Paula and Bobby
Parents of Lillie
Acromelic Frontonasal Dysostosis (AFND)
What is Acromelic Frontonasal Dysostosis (AFND)?
This rare disease is a rare subtype of frontal dysostosis syndrome which also presents with limb abnormalities and central nervous system malformations in affected individuals.
It occurs in less than 1 in 1 million live births.
Abnormalities affecting the digits, as well as unique facial features are common with the syndrome.
This syndrome is also known as:
Acromelic frontonasal "dysplasia"
What gene changes cause Acromelic Frontonasal Dysostosis (AFND)?
Mutations in the ZSWIM6 gene are believed to cause the syndrome although research into its exact causes are ongoing. The condition is believed to be inherited in an autosomal dominant pattern.
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 Acromelic Frontonasal Dysostosis (AFND)?
Preaxial polydactyly, or extra digits on the foot closest to the big toes is one major defining feature of the syndrome. As are abnormal toenails.
Facial characteristics of the syndrome include an abnormal area between the eyebrows, clefting of the nose and nasal tip, a broader than average nasal tip, wide-set eyes, a large fontanelle, with a short and broad skull, club feet and a cleft palate.
Possible clinical traits/features:
Intellectual disability, Meningocele, Midline defect of the nose, Myopia, Cleft upper lip, Cryptorchidism, Large sella turcica, Encephalocele, Ventriculomegaly, Agenesis of corpus callosum, Hypoplasia of the corpus callosum, Hypertelorism, Glaucoma, U-Shaped upper lip vermilion, Vertical clivus, Bifid nose, Preaxial polydactyly, Retrocerebellar cyst, Telecanthus, Ptosis, Hypopituitarism, Talipes equinovarus, Onychogryposis, Autosomal dominant inheritance, Seizure, Syndactyly, Choroid plexus cyst, Cleft palate, Brachycephaly, Abnormality of the nasal alae, Broad nasal tip
How does someone get tested for Acromelic Frontonasal Dysostosis (AFND)?
The initial testing for Acromelic Frontonasal Dysostosis 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 Acromelic Frontonasal Dysostosis
Acromesomelic dysplasia, type Maroteaux (AMDM) is a rare autosomal recessive skeletal dysplasia which belongs to the group of acromesomelic dysplasias (Maroteaux et al., 1971; Langer and Garrett, 1980). AMDM is characterized by severe dwarfism with disproportionate shortening of the extremities and spine, predominantly affecting the middle and distal segments of limbs (Langer and Garrett, 1980; Saadullah et al., 2012). Birth lengths and radiographs are normal in AMDM newborns, but skeletal growth is decelerated after birth due to abnormal endochondral ossification and results in severe short stature (Langer and Garrett, 1980; Borrelli et al., 1983; Saadullah et al., 2012).
The short stature might be noted at birth but mostly becomes obvious during the first year of life. The forearms are bowed and the fingers and toes are very short. The head is relatively large with frontal bossing. The radial head might be dislocated. Eventual stature is below the 3rd centile. Delayed gonadal function has been reported in some patients and very occasionally corneal ulcers have occurred. Radiologically there are short and broad proximal and middle phalanges, cone shaped epiphyses and invaginated metaphyses. The forearm bones are shorter than the humerus. The vertebral bodies have a central anterior protrusion. Many cases appear to be autosomal recessive but Ohba et al. (1989) reported an affected father and son, suggesting possible autosomal dominant inheritance. Minty and Hall (1993) reported a brother and sister with the condition who both had hypomagnesaemia. The brother also had hypocalcaemia that responded to oral calcium supplements.
Ferraz et al., (1997) reported an affected mother and son with what they felt was a variant form of the condition. The radii were curved and there was unusual slight angulation of the distal ulnar in the mother. The hands were short with marked shortening of the second and fifth fingers.
A good review of the genetics of the condition is provided. Kant et al., (1998) mapped the gene to 9p13-9q12. Faivre et al., (2000) reported linkage of the gene to 9p13-q12 in four consanguineous families, but exclusion of linkage in a fifth family with a mild form of the disease. Ianakiev et al., (2000) also mapped the gene to the pericentromeric region of chromosome 9 in a families from the isolated islands of St Helena.
No organ systems are affected in AMDM patients other than the skeletal system (Bartels et al., 2004; Pagel-Langenickel et al., 2007). X-rays show short, broad fingers, square, flat feet, and shortening of the long bones (particularly the forearms). The radius is bowed, the ulna is shorter than the radius, and its distal end is occasionally hypoplastic. The skull is dolichocephalic and a shortness of the trunk, with decreased vertebral height and narrowing of the lumbar interpedicular distances, is consistently observed. The facial appearance and intelligence are normal (Langer and Garrett, 1980; Faivre et al., 2000).
Compound heterozygous or homozygous mutations of NPR2 have been found to be responsible for AMDM (Bartels et al., 2004; Saadullah et al., 2012). According to Wang et al. (2015), 29 functional sequence variants associated with AMDM in the NPR2 gene had been reported by 2015 (Bartels et al., 2004; Hachiya et al., 2007; Castro-Feijóo et al., 2012; Khan et al., 2012).
Wang et al. (2016) presented three additional individuals with the AMDM phenotype caused by compound heterozygous or homozygous loss-of-function mutations in the NPR2 gene. All of them had short stature. One individual had elbow stiffness. Their intelligence and cognitive development were normal. The following features were observed: markedly short upper and lower extremities, brachydactyly, macrodactyly of the great toes and relatively tiny toes, radial head dislocation and flexion contracture of both elbow joints. Radiographs revealed mesomelic shortening, metatarsal and phalanges of the big toes longer than those of other toes, cone-shaped phalangeal epiphyses, bilateral dysplastic acetabula, platyspondyly of thoracolumbar spine with wedging of vertebral bodies posteriorly and spinal canal stenosis, and widening of the metaphyses in the distal femur and proximal tibia.
* This information is courtesy of the L M D.
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