Cutis Laxa, Autosomal Recessive, Type Iid

A number sign (#) is used with this entry because of evidence that autosomal recessive cutis laxa type IID (ARCL2D) is caused by homozygous mutation in the ATP6V1A gene (607027) on chromosome 3q13.

Description

Autosomal recessive cutis laxa type IID (ARCL2D) is characterized by generalized skin wrinkling with sparse subcutaneous fat and dysmorphic progeroid facial features. Most patients also exhibit severe hypotonia as well as cardiovascular and neurologic involvement (summary by Van Damme et al., 2017).

For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive cutis laxa, see ARCL1A (219100).

Clinical Features

Van Asbeck et al. (2014) reported a German boy who had an apparently novel form of cutis laxa, with abnormal fat distribution, cardiomyopathy, and cataract. He was born with hypotonia, generalized cutis laxa, abnormal fat distribution in the genital region and hips, and dysmorphic features including receding forehead, triangular face, prominent ears, loose supraorbital skin, small palpebral fissures, bilateral cataract, strabismus, and retrognathia. In the first year of life, he developed failure to thrive and his growth curve fell from the 97th centile at birth to the 25th centile by age 3 years; at age 14 years, he exhibited a marfanoid habitus. At age 8 months, he was diagnosed with cardiomyopathy; echocardiography at age 4 years showed mild hypertrophy of the interventricular septum with normal ejection fraction, and electrocardiogram showed long QT interval with incomplete right bundle branch block. Microcephaly became apparent at 1 year of age, and brain MRI revealed enlarged ventricles with white matter involvement and periventricular parietooccipital gliosis. He had a severe speech delay as well as motor delay, and did not walk independently until 5 years of age. The sagging skin improved, and by age 8 months was most prominent at the neck and axillary regions. The authors noted that this patient showed clinical features overlapping those of ARCL2A (219200), including abnormal fat distribution, generalized cutis laxa improving over time, late-closing fontanel, microcephaly, failure to thrive, and an initially abnormal ApoC-III (APOC3; 107720) glycosylation pattern that normalized by age 6 years.

Van Damme et al. (2017) studied 3 unrelated patients with cutis laxa, including a German boy originally described by Van Asbeck et al. (2014). All affected individuals exhibited generalized skin wrinkling with sparse subcutaneous fat and had dysmorphic progeroid facial features, including a 'mask-like' triangular face, short forehead, hypertelorism, entropion, low-set ears with misfolded helices, beaked nose with broad nasal base and narrow nostrils, and a short pointed chin. Additional features in a Pakistani male infant included severe bilateral club feet, dislocation of the hips, flexion contractures of all joints, and camptodactyly; he also had micropenis, cryptorchidism, and right inguinal hernia. Echocardiography revealed a small atrial septal defect with tortuous aortic arch, and his neonatal course was complicated by progressive cardiac failure, pneumonia, and sepsis. The patient died after a long period of intensive treatment. The third patient was a Turkish male infant with cutis laxa, who also had a ventricular septal defect. All 3 patients exhibited neurologic features, including severe speech delay in the German boy as well as a generalized tonic-clonic seizure at age 14 years; generalized and complex partial seizures in the Pakistani infant, in whom MRI was suggestive of polymicrogyria with a thin corpus callosum; and an anatomic variant of the cavum septum pellucidum in the Turkish infant. In all affected individuals, mass spectrometry of intact transferrin showed glycosylation abnormalities, with a consistent increase in the abundance of the transferrin glycoform corresponding to the loss of 1 sialic acid.

Molecular Genetics

In 3 probands with cutis laxa, including a 15-year-old German boy originally described by Van Asbeck et al. (2014), Van Damme et al. (2017) performed whole-exome sequencing and identified homozygous missense mutations in the ATP6V1A gene: the German boy was homozygous for an R338C substitution (607027.0001), and the Pakistani and Turkish male infants were both homozygous for a G72D substitution (607027.0002). The mutations segregated with disease in each family, and neither was found in in-house exome cohorts or in the ExAC database. Complexome profiling in cultured fibroblasts showed a markedly reduced abundance of the assembled V1 domain and of the complete membrane-bound V1V0 complex, and the mutations were also shown to affect protein glycosylation. Van Damme et al. (2017) proposed including this form of cutis laxa in the current classification of congenital disorders of glycosylation (CDG), as 'ATP6V1A-related CDG.'

Exclusion Studies

In a 13-year-old German boy with cutis laxa, Van Asbeck et al. (2014) analyzed 12 cutis laxa- and progeroid-associated genes and did not find any causative mutations.