Acrogeria, Gottron Type

Clinical Features

Gottron (1940) reported a brother and sister, aged 16 and 19 years, whose hands and feet had appeared old since infancy because of thin skin. General physical and mental development were normal. Less severe skin atrophy was present elsewhere. Huttova et al. (1967) also described affected sibs. The disorder is often misdiagnosed as the Ehlers-Danlos syndrome (EDS). Indeed, this may be Ehlers-Danlos syndrome type IV (130050). Some of the features are seen in mandibuloacral dysplasia (248370).

De Groot et al. (1980) defended the existence of acrogeria as an entity distinct from EDS IV. They observed affected mother and son, the first instance of 2 generations being affected and only the second instance of familiality, Gottron's being the first. The mother was the seventh of 10 children in a nonconsanguineous family. Vessels were conspicuous over the trunk. The mother showed elastosis perforans as did the female reported by Gottron and 2 previously reported patients. Small stature and micrognathia were present in several reported patients. Unlike EDS IV, cigarette-paper scars and intestinal catastrophes were not features. De Groot et al. (1980) found reports of 19 cases. Gilkes et al. (1974) introduced the term metageria for the premature aging syndrome that he reported. Greally et al. (1992) suggested the term acrometageria. They reported the case of a boy with aged facies, scoliosis, wrinkled skin of the feet and hands, joint hypermobility, and mental retardation. No abnormality of type III collagen (COL3A1; 120180) was demonstrated.

Blaszczyk et al. (2000) described a 46-year-old mother and her 20-year-old son with presumed acrogeria of the Gottron type. Abnormality of type III collagen was excluded. The appearance of the hands was strikingly that for which acrogeria is an appropriate description. Skin atrophy of the distal limbs had been noted since age 7 in the mother and age 3 in the son. The son had brownish discoloration of the skin of the anterior aspects of the legs with bruising and ulcerations. The striking features illustrated by photographs were beaked nose and conspicuous mandible. Another son, aged 24, was said not to have acrogeria. Jablonska (2001) stated that the beaked nose and jutting chin were not present in the unaffected son.

Rezai-Delui et al. (1999) described a highly consanguineous family from a small village in Iran in which 4 members (3 males and 1 female) in the sixth generation had acrogeria. All 4 patients showed growth deficiency, which began in the first year of life, and bore a striking resemblance to each other, with proportionate short stature, beaked nose, protruding eyes, receding chins, slender extremities, prominent joints, and cutaneous atrophy. All had dystrophic nails and sparse hair, marked delay in onset and completion of the primary dentition, and displaced and missing permanent dentition. Two patients had mildly hypermobile joints in infancy, and 2 patients, aged 5 and 7 years, had various degrees of limitation of movement of the knees, wrists, and elbows. Two of the patients died suddenly at age 30 months and age 3 years. Radiologic features included micrognathia, wide sutures and fontanels, wormian bones, delayed ossification of carpal bones, coxa valga, and avascular necrosis of the femoral head. None of the parents were affected. Maroofian et al. (2018) reported that the 2 other affected patients in this family also died suddenly of unknown cause.

Inheritance

The transmission pattern of Gottron-type acrogeria has suggested autosomal dominant inheritance in some families (e.g., Jansen et al., 2000 and Hadj-Rabia et al., 2014) and autosomal recessive inheritance in others (Rezai-Delui et al., 1999).

Molecular Genetics

In a 43-year-old man with a diagnosis of Gottron-type acrogeria, Jansen et al. (2000) identified a heterozygous mutation in the COL3A1 gene: a G-C transversion in exon 48, resulting in a gly1006-to-arg substitution. However, the article made no mention of vascular imaging in the patient.

In a 36-year-old man with a diagnosis of Gottron-type acrogeria, Hadj-Rabia et al. (2014) excluded mutation in the COL3A1 gene. By screening for mutation in the LMNA gene (150330), they identified a heterozygous transition (c.1771T-A) in exon 11, resulting in a cys591-to-ser substitution. The patient reported that his father was affected, but his DNA was not available for study.

Maroofian et al. (2018) studied the consanguineous Iranian family in which 4 members were described by Rezai-Delui et al. (1999) as having an autosomal recessive form of Gottron-type acrogeria. Because no biologic samples from the 4 deceased patients were available, they directly sequenced the LMNA and ZMPSTE24 (606480) genes in the parents and 1 healthy sib of 2 affected sibs. No mutations were found in the LMNA gene, but the parents and the proband's unaffected brother were heterozygous for a 3-bp deletion (c.1052_1054delTTA) in exon 8 of the ZMPSTE24 gene, predicted to result in deletion of an isoleucine (Ile351del) in the highly conserved transmembrane helix VI region. The variant was not found in the 1000 Genomes Project, dbSNP, Exome Variant Server, or the Greater Middle East Variome Project databases or in an in-house ethnically matched database. It was found in 1 of 246,128 alleles in the gnomAD database. The authors noted that in the absence of DNA or cells derived from any of the patients, the link between this novel mutation, in its homozygous state, and the Gottron acrogeria phenotype cannot be established confidently in this family.