Table of Contents  
CASE REPORT
Year : 2015  |  Volume : 8  |  Issue : 5  |  Page : 672-674  

Craniofrontonasal dysplasia syndrome: A rare case


Department of Pediatrics, Burdwan Medical College and Hospital, Burdwan, West Bengal, India

Date of Web Publication10-Sep-2015

Correspondence Address:
Biswajit Biswas
Department of Pediatrics, Burdwan Medical College and Hospital, Burdwan - 713 104, West Bengal
India
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Source of Support: Nil., Conflict of Interest: None declared.


DOI: 10.4103/0975-2870.164955

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  Abstract 

Craniofrontonasal dysplasia syndrome (CFND) (Online Mendelian Inheritance in Man database Number 304110), first described as a distinct entity by Professor Michael Cohen from Canada in 1979, is a very rare X-linked inherited disorder characterized by abnormalities of the head and face (cranio-facial area), hands and feet, and certain skeletal bones. Phenotypic expression varies greatly amongst affected individuals, where females are more commonly and generally more severely affected than males. We are presenting a newborn with this rare and peculiar syndrome, probably the first case from India to make physicians aware of this condition, so that more number of cases are being reported to help establishing an uniform clinical diagnostic criteria for CFND in the near future.

Keywords: Craniofrontonasal dysplasia, craniofrontonasal dysplasia syndrome, newborn


How to cite this article:
Biswas B, Mondal M, Roy A, Das R. Craniofrontonasal dysplasia syndrome: A rare case. Med J DY Patil Univ 2015;8:672-4

How to cite this URL:
Biswas B, Mondal M, Roy A, Das R. Craniofrontonasal dysplasia syndrome: A rare case. Med J DY Patil Univ [serial online] 2015 [cited 2019 Mar 24];8:672-4. Available from: http://www.mjdrdypu.org/text.asp?2015/8/5/672/164955


  Introduction Top


Craniofrontonasal syndrome is an X-linked developmental disorder that shows paradoxically greater severity in heterozygous females than in hemizygous males. Females have frontonasal dysplasia, cranio-facial asymmetry, craniosynostosis, bifid nasal tip, grooved nails, wiry hair, and abnormalities of the thoracic skeleton, whereas males typically show only hypertelorism.[1],[2]


  Case Report Top


A girl weighing 2.6 kg, with a head circumference of 33 cm and a length of 47 cm at birth was admitted to our sick neonatal care unit with cleft lip and palate and associated feeding difficulty. The baby was born by cesarean section to primipara mother. Her medical and obstetric history was unremarkable. She had not used oral contraceptives.

The parents were nonconsanguineous. Father had prominent hypertelorism as a single noticeable dysmorphic feature, and there was no family history of any other congenital anomaly. Mother had regular antenatal care during this pregnancy and tested negative for hepatitis B, toxoplasma, cytomegalovirus and HIV antibodies and was immune to rubella. A single antenatal ultrasound at 16 weeks reported normal study.

On admission, baby was pink in room air with normal vital parameters. She was initially put on intravenous fluid and gavage feeding through nasogastric tube. Gradually oral feeding was established, and mother was trained to use long and narrow handled spoon for feeding.

Phenotypic features showed brachycephaly with a broad prominent forehead retracted supra-orbital ridges, prominent ocular hypertelorism, mild downslanting of palpebral fissures and broad nasal bridge. Mouth was tent-shaped with noticeable asymmetry. Bilateral complete cleft lip with complete cleft palate was noted [Figure 1a]. High arching of the palate was also evident. Coronal sutures were closed with ridging. Ears were low set, and neck was short without webbing. Shoulders were rounded and sloping and could be proximated anteriorly close to the midline [Figure 1b] indicating clavicular dysplasia. Nipples were placed widely and asymmetrically. Examination of the spine revealed scoliosis in the thoracolumbar region. Great toes were broad, and there was partial syndactyly of second, third and fourth toes bilaterally. Clinodactyly of both the fifth toe was obvious [Figure 1c]. Fingers of the hands were long with relatively broad thumb. Finger and toe nails were concave and hypoplastic, but no longitudinal cleft was found. Examination of the major organ systems did not reveal any other significant abnormality.
Figure 1a: Photograph showing ocular hypertelorism, downslanting of eyes, broad nasal bridge, tent-shaped mouth with asymmetry, bilateral cleft lip and palate, brachycephaly, broad prominent forehead, retracted supra-orbital ridges, rounded and sloping shoulder, widely and asymmetrically placed nipple

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Figure 1b: Shoulders were rounded and sloping and could be proximated anteriorly close to the midline

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Figure 1c: Photograph showing broad great toe, partial syndactyly of second, third and fourth toes bilaterally, clinodactyly of both the fifth toes

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Radiologic skeletal survey by the roentgenogram revealed asymmetry of the facial bones, dysplastic scapulae and clavicles, and thoracolumbar scoliosis [Figure 2a] and [Figure 2b]. A detailed ultrasound study of the abdomen and an echocardiogram were normal. Routine blood parameters were normal.
Figure 2a: Plain roentgenogram skull showing facial asymmetry

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Figure 2b: Infantogram showing scoliosis of the thoracolumbar spine, dysplastic clavicle and scapula

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Craniofrontonasal dysplasia syndrome (CFND) was diagnosed based on craniofacial features and associated skeletal abnormalities. Hypertelorism in the father further confirmed the possibility. Karyotype showed 46, XX, normal female genotype. Further genetic testing (mutation analysis), however, was not possible in our case due economic constraints on the part of the family.

Baby was discharged on day 8 with appropriate counseling of the family and was advised to follow-up.


  Discussion Top


Craniofrontonasal dysplasia is a very rare genetic condition with an incidence varying from 1:100,000 to 1:120,000.[3] Phenotypic expression varies greatly between individuals.

