Paula and Bobby
Parents of Lillie
Craniofrontonasal syndrome (CFNS)
What is Craniofrontonasal Syndrome?
Craniofrontonasal syndrome is a rare genetic condition with just 115 cases reported worldwide to date.
The main symptom of this rare disease is the premature fusing together of the bones of the skull. This cause the unique facial features associated with the syndrome.
CFND Craniofrontonasal Dysostosis; Craniofrontonasal Dysplasia; Cfnd
What gene change causes Craniofrontonasal Syndrome?
The syndrome is an X-linked recessive genetic disorder. It affects females more frequently and more severely than males. Most males are not diagnosed with the condition. Due to the nature of the genetic inheritance of this X-linked disorder fathers can not pass it to their sons.
Syndromes inherited in an X-linked recessive pattern generally only affect males. Males only have one X chromosome, and so one copy of a gene mutation on it causes the syndrome. Females, with two X chromosomes, only one of which will be mutated, are not likely to be affected.
what are the main symptoms of Craniofrontonasal Syndrome?
Premature closure of the bones of the skull, as it is developing, causes most of the unique facial and head characteristics of the syndrome.
These include facial asymmetry, a slit in the top of the nose, a broad nose, widely spaced eyes, eyes that look in different directions, a webbed neck and sloping shoulders.
Sometimes there is an impact on brain development and mild intellectual disability may be a potential secondary symptom.
Possible clinical traits/features:
Muscular hypotonia, Hemihypotrophy of lower limb, Low posterior hairline, Intellectual disability, Midline defect of the nose, Pectus excavatum, Joint laxity, Joint hypermobility, Toe syndactyly, Plagiocephaly, Hand polydactyly, Nystagmus, Sensorineural hearing impairment, Short neck, Thickened nuchal skin fold, Shawl scrotum, Widow's peak, Cleft palate, Oral cleft, Congenital pseudoarthrosis of the clavicle, Aplasia/Hypoplasia of the corpus callosum, Aplasia/Hypoplasia of the nipples, Axillary pterygium, Broad hallux, Bifid nasal tip, Brachycephaly, Wide nasal bridge, Abnormality of the clavicle, Abnormal fingernail morphology, Abnormal toenail morphology, Abnormal palate morphology, Abnormality of the dentition, Abnormality of the shoulder, Abnormality of the rib cage, Hypertelorism, High anterior hairline, Hypospadias, Hypoplasia of the corpus callosum, Fragile nails, Cognitive impairment, Global developmental delay, Short stature, Hypoplastic nasal tip, Craniosynostosis, Cryptorchidism, Coronal craniosyno
How does someone get tested for Craniofrontonasal Syndrome?
The initial testing for Craniofrontonasal syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.
Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.
Medical information on Craniofrontonasal Syndrome
This condition combines frontonasal dysplasia with craniosynostosis. The clinical features are severe hypertelorism, a broad bifid nose, frontal bossing (which might be asymmetrical), a low posterior hairline with an anterior widow's peak, and occasionally a cleft lip and palate.
Radiographs of the skull show premature coronal synostosis. Most children have a normal intelligence, although mild delay has been reported.
If the palate is intact, it is often high with widely spaced teeth and mal-eruption. Neck webbing, rounded shoulders, abnormal clavicles and raised scapulae are all features. In the limbs there is often longitudinal splitting of the nails, occasionally skin syndactyly, and the fingers and toes might be deviated distally or, occasionally, hypoplastic.
McPherson et al., (1991), in an abstract, reported a female with a del(X)(p22.2)->pter with features of the condition.
Note that Ward et al., (1993) reported a female infant with a de novo reciprocal translocation (46,XX,t(1;18)(p31;q11)) with preaxial polysyndactyly, craniosynostosis and partial agenesis of the corpus callosum.
Mulvihill et al., (1993) reported a family with features of craniofrontonasal dysplasia. An interstitial deletion of 10p with breakpoints at p11.21 and p11.23 was found in three affected family members who were tested.
Feldman et al., (1997) mapped the gene to Xp22 and noted the association with cleft lip and palate in four out of 12 affected males (one with a pseudo cleft). The main manifestation in males was otherwise just hypertelorism. Pulleyn et al., (1999) provide further evidence for linkage to Xp12-Xp22 region. The gene eprin-B1 (EFNB1) has now been identified (Wieland et al., 2004, Twigg et al., 2004). It is a marker of tissue boundary formation.
Saavedra et al., (1996) reported 41 cases from Mexico, of whom 35 were female and six were male. Most cases were sporadic, but there were seven familial cases. Unusual manifestations that were noted included thick wiry and curly hair with irregularities in disposition of keratin filaments on scanning EM, anterior cranium bifidum, axillary pterygia, unilateral breast hypoplasia, and asymmetric lower limbs.
Kapusta et al., (1992) reported seven classical cases of the condition. One case was male. In two fathers of female cases, there were mild features of the condition. An unaffected father, with a mutation, and his two severely affected daughters were reported by Ozyilmaz et al., (2015). Natarajan et al., (1993) reported the syndrome in two male sibs with normal parents.
In a series of patients (van den Elzen et al., 2014), 91% had a bifid nose, 91% a columella indentation and 90% had a low implantation of the breasts (one unconvincing picture shown). Cantrell et al., (1994), Reardon et al., (1990) and Webster and Deming (1950) reported probable cases with unilateral absence of the pectoralis major muscle (ie. features of Poland anomaly). Erdogan et al., (1996) also reported a case with this association. There was polythelia of the left breast.
There are more females reported than males. Males may be less severely affected than females, and Devriendt et al., (1995) reported this phenomenon in a mother and son. Grutzner et al., (1988) suggested that inheritance is X-linked dominant but could not explain why females were more severely affected than males.
Twigg et al., (2006), have addressed the question as to why there are so few affected males. By using the gene EFNB1 (see below) they showed that of 17 germline mutations, 15 arose from the father, hence the relative scarcity in males. Postzygotic mutations (six out of 53), which would be expected to occur twice as frequently in female embryos and may be more likely to manifest because of X inactivation, also contributed to the excess of females.
Congenital diaphragmatic hernia can be part of the clinical picture (Hogue et al., 2010). Diaphragmatic hernia may be a rare association (Brooks et al., 2002, McGaughran et al., 2002, and Vasudevan et al., 2006).
Two females with de novo deletions of EFNB1 had in addition deletions of OPHN1 and PJA1 (Wieland et al., 2007). A third with mental slowness had only the additional deletion of OPHNI. The authors state that there might be implications for the male offspring in terms of intellectual disability and anhidrotic ectodermal dysplasia.
Six males were investigated by Twigg et al., (2013) who found that males mosaic for the EFNB1 mutation are more severely affected than hemizygous males.
Inoue et al. (2017) reported a family with three individuals with this syndrome and bilateral cleft lip and palate.
* This information is courtesy of the L M D.
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