail
MedGen UID:
140853
Concept ID:
C0423820
Finding
Longitudinal, linear prominences in the nail plate.
Curly hair
MedGen UID:
488919
Concept ID:
C0558165
Finding
Axillary pterygium
MedGen UID:
335019
Concept ID:
C1844738
Finding
Presence of a cutaneous membrane (flap) in the armpit.
Fragile nails
MedGen UID:
341661
Concept ID:
C1856963
Finding
Nails that easily break.
Breast hypoplasia
MedGen UID:
75594
Concept ID:
C0266013
Congenital Abnormality
Underdevelopment of the breast.
Unilateral breast hypoplasia
MedGen UID:
335016
Concept ID:
C1844722
Finding
Underdevelopment of the breast on one side only.
Exotropia
MedGen UID:
4613
Concept ID:
C0015310
Disease or Syndrome
A form of strabismus with one or both eyes deviated outward.
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).
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVCraniofrontonasal syndrome
Follow this link to review classifications for Craniofrontonasal syndrome in Orphanet.

Professional guidelines

PubMed

Dupré S, Care H, Gordon Z, Wall SA, Wilkie AOM, Johnson D, Kilcoyne S
J Craniofac Surg 2020 Jun;31(4):e362-e368. doi: 10.1097/SCS.0000000000006367. PMID: 32371695

Curated

EuroGentest, 2008

Recent clinical studies

Etiology

Raposo-Amaral CE, Resende G, Denadai R, Ghizoni E, Raposo-Amaral CA
Childs Nerv Syst 2021 Sep;37(9):2873-2878. Epub 2021 Apr 16 doi: 10.1007/s00381-021-05134-7. PMID: 33864106
Dupré S, Care H, Gordon Z, Wall SA, Wilkie AOM, Johnson D, Kilcoyne S
J Craniofac Surg 2020 Jun;31(4):e362-e368. doi: 10.1097/SCS.0000000000006367. PMID: 32371695

Diagnosis

Niethamer TK, Teng T, Franco M, Du YX, Percival CJ, Bush JO
PLoS Genet 2020 Feb;16(2):e1008300. Epub 2020 Feb 24 doi: 10.1371/journal.pgen.1008300. PMID: 32092051Free PMC Article
Ferrarini A, Gaillard M, Guerry F, Ramelli G, Heidi F, Keddache CV, Wieland I, Beckmann JS, Jaquemont S, Martinet D
Am J Med Genet A 2014 Feb;164A(2):346-52. Epub 2013 Dec 13 doi: 10.1002/ajmg.a.36140. PMID: 24376213
Zafeiriou DI, Pavlidou EL, Vargìami E
Pediatr Neurol 2011 Feb;44(2):83-7. doi: 10.1016/j.pediatrneurol.2010.10.012. PMID: 21215906
Rice DP
Front Oral Biol 2008;12:91-106. doi: 10.1159/000115034. PMID: 18391497
Morris CA, Palumbos JC, Carey JC
Am J Med Genet 1987 Jul;27(3):623-31. doi: 10.1002/ajmg.1320270315. PMID: 3631134

Therapy

Niethamer TK, Larson AR, O'Neill AK, Bershteyn M, Hsiao EC, Klein OD, Pomerantz JH, Bush JO
Stem Cell Reports 2017 Mar 14;8(3):529-537. Epub 2017 Feb 23 doi: 10.1016/j.stemcr.2017.01.017. PMID: 28238796Free PMC Article
Makarov R, Steiner B, Gucev Z, Tasic V, Wieacker P, Wieland I
BMC Med Genet 2010 Jun 17;11:98. doi: 10.1186/1471-2350-11-98. PMID: 20565770Free PMC Article
Wieland I, Makarov R, Reardon W, Tinschert S, Goldenberg A, Thierry P, Wieacker P
Eur J Hum Genet 2008 Feb;16(2):184-91. Epub 2007 Nov 28 doi: 10.1038/sj.ejhg.5201968. PMID: 18043713
Wieacker P, Wieland I
Mol Genet Metab 2005 Sep-Oct;86(1-2):110-6. doi: 10.1016/j.ymgme.2005.07.017. PMID: 16143553
Wieland I, Jakubiczka S, Muschke P, Wolf A, Gerlach L, Krawczak M, Wieacker P
Cytogenet Genome Res 2002;99(1-4):285-8. doi: 10.1159/000071605. PMID: 12900576

Prognosis

Bukowska-Olech E, Gawliński P, Jakubiuk-Tomaszuk A, Jędrzejowska M, Obersztyn E, Piechota M, Bielska M, Jamsheer A
Orphanet J Rare Dis 2021 Jun 26;16(1):286. doi: 10.1186/s13023-021-01914-1. PMID: 34174922Free PMC Article
Acosta-Fernández E, Zenteno JC, Chacón-Camacho OF, Peña-Padilla C, Bobadilla-Morales L, Corona-Rivera A, Romo-Huerta CO, Zepeda-Romero LC, López-Marure E, Acosta-León J, García-Cruz D, Maciel-Cruz EJ, Corona-Rivera JR
Am J Med Genet A 2020 May;182(5):1223-1229. Epub 2020 Feb 5 doi: 10.1002/ajmg.a.61506. PMID: 32022998
Hogue J, Shankar S, Perry H, Patel R, Vargervik K, Slavotinek A
Am J Med Genet A 2010 Oct;152A(10):2574-7. doi: 10.1002/ajmg.a.33596. PMID: 20734337
Makarov R, Steiner B, Gucev Z, Tasic V, Wieacker P, Wieland I
BMC Med Genet 2010 Jun 17;11:98. doi: 10.1186/1471-2350-11-98. PMID: 20565770Free PMC Article
Mulliken JB, Gripp KW, Stolle CA, Steinberger D, Müller U
Plast Reconstr Surg 2004 Jun;113(7):1899-909. doi: 10.1097/01.prs.0000122202.26792.bf. PMID: 15253176

Clinical prediction guides

Bukowska-Olech E, Gawliński P, Jakubiuk-Tomaszuk A, Jędrzejowska M, Obersztyn E, Piechota M, Bielska M, Jamsheer A
Orphanet J Rare Dis 2021 Jun 26;16(1):286. doi: 10.1186/s13023-021-01914-1. PMID: 34174922Free PMC Article
Ferrarini A, Gaillard M, Guerry F, Ramelli G, Heidi F, Keddache CV, Wieland I, Beckmann JS, Jaquemont S, Martinet D
Am J Med Genet A 2014 Feb;164A(2):346-52. Epub 2013 Dec 13 doi: 10.1002/ajmg.a.36140. PMID: 24376213
van den Elzen ME, Twigg SR, Goos JA, Hoogeboom AJ, van den Ouweland AM, Wilkie AO, Mathijssen IM
Eur J Hum Genet 2014 Aug;22(8):995-1001. Epub 2013 Nov 27 doi: 10.1038/ejhg.2013.273. PMID: 24281372Free PMC Article
Makarov R, Steiner B, Gucev Z, Tasic V, Wieacker P, Wieland I
BMC Med Genet 2010 Jun 17;11:98. doi: 10.1186/1471-2350-11-98. PMID: 20565770Free PMC Article
Mulliken JB, Gripp KW, Stolle CA, Steinberger D, Müller U
Plast Reconstr Surg 2004 Jun;113(7):1899-909. doi: 10.1097/01.prs.0000122202.26792.bf. PMID: 15253176

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