Paula and Bobby
Parents of Lillie
Acrofacial Dysostosis 1, Nager Type (AFD1)
What is Acrofacial Dysostosis 1, Nager Type (AFD1)?
This rare disease is a genetic condition, with currently more than 75 cases reported to date.
Symptoms may vary but generally infants born with the condition require assistance with feeding and possible assistance with breathing, related to the specific unique physical features of the condition.
The majority of cases of the syndrome are not inherited, and are the first in a family.
This syndrome is also known as:
Afd; Nager Type Mandibulofacial Dysostosis; Treacher Collins Type; With Limb Anomalies; Nager Acrofacial Dysostosis; Nager Syndrome
What gene change causes Acrofacial Dysostosis 1, Nager Type (AFD1)?
Mutations in the SF3B4 gene are responsible for the syndrome. The majority of cases are de novo mutations, meaning there is no known previous family history or inheritance pattern. But the syndrome has been noted to have been passed on in both an autosomal dominant or recessive way.
In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation which occurs during the reproductive process.
Autosomal recessive inheritance means an affected individual receives one copy of a mutated gene from each of their parents, giving them two copies of a mutated gene. Parents, who carry only one copy of the gene mutation will not generally show any symptoms, but have a 25% chance of passing the copies of the gene mutations onto each of their children.
In the case of autosomal dominant inheritance just one parent is the carrier of the gene mutation, and they have a 50% chance of passing it onto each of their children. Syndromes inherited in an autosomal dominant inheritance are caused by just one copy of the gene mutation.
what are the main symptoms of Acrofacial Dysostosis 1, Nager Type (AFD1)?
Symptoms are known to vary widely amongst individuals with the condition, and even amongst family members with the same diagnosis.
Unique facial characteristics of the syndrome include absent or small thumbs, underdeveloped cheekbones, a smaller lower jaw, an abnormally shaped nose, a wide mouth, absent eyebrows and an absent ear canal which can cause hearing loss. A cleft palate is also not uncommon.
The syndrome does not generally affect an individual’s intellectual ability but speech delay is a symptom of the condition and related to hearing loss.
Bone abnormalities are a common feature also. This tends to affect the forearms and elbows of an individual but can also affect the bones in the legs and feet.
Possible clinical traits/features:
Malar flattening, Limitation of joint mobility, Hip dislocation, Cleft upper lip, Cleft palate, Malformation of the heart and great vessels, Lower eyelid coloboma, Atresia of the external auditory canal, Downslanted palpebral fissures, Conductive hearing impairment, Autosomal dominant inheritance, Phocomelia, Posteriorly rotated ears, Polymicrogyria, Unilateral renal agenesis, Wide mouth, Trismus, Velopharyngeal insufficiency, Retrognathia, Preauricular skin tag, Patent ductus arteriosus, Overlapping toe, Sparse lower eyelashes, Toe syndactyly, Urticaria, Foot oligodactyly, Non-midline cleft lip, Intellectual disability, Low-set ears, Low-set, posteriorly rotated ears, Limited elbow extension, Laryngeal hypoplasia, Abnormal nasal morphology, Micrognathia, Neurological speech impairment, Broad hallux, Aplasia/Hypoplasia of the radius, Aplasia/Hypoplasia of the eyebrow, Aqueductal stenosis, Aplasia/Hypoplasia of the thumb, Aganglionic megacolon, Triphalangeal thumb, Absent thumb, Absent radius
How does someone get tested for Acrofacial Dysostosis 1, Nager Type (AFD1)?
The initial testing for Acrofacial Dysostosis 1, Nager Type (AFD1) 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 Acrofacial Dysostosis 1, Nager Type (AFD1)
This syndrome consists of a form of acrofacial dysostosis resembling Treacher Collins syndrome combined with predominantly radial limb defects. The facial defects include an antimongoloid eye slant, malar and mandibular hypoplasia and small, malformed or low-set ears. The thumbs may be absent or hypoplastic and there may be hypoplasia of the radius with radioulnar synostosis. Thompson et al., (1985) reported a case with tetralogy of Fallot. Fryns et al., (1996) reported an adult with features of the condition who had mild mental handicap. Neurological examination revealed hemiparesis of the left arm and severe spastic diplegia of the lower legs with general hyperreflexia. Conductive hearing loss was noted in 90% of cases (Herrmann et al., 2005). Inheritance is uncertain because there is evidence for both autosomal dominant and recessive inheritance in different families.
Bonthron et al., (1993) reported an affected girl whose maternal grandmother had dysplastic thumbnails, and a maternal aunt had a ""stub thumb"" (brachydactyly type D) as did the maternal greatgrandfather. The authors suggested that these might be minor features of Nager syndrome but this seems highly speculative. Zori et al., (1993) reported an affected female with an apparently balanced X;9 translocation (X;9)(p22.1;q32). The mother was phenotypically normal, but mosaic for this translocation. Waggoner et al., (1999) reported a convincing case with a 1q12-21.3 deletion.
David et al., (1996) reported a child with overlapping features of MURCS association, Nager acrofacial dysostosis and VACTERL association. There was bilateral aplasia of the thumbs, mandibulofacial dysostosis, left pulmonary agenesis, Klippel-Feil anomaly, and vertebral synostoses. Preaxial polydactyly, a VSD and radio-ulnar synostosis were additional features reported by Kavadia et al., (2004).
Differentiation between Nager and Rodriguez syndromes can be difficult (Gana et al., 2013). These authors reported 2 fetuses, one possibly a severe Nager (there was severe clubbing of the feet) and the other more severe, and possibly Rodriguez (with severe lower limb abnormalities).
Scapoli et al., (2003) reported a cases with a spontaneous expression of the common fragile site at 3p14. Dimitrov et al., (2005) express the opinion that the different acrofacial dysostoses represent a spectrum of possibly, a single condition. In support of this they report patients with overlapping features.
41 individuals from 35 families were investigated by Bernier et al., (2012). Twenty (57%) of the families were found to have a heterozygous mutation in SF3B4, a component of the U2 pre-mRNAspliceosome complex
Nine out of 14 families looked at by Petit et al., (2014) had SF3B4 mutations. - these were heterozygous mutations.
Cassina et al. (2016) described three related patients with Nager syndrome and a novel synonymous mutation in the SF3B4 gene. Patient 1, a three year old boy, had facial anomalies, speech delay (due to severely limited mandible movements), floating left thumb, type II hypoplasia of the right thumb and limited forearm pronation–supination. Facial features included severe down-slanting palpebral fissures, sparse lower eyelashes, micrognathia (prenatally diagnosed), submucous cleft palate, severe microretrognathia and malar hypoplasia. Audiometric and TC evaluations revealed a moderate bilateral conductive hearing loss with mild stenosis of the external auditory canals and bilateral dysplasia of the middle ear. The mother and grandmother of patient 1 had milder features which included asymmetric face, down-slanting palpebral fissures, microretrognathia and type II hypoplasia of the left thumb. The grandmother was also born with unspecified mandible anomalies and cleft palate.
* This information is courtesy of the L M D.
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