Cutis Laxa, Autosomal Recessive, Type Iic

A number sign (#) is used with this entry because of evidence that autosomal recessive cutis laxa type IIC (ARCL2C) is caused by homozygous mutation in the ATP6V1E1 gene (108746) on chromosome 22q11.

Description

Autosomal recessive cutis laxa type IIC (ARCL2C) 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 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

Alazami et al. (2016) reported a consanguineous Saudi family (10DG0257) with 2 affected brothers with a cutis laxa syndrome. The index case presented at 1 year of age with cutis laxa and multiple congenital anomalies. He had been born at term via spontaneous vaginal delivery but spent 2 months in the NICU requiring mechanical ventilation. He had a dysplastic right kidney, bilateral nephrocalcinosis, and pyloric stenosis. Growth parameters were all low, but over time he experienced some catchup growth. Dysmorphic features included a short forehead, blepharophimosis, strabismus, entropion, infraorbital puffiness, maxillary hypoplasia, crowding of the teeth, prominent jaw, saggy cheeks, an abnormal bulge of the upper third of the nasal spine, saddle nose, anteverted nares, long philtrum, midline cleft palate, wrinkly skin of the neck and abdomen, prominent veins, bilateral undescended testicles, micropenis, mild camptodactyly, and overriding toes. He had asthma and frequent pneumonias, and brain MRI revealed mildly dilated ventricular system. He had muscle weakness with positive Gowers sign on neurologic exam. His younger brother presented at 2 years of age. He had been born at 37 weeks of gestation via emergency cesarean section; pregnancy had been uncomplicated until the 8th month, when oligohydramnios, congenital heart disease, and hydronephrosis were diagnosed on ultrasound. Apgar scores and growth parameters at birth were normal, but he was dysmorphic in a way nearly identical to his older brother. He remained in the NICU for 3 weeks, during which echocardiogram revealed small patent foramen ovale, small patent ductus arteriosus, mild tricuspid regurgitation, and increased pulmonary pressure. The left kidney was low lying with grade I hydronephrosis, while the right kidney was in normal position with no hydronephrosis. Head ultrasound revealed mild dilatation of the lateral ventricles. Repeat echocardiogram at 2 years of age showed no patent ductus arteriosus, but a small patent foramen ovale and trace mitral and tricuspid regurgitation. Kidney ultrasound revealed preserved corticomedullary differentiation without hydronephrosis. At 1 year of age he could stand and walk with support, and say mama and baba. At 2 years growth was normal but cutis laxa was obvious with dysmorphic features including blepharophimosis, entropion, hypertelorism, malar hypoplasia, and severe microstomia. He also had overriding toes.

Van Damme et al. (2017) studied 2 Iranian sisters and a Kuwaiti sister and brother with autosomal recessive cutis laxa. 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 the Iranian proband included hypotonia, clenched hands, ulnar deviation of the fingers, congenital hip dysplasia, flexion contractures of the knees, and club feet. Echocardiography revealed severe dilation of the ascending aortic root and moderate biventricular hypertrophy. She died at age 4 months. A second pregnancy in that family was terminated at 21 weeks' gestation due to increased nuchal thickness and cardiac abnormalities on prenatal ultrasound. Autopsy of the female fetus showed right hypoplastic heart syndrome, with a hypoplastic right ventricle, tricuspid valve stenosis, and hypoplastic pulmonary artery. The Kuwaiti sibs both had bilateral pneumothorax shortly after birth, and also exhibited high-arched palate with dental crowding, severe muscle hypoplasia that limited their mobility, scoliosis, and flat feet. Echocardiography at age 10 years in the sister revealed mild dilation of the right ventricle with reduced diastolic compliance, atrial septal defect, mitral valve prolapse, and aortic and tricuspid insufficiency; electrocardiography showed incomplete right bundle branch block. She also had hypermobile joints. Her 9-year-old brother, who had a normal echocardiogram, was born with bilateral cryptorchidism and bilateral inguinal hernias, and also had temporomandibular joint dysfunction with recurrent dislocations.

Molecular Genetics

In 2 brothers from a Saudi family with a cutis laxa syndrome, Alazami et al. (2016) detected homozygosity for an arg212-to-trp mutation in the ATP6V1E1 gene (R212W; 108746.0002).

In affected individuals from an Iranian family and a Kuwaiti family with cutis laxa, Van Damme et al. (2017) performed whole-exome sequencing and identified homozygosity for 2 different missense mutations in the ATP6V1E1 gene: L128P (108746.0001) in the Iranian family, and R212W (108746.0002) in the Kuwaiti family. The mutations segregated with disease in both families, and were not 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 congenital disorder of glycosylation (CDG) classification as 'ATP6V1E1-related CDG.'