Cutis Laxa, Autosomal Dominant 3

A number sign (#) is used with this entry because of evidence that autosomal dominant cutis laxa-3 (ADCL3) is caused by heterozygous mutation in the ALDH18A1 gene (138250) on chromosome 10q24.

Homozygous mutation in ALDH18A1 can cause autosomal recessive cutis laxa type IIIA (ARCL3A; 219150).

Description

Autosomal dominant cutis laxa-3 is characterized by thin skin with visible veins and wrinkles, cataract or corneal clouding, clenched fingers, pre- and postnatal growth retardation, and moderate intellectual disability. In addition, patients exhibit a combination of muscular hypotonia with brisk muscle reflexes (Fischer-Zirnsak et al., 2015).

For a general phenotypic description and discussion of genetic heterogeneity of autosomal dominant cutis laxa, see ARCL1 (123700).

Clinical Features

Jukkola et al. (1998) reported a Finnish boy with a lethal connective tissue disorder characterized by extreme hypermobility of the joints, lax skin, cataracts, severe growth retardation, and insufficient production of type I and type II procollagens. Prenatal evaluation revealed oligohydramnios and poor fetal growth. At birth he was small for dates and had thin and translucent skin, increased visibility of superficial veins, reduced subcutaneous fat tissue, bilateral inguinal hernia, extremely loose joints with dislocation of the left hip, and left pes calcaneovalgus as well as right clubfoot. He had a large head with frontal bossing, and fontanels and cranial sutures were wide open. Jukkola et al. (1998) commented that the child's facial appearance bore a close resemblance to patients with geroderma osteodysplasticum (231070). Bilateral cataracts were present, but fundi were normal. He held his wrists in volar flexion, with adducted thumbs. X-rays showed asymmetric skull with anteroposterior flattening, thin cranial bones, and multiple wormian bones. The right side of the atlas was attached to the base of the skull, causing mild scoliosis. Abdominal ultrasound revealed agenesis of the right kidney. The patient died at age 3 years from progressive spinal stenosis due to failure of connective tissue structures joining the skull and spine. At autopsy, the aortic valve was noted to be thin, translucent, and insufficient, despite a normal echocardiogram a few days previously.

Fischer-Zirnsak et al. (2015) studied 8 unrelated children, including the Finnish boy reported by Jukkola et al. (1998), who exhibited a progeroid de Barsy-like cutis laxa phenotype. Their family histories were negative for cutis laxa or other connective tissue disorders, miscarriage, early abortion, or consanguinity. All affected individuals showed characteristic facies involving a triangular face, a prominent and broad forehead, cataracts or corneal clouding, and prominent low-set ears. In addition, all probands presented with prenatal growth retardation, which continued postnatally in 7 of them. All 8 had lax, thin skin with visible veins as well as joint hyperlaxity; 6 presented with cataracts, 5 with adducted thumbs, and 4 with cranial vessel tortuosity. Psychomotor development was delayed in all probands, and 1 was diagnosed with an autism spectrum disorder. At least 3 probands had brisk peripheral reflexes, and 2 exhibited foramen magnum stenosis. Age at last evaluation ranged from 2 to 13 years.

Molecular Genetics

In 8 unrelated children with a progeroid de Barsy-like cutis laxa phenotype, who were negative for mutation in the PYCR1 gene (179035), Fischer-Zirnsak et al. (2015) identified heterozygosity for 3 different missense mutations in the ALDH18A1 gene, all involving the highly conserved arg138 residue (R138W, R138Q, and R138L; 138250.0014-138250.0016). In all 6 families for which parental DNA was available, the mutation was shown to have arisen de novo. Studies in patient fibroblasts demonstrated that the R138W mutant protein had an altered submitochondrial distribution and reduced enzymatic activity compared to wildtype.