Paula and Bobby
Parents of Lillie
Arthrogryposis, Distal, Type 2A (DA2A)
What is Arthrogryposis, Distal, Type 2A (DA2A)?
Arthrogryposis, Distal, Type 2A as it is also known, is part of a group of disorders that present with multiple congenital contractures, which make it difficult for individuals to move specific parts of the body.
To date there have been just 100 cases diagnosed since it was first identified in 1938.
This syndrome is also known as:
Cranio-carpo-tarsal dystrophy; Craniocarpotarsal Dysplasia; Craniocarpotarsal Dystrophy DA2A; Freeman-sheldon Syndrome; Fss FSS Whistling face syndrome; Whistling Face-windmill; Vane Hand Syndrome
What gene changes cause Arthrogryposis, Distal, Type 2A (DA2A)?
Mutations to the MYH3 gene on chromosome 17 are responsible for the syndrome. The condition is largely the result of de novo mutations on the gene, but it has also been found to have been inherited in an autosomal dominant pattern.
Very rarely research suggests that the condition is inherited in an autosomal recessive pattern which seems to cause a more serious form of the syndrome, with more significant neurological disorders and more severe intellectual disability. Further research suggests it may also be inherited as an x-linked condition in very rare instances.
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.
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 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.
What are the main symptoms of Arthrogryposis, Distal, Type 2A (DA2A)?
Defects and abnormalities in the hands, feet, head and face are some of the main symptoms of the syndrome.
Facial features of the syndrome include a high palate, a very small tongue, widely spaced and deep set eyes, and crossed eyes.
Other issues, particularly in infancy include feeding difficulties related to swallowing, frequent vomiting and a failure to thrive.
Possible clinical traits/features:
Strabismus, Microcephaly, Rocker bottom foot, Talipes equinovarus, Chin with H-shaped crease, Flat face, Camptodactyly, Shoulder flexion contracture, Spina bifida occulta, Dimple chin, Prominent forehead, Ptosis, Telecanthus, Narrow mouth, Short nose, Long philtrum, Malignant hyperthermia, Mandibular prognathia, Mask-like facies, Joint contracture of the hand, Kyphoscoliosis, Knee flexion contracture, Inguinal hernia, Intellectual disability, Muscle weakness, Flexion contracture of toe, Underdeveloped nasal alae, Hypoplasia of the brainstem, Postnatal growth retardation, Hip contracture, High palate, Abnormality of the skin, Nasal speech, Cryptorchidism, Arthrogryposis multiplex congenita, Malar flattening, Epicanthus, Deeply set eye, Hip dislocation, Abnormal auditory evoked potentials, Small for gestational age, Failure to thrive, Fever, Autosomal dominant inheritance, Autosomal recessive inheritance, Whistling appearance, Short neck, Ulnar deviation of the hand or of fingers of the hand, Seizure, Adducted
How does someone get tested for Arthrogryposis, Distal, Type 2A (DA2A)?
The initial testing for Freeman-Sheldon 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 Arthrogryposis, Distal, Type 2A
Microstomia seems to occur in most cases. In addition the mouth is puckered with an H-shaped defect on the chin, giving the appearance of a whistling face. The nose is small, the philtrum long and the eyes are deepset. The other cardinal feature is camptodactyly with ulnar deviation of the digits. The feet are similarly involved, but might only present clinically with a vertical talus. Joint contractures elsewhere and a scoliosis are additional features. Intelligence is usually normal. Some children have full cheeks and some supraorbital fullness. In general the muscles are thin and there is evidence of an underlying myopathy.
There is probably an autosomal recessive form, which is difficult to distinguish, but which may be more severe. Carakushansky et al., (2004) reported sibs with the condition, who appear to have the usual phenotype. Zampino et al., (1996) reported a case with a severe form of the condition who had cerebellar and brainstem atrophy and absent auditory brainstem responses. The child died at five months of respiratory failure. Schrander-Stumpel et al., (1991) described three unrelated infants with features overlapping with Marden-Walker syndrome, Freeman-Sheldon syndrome and Illum (1988) (q.v.), but with no detailed neuropathology. They had distal arthrogryposis, severe developmental retardation, facial anomalies as seen in this syndrome (""whistling face""), and Pierre Robin sequence. It is also difficult to classify the infant reported by Sackey et al., (1995). This boy died at the age of 17 months with camptodactyly, talipes, inguinal hernia, joint contractures, cerebral atrophy, and seizures. Photographs show puffiness of the hands and feet and pale optic discs were noted so this infant may have had a variant of PEHO syndrome.
Hennekam et al., (1992) reported a female infant with some features of Freeman-Sheldon syndrome but with developmental delay. The mother had total alopecia and a maternal autoimmune defect was postulated as a cause of the fetal abnormalities. Galliani and Matt (1993) reported a 10 1/2-week male with this condition who presented with laryngomalacia. Striated muscle cells within peripheral nerve trunks were found on histological examination of the arytenoid submucosa.
Krakowiak et al., (1998) reported a large family with distal arthrogryposis, but with a distinctive facial appearance that they felt resembled Freeman-Sheldon syndrome. This was characterised by a triangular face, prominent nasolabial folds, downslanting palpebral fissures, a small mouth, and a prominent chin. Occasional cases can have normal limbs (Toydemir et al., 1999: Gorlin 2000).
The gene for this condition was mapped to 11p15.5 (Krakowiak et al., 1997). There is an excellent review by Stevenson et al., (2006). Mutations in the embryonic myosin heavy chain gene (MYH3) at 17p13 have now been shown to cause the syndrome (Toydemir et al., 2006).
Ali et al. (2017) described a male patient with Freeman-Sheldon syndrome and a missense mutation in the MYH3 gene. Clinical characteristics included multiple contractures with camptodactyly of both hands, right congenital vertical talus, left talipes equinovarus, and downward curved penis. Dysmorphic features were ocular hypertelorism, squinted eyes, wide and flat nasal bridge, microstomia, puckered lips, micrognathia, and low-set ears.
* This information is courtesy of the L M D.
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