Most of the males are mildly affected (with hypertelorism only). Females have frontonasal dysplasia (widely-spaced eyes or the hypertelorism, and flat and broad nose with a vertical groove on the top of the nose), coronal craniosynostosis with brachycephaly and frontal bossing. Skeletal deformities may include a short neck, rounded and sloping shoulders, abnormalities involving scapula (Sprengel anomaly) and the clavicle (pseudoarthrosis), broad first toes, short first fingers, brachydactyly, clinodactyly, gaps between the first and second toes, long fingers and toes, syndactyly, polydactyly, camptodactyly, scoliosis and hyper extensible joints. The following facial abnormalities may be seen: Microcephaly, facial asymmetry, downslanting palpebral fissures, dry, curly and frizzy hair, widows peak, low posterior hairline, webbed neck, highly arched palate, cleft lip and palate, malocclusion, abnormal auditory ossicles, and sensorineural deafness. Diaphragmatic hernia, pectus excavatum, shawl scrotum, hypospadias and agenesis of the corpus callosum occur occasionally.[3],[4],[5],[6]

It is a very peculiar X-linked syndrome because females are affected whereas male carriers show no or only mild abnormalities.[1],[2] Very often the condition is not diagnosed in males unless they are a member of the family known to have the condition or the father of a daughter with the condition. The risk that an affected female will pass the disease on her daughter or son is 50%. An affected male will pass the disease on to all of his daughters but none of his sons.[3]

The syndrome is mostly caused by mutations in the ephrin-B1 (EFNB-1) gene. This gene encodes EFNB-1 protein and maps to Xq13.1.[1],[2] This protein appears to be important for normal development of the frontonasal neural crest, which is a structure in a growing embryo that becomes the face and skull. The absent or mild phenotype in male carriers may be explained by the promiscuity of the EFNB ligand/receptor system. The more severe manifestation in females may be explained by cellular interference that is caused by a combination of EFNB ligand/receptor promiscuity and the consequences of random X inactivation in distinct cellular compartments.[3],[7]

The treatment is always surgical and is based on each patients specific phenotypic presentation.[8] The preferred age for correction of craniosynostosis is between 6 and 9 months of age.[9] Treatment of orbital hypertelorism is delayed until the age of 5-8 years old, after permanent dentition.[8] A bifid nose tip is only treated at the age of 18 years, when the patient's skeleton has fully matured.[8],[10]

Genetic counseling or prenatal screening may be advised if there is a reason to suspect the presence of carrier status in any of the parent.[3],[4] Prenatal screening by ultrasound may be attempted by meticulous searching for hypertelorism or a bifid nasal tip.

We conclude, as genotype-phenotype correlation in CFND is not yet very clear, more information about the phenotypic features are needed and possible diagnostic criteria based on those features need to be laid down to improve diagnosis of new patients.

 
  References Top

1.
Wieland I, Jakubiczka S, Muschke P, Cohen M, Thiele H, Gerlach KL, et al. Mutations of the ephrin-B1 gene cause craniofrontonasal syndrome. Am J Hum Genet 2004;74:1209-15.  Back to cited text no. 1
    
2.
Twigg SR, Kan R, Babbs C, Bochukova EG, Robertson SP, Wall SA, et al. Mutations of ephrin-B1 (EFNB1), a marker of tissue boundary formation, cause craniofrontonasal syndrome. Proc Natl Acad Sci U S A 2004;101:8652-7.  Back to cited text no. 2
    
3.
Available from: http://www.headlines.org.uk/medical_leaflets/HL18_Craniofrontonasal_Syndrome.pdf. [Last accessed on 2014 June 7].  Back to cited text no. 3
    
4.
Zafeiriou DI, Pavlidou EL, Vargìami E. Diverse clinical and genetic aspects of craniofrontonasal syndrome. Pediatr Neurol 2011;44:83-7.  Back to cited text no. 4
    
5.
Grutzner E, Gorlin RJ. Craniofrontonasal dysplasia: Phenotypic expression in females and males and genetic considerations. Oral Surg Oral Med Oral Pathol 1988;65:436-44.  Back to cited text no. 5
    
6.
Vasudevan PC, Twigg SR, Mulliken JB, Cook JA, Quarrell OW, Wilkie AO. Expanding the phenotype of craniofrontonasal syndrome: Two unrelated boys with EFNB1 mutations and congenital diaphragmatic hernia. Eur J Hum Genet 2006;14:884-7.  Back to cited text no. 6
    
7.
Beutler E, Yeh M, Fairbanks VF. The normal human female as a mosaic of X-chromosome activity: Studies using the gene for C-6-PD-deficiency as a marker. Proc Natl Acad Sci U S A 1962;48:9-16.  Back to cited text no. 7
    
8.
Kawamoto HK, Heller JB, Heller MM, Urrego A, Gabbay JS, Wasson KL, et al. Craniofrontonasal dysplasia: A surgical treatment algorithm. Plast Reconstr Surg 2007;120:1943-56.  Back to cited text no. 8
    
9.
Panchal J, Uttchin V. Management of craniosynostosis. Plast Reconstr Surg 2003;111:2032-48.  Back to cited text no. 9
    
10.
van den Elzen ME, Versnel SL, Wolvius EB, van Veelen ML, Vaandrager JM, van der Meulen JC, et al. Long-term results after 40 years experience with treatment of rare facial clefts: Part 2 — Symmetrical median clefts. J Plast Reconstr Aesthet Surg 2011;64:1344-52.  Back to cited text no. 10
    


    Figures

  [Figure 1a], [Figure 1b], [Figure 1c], [Figure 2a], [Figure 2b]



 

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