Autosomal recessive cutis laxa syndrome revisited

Abstract

The clinical spectrum of the autosomal recessive cutis laxa syndromes is highly heterogeneous with respect to organ involvement and severity. One of the major diagnostic criteria is to detect abnormal elastin fibers. In several other clinically similar autosomal recessive syndromes, however, the classic histological anomalies are absent, and the definite diagnosis remains uncertain. In cutis laxa patients mutations have been demonstrated in elastin or fibulin genes, but in the majority of patients the underlying genetic etiology remains unknown. Recently, we found mutations in the ATP6V0A2 gene in families with autosomal recessive cutis laxa. This genetic defect is associated with abnormal glycosylation leading to a distinct combined disorder of the biosynthesis of N- and O-linked glycans. Interestingly, similar mutations have been found in patients with wrinkly skin syndrome, without the presence of severe skin symptoms of elastin deficiency. These findings suggest that the cutis laxa and wrinkly skin syndromes are phenotypic variants of the same disorder. Interestingly many phenotypically similar patients carry no mutations in the ATP6V0A2 gene. The variable presence of protein glycosylation abnormalities in the diverse clinical forms of the wrinkled skin-cutis laxa syndrome spectrum necessitates revisiting the diagnostic criteria to be able to offer adequate prognosis assessment and counseling. This paper aims at describing the spectrum of clinical features of the various forms of autosomal recessive cutis laxa syndromes. Based on the recently unraveled novel genetic entity we also review the genetic aspects in cutis laxa syndromes including genotype-phenotype correlations and suggest a practical diagnostic approach.

Figure 1

(a–h) The characteristic facial features (dyscrania due to open fontanel, down-slanting palpebral fissures, posterior-rotated, prominent ears, long philtrum, short, broad nose) of six patients with ARCL II at different ages (a and f) patient 5^* at neonatal and 1 year of age, (b) patient 2^* at 1.5 years, (c and h) patient 1^* at 3 and 13 years of age, (d) patient 9^* at 11 years of age, (e, g and h) patient 6^* at 20 years. (^*3). (i–l) Skin anomalies with abnormal fat distribution and improving cutis laxa in four patients with ARCL II at different ages (i) patient 7^* at 1.5 years of age, (j) patient 6^* at 1 year of age (k) patient 3^* at 5 years of age and (l) patient 8^* at 14 years of age (^*: Patient numbers refer to the paper of Kornak et al).

Figure 2

Central nervous system anomalies on MRI T2-weighed images in two patients demonstrating cobblestone-like brain dysgenesis (a–f) (Patient 9 and 10 in the paper of Kornak et al).

Figure 3

(a) Schematic structure of the V-ATPase complex (based on and adapted from Qi et al³⁹) (b) Gene structure of ATP6V0A2.

Figure 4

(a) Plasma transferrin isofocusing (N-glycosylation screen). (b). Plasma Apolipoprotein C-III isofocusing (mucin type O-glycosylation screen). Characteristic profiles for: CL, cutis laxa patients with the ATP6V0A2 defect; COG7, patients with a defect in subunit-7 of the COG complex; C, controls.

Figure 5

Diagnostic flowchart in inherited cutis laxa (^*Rule out Costello Syndrome in case of clinical suspicion; ^**Dominant cases might phenotypically overlap).