What is Acrogeria²?

Acrogeria² is a rare disease. It is also known as EDS IV.

This condition has always been referred to in the older literature as acrogeria, but more recently it has been included under EDS IV. The manifestations are known to be heterogeneous, although a defect of type III collagen is a common factor. There are severe autosomal recessive and milder recessive and dominant forms. Apart from a tendency to arterial rupture there can be rupture of other internal organs such as the bowel (Collins et al., 1999) and gravid uterus. There are characteristic facial features in some cases consisting of premature ageing because of thin skin, a pinched nose, prominent eyes and a thin, drawn appearance. The skin of the hands and feet is atrophic with prominent tortuous veins. Acro-osteolysis and Raynaud phenomenon may occur. The skin may not be hyperelastic and joint hypermobility can be minimal and limited to the small joints of the hands and feet. Inguinal hernia, keratoconus, periodontal disease and varicose veins may occur.
Death can occur in the second or third decade of life due to aortic rupture, or sometimes earlier due to rupture of other arteries or internal organs. Palmeri et al., (2003) reported a mutation proven family where, apart from acrogeric features, there was also a neurological presentation including chronic muscle pain and cramps, Achilles tendon retraction, finger flexion contractures, ischemic strokes and seizures.Nishiyama et al., (2001) reported a family where myocardial infarctions occurred between the age of 25 and 60 years in the absence of coronary stenosis. A point mutation in the COL3A1 gene was demonstrated. Other features were pneumothorax, mediastinal emphysema and splenic artery rupture. Wunderlich et al., (2005) reported a case with severe aortic regurgitation and Lipinski et al., (2009) a case with deep vein thrombosis due to compression by large posterior tibial artery pseudoaneurism. A Dandy-Walker variant malformation has also been recorded (Notaridis et al., 2006). Keloids and amniotic band constrictions have been reported (Burk et al., 2007).
Palmeri et al., (2003) reported a family where, apart from acrogeric features, there was also a neurological presentation including chronic muscle pain and cramps, Achilles tendon retraction, finger flexion contractures, ischemic strokes and seizures. Premature loss of teeth hasalso been reported (Badauy et al., 2007).
Note the association with some bleeding disorders (Umekoji et al., 2008, Kaliyadan and Namboothiri, 2009)
Pepin et al., (2001) carried out an extensive review of 220 biochemically proven cases and 199 affected relatives with EDS IV. COL3A mutations were found in 135 index patients, but did these not correlate with clinical features. 25% of index patients had a first complication (usually bowel or arterial rupture) by the age of 20 years and more than 80% had had at least one complication by the age of 40 years. The nature of the first complication (bowel or arterial) did not seem to correlate with the nature of a second. The median survival of the entire cohort was 48 years, with the cause of death usually being arterial rupture, mainly of thoracic or abdominal vessels. About 10% of deaths resulted from central nervous system haemorrhage. Intracranial aneurysms (berry aneurysms) may also occur. North et al., (1995) reviewed the records of 202 individuals and found that 19 had had cerebrovascular complications. The average age of presentation of these complications was 28.3 years (range 17 to 48 years). The authors recommend non-invasive procedures such as Doppler and magnetic resonance angiography and suggest that anticoagulant therapy should be used with caution. Dowton et al., (1996) reported a case with respiratory problems (haemoptysis, haemo-pneumothorax and cavitary lesions in both lungs). They review the respiratory complications in this disorder. Hamel et al., (1998) stress the phenotypic variability with cases showing features of EDS type II, III, IV. There is no correlation between the type of collagen III abnormality and the clinical phenotype. The family reported as an example of acrogeria by Rezai-Delui et al., (1999) where four individuals from three inbred sibships were affected, probably had mandibulo-acral dysplasia (qv).
Nuytinck et al., (1994) review the mutational changes in the type III collagen gene in this condition. They point out that most mutations map to the extreme carboxyl-terminal end of the collagen type III chain (Kontusaari et al., 1992; Narcisi et al., 1993; Richards et al., 1993). Smith et al., (1997) also reviewed phenotype-genotype correlations. Pope et al., (1996) attempted further genotype-phenotype correlation in cases with COL3A1 mutations, most of which were heterozygous. Schwarze et al., (1997) presented data suggesting that splice-site mutations were common. Schwarze et al., (2001) reported four cases with mutations resulting in a null allele, which nevertheless caused a phenotype similar to classical EDS type IV. Phenotypes range from acrogeria to a normal physical appearance with tendency to arterial rupture. Beighton et al., (1998) provide an up to date classification.
Kroes et al., (2003) reported a mother and son with Ehlers-Danlos syndrome (EDS) type IV and, in the mother, amniotic band-like constrictions on one hand, a unilateral clubfoot, and macrocephaly caused by normal-pressure hydrocephaly and, in the son, an esophageal atresia and hydrocephaly. Protein analysis of collagen III in cultured fibroblasts of the mother showed no abnormalities. However, DNA analysis of the COL3A1 gene revealed a pathogenic mutation (388G-->T) in both the mother and the son.

NB: for those with this clinical picture, but normal type III collagen, see under Loeys-Dietz type II.

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* This information is courtesy of the L M D.

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What gene changes cause Acrogeria²?

The syndrome is inherited in the following inheritance pattern/s:

Autosomal Recessive - 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.

Autosomal Dominant - 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.

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 that occurs during the reproductive process.

The syndrome can be caused by mutations in the following gene/s location/s:

What are the main symptoms of Acrogeria²?

The typical symptoms of the syndrome are:

How does someone get tested for Acrogeria²?

The initial testing for Acrogeria² can begin with facial genetic analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the type of genetic testing needed. 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.

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