A Novel Elastin Gene Mutation in a Vietnamese Patient with Cutis Laxa

Abstract

We report a 3-year-old girl from Vietnam with severe congenital cutis laxa, no cardiovascular, pulmonary, neurological or visceral involvement and no family history of cutis laxa. Mutational analysis of the elastin (ELN) gene identified heterozygosity for a previously unreported, de novo c.2184delT mutation in exon 30, not present in either parent.

Cutis laxa comprises a group of conditions characterized by loose, inelastic, redundant and wrinkled skin, caused by mutations in a group of genes, crucial to the genesis of elastic fibers (1-3) (Table 1).

Table 1. Types of inherited cutis laxa and characteristics relevant to this case.

Disorder*	Distinguishing Clinical Features	Gene
ADCL	Pulmonary and cardiovascular manifestations absent, milder or later onset	ELN
ARCL1A	Supravalvular aortic stenosis, lethal developmental emphysema	FBLN5
ARCL1B	Arterial tortuosity, lethal pulmonary hypertension, bone fragility	FBLN4
		EFEMP2
ARCL1C Urban-Rifkin-Davis syndrome	Severe gastrointestinal and urinary malformations, lethal developmental emphysema mild cardiovascular involvement	LTBP4
ARCL2A	Growth and developmental delay, abnormal glycosylation of serum proteins	ATP6V0A2
ARCL2B	Growth and developmental delay, triangular face, normal glycosylation	PYCR1
XLCL	Occipital exostoses, pili torti	ATP7A
ARCL3A DeBarsy syndrome	Growth and developmental delay, corneal clouding, athetoid movements	ALDH18A1
Geroderma osteodysplasticum	Bone fragility, short stature	GORAB
Macrocephaly alopecia cutis laxa scoliosis syndrome	Macrocephaly, alopecia, scoliosis	RIN2

^*ADCL, autosomal dominant cutis laxa; ARCL, autosomal recessive cutis laxa; XLCL, X-linked cutis laxa;

A 3-year-old Vietnamese female from the Mekong River Delta area was initially diagnosed clinically with progeria syndrome due to her markedly aged physical appearance. Neither her parents nor her two older siblings were affected. Her mother noticed lax skin at the age of 4 months, with no history of antecedent infections or inflammatory conditions.

At the age of 2 years, the proband developed an inguinal hernia, which was repaired 1 month prior to evaluation at our facility. She exhibited age-appropriate development. On physical examination no cardiovascular, respiratory, intra-abdominal, or neurologic deficits were detected. There was no hair loss. She had mild frontal bossing, a long philtrum, prominent nasolabial folds, and fine wrinkles across her forehead. Deep skin wrinkling was observed on her body, with multiple marked skin folds across her chest, abdomen, back, and extremities. On her torso and lower extremities the skin folds were especially excessive and the skin lacked elastic rebound (Fig. 1). Total body anterior-posterior X-ray study and abdominal-thoracic cavity ultrasound were performed, and there were no emphysematous changes, aortic structural deformities or diaphragmatic abnormalities.

Figure 1.

Generalized skin laxity and wrinkling in the proband.

Cutis laxa was strongly suspected. Based on the absence of bone fragility, alopecia, and lipodystrophy, the diagnosis of progeria was excluded. The absence of severe cardiovascular or pulmonary manifestations made autosomal recessive cutis laxa type 1 unlikely, and the lack of growth and developmental delay excluded autosomal recessive cutis laxa types 2 and 3 as well as geroderma osteodysplasticum. Her gender made X-linked cutis laxa less likely and the lack of macrocephaly, alopecia and scoliosis led to the elimination of macrocephaly-alopecia-cutis laxa-scoliosis syndrome as a possible diagnosis, making autosomal dominant cutis laxa the most likely candidate (Table 1).

Blood samples from the patient, both parents and both siblings were obtained under consent. The last 5 exons of the elastin gene (ELN), where most cutis laxa mutations are localized, were subjected to mutational analysis by direct DNA sequencing. A single nucleotide deletion c.2184delT (ENST00000358929) was found in exon 30 (Fig. 2a). The parents and siblings of the patient were negative for the mutation, indicating that the proband was heterozygous for a de novo mutation. Although this mutation is novel, it is predicted to behave similarly to other previously described frameshift mutations within exon 30 of ELN (4, 7).

Mutations in ELN predominate as the underlying cause of autosomal dominant cutis laxa (4-6). Approximately 30% of patients with ADCL have been found to carry de novo dominant mutations in ELN (1, 2). A recent study reported 5 de novo ELN frame shift mutations in 6 ADCL-affected individuals, including a pair of identical twins (4). These findings highlight the importance of considering de novo dominant mutations in as a cause of disease in individuals with cutis laxa and a lack of family history.