A number sign (#) is used with this entry because of evidence that aplasia cutis congenita with ectrodactyly skeletal syndrome (ACCES) is caused by heterozygous mutation in the UBA2 gene (613295) on chromosome 19q13.

Aplasia cutis congenita and ectrodactyly skeletal syndrome (ACCES) is characterized by highly variable expressivity, even within the same family. Most patients exhibit scalp defects, whereas ectrodactyly is less common; however, more variable and less obvious digital and skeletal anomalies are often present. Early growth deficiency and neurodevelopmental delay are also commonly seen (Schnur et al., 2021).

Marble and Pridjian (2002) described a mother and 2 children with scalp defects, polythelia, developmental delay, and microcephaly, who were later found to have a mutation in the UBA2 gene by Schnur et al. (2021). All 3 were born with areas of scalp aplasia that healed by 8 to 18 months of age. The proband was a 7.5-year-old girl who was developmentally delayed and in special education. Examination showed irregular patchy well-healed scalp defects, and facial dysmorphisms included thin upper lip vermilion, smooth philtrum, eversion of lower lip, micrognathia, thick and laterally protruding ears, medial eyebrow flare, wide nasal bridge, and wide alar base. She also had a single supernumerary nipple. Her 4.5-year-old brother also exhibited developmental delay with learning problems. His facial features were similar to those of his sister, and he also had a supernumerary nipple. Their mother, who left school in the tenth grade due to learning difficulties, had several irregular healed scalp defects and facial features similar to those of her children, as well as supernumerary nipples. The boy and the mother were both microcephalic, with head circumference at or below the 3rd centile. None of the 3 exhibited limb anomalies, and x-rays of the hands and feet were normal.

Marble et al. (2017) reported a 2.5-year-old girl with scalp defects and hip dysplasia, and mutation in the UBA2 gene. She was born with ACC of the posterior scalp. She had delayed motor skills in infancy, but development and cognition were age-appropriate at 2.5 years of age. A hip click was noted at age 18 months, and imaging showed bilateral femuroacetabular dysplasia, marked delay in the formation of the femoral ossific nuclei, and bilateral hip dislocation. Other features included tall forehead, Duane anomaly, strabismus, and bilateral fifth-finger clinodactyly. A healed area of scalp defect at the occiput was observed.

Yamoto et al. (2019) studied a Japanese male proband with bilateral ectrodactyly of the hands and feet and mutation in the UBA2 gene. Limited clinical information was available, but the patient was reported to exhibit bilateral tibial deficiency as well as undermasculinized genitalia.

Wang et al. (2020) reported a 4-year-old boy with ACC and ectrodactyly and mutation in the UBA2 gene. He was born with 2 distinct scalp defects at the midline of the occiput as well as bilateral ectrodactyly of the hands. The feet were not described. Additional findings included tracheoesophageal fistula, horseshoe kidney, and low-lying conus medullaris. Cognitive and motor development were normal. His mother had isolated ACC.

Aerden et al. (2020) described an 8-year-old boy with bilateral ectrodactyly of the feet and mutation in the UBA2 gene. In addition to an overall appearance of ectrodactyly, the proband's feet exhibited complex malformations, including polydactyly, with a supernumerary hypoplastic metatarsal between the first and second metatarsals of the right foot, but absence of the phalanges of the second and third metatarsals, and cutaneous syndactyly of the middle toes bilaterally. Both fifth toes lacked the middle phalanx, and some other toes also lacked the middle and/or terminal phalanx. His hands were normal. He had mild hip instability that resolved spontaneously. Other features included retrognathia, low-set prominent ears, strabismus with hypermetropia, sparse scalp hair, increased hair growth on the back, and a supernumerary nipple. During infancy, he had feeding difficulties and recurrent respiratory infections, associated with failure to thrive. He had delayed speech and learning difficulties; at age 8 years he was diagnosed with autism spectrum disorder and had a total intelligence quotient of 76.

Using GeneDx and GeneMatcher, Schnur et al. (2021) ascertained a cohort of 16 patients in 7 unrelated families with ACC and/or ectrodactyly, and mutation in the UBA2 gene. Family 3 was originally reported by Marble and Pridjian (2002). The cohort exhibited highly variable inter- and intrafamilial expression of dermatologic, skeletal, extremity, neurologic, cardiac, and renal features. In family 1, ACC and ectrodactyly were both present, as well as microcephaly and other skeletal anomalies. Families 2, 6, and 7 exhibited ectrodactyly and other skeletal anomalies without ACC, and 1 of 3 affected brothers in family 2 also had microcephaly. Families 3, 4, and 5 had ACC without ectrodactyly, with microcephaly present in the probands from families 3 and 4, and other skeletal anomalies in the probands from families 4 and 5. Facial dysmorphisms included tall forehead and high anterior hairline, hypertelorism, broad nasal root, and low-set ears. Other ocular and dental anomalies were also noted. Additional features observed were also variable, and included cardiovascular defects such as atrial septal defect, bicuspid aortic valve, and aberrant right subclavian artery, as well as renal anomalies, such as hypoplastic kidneys, hydronephrosis, and reduced renal function. Cryptorchidism was present in 4 of 9 male patients; other genitourinary anomalies included inguinal hernia, hydrocele, and hypospadias.

Schnur et al. (2021) reviewed the clinical characteristics of published patients with UBA2 mutations and found that the most specific aspects of the UBA2-related phenotype were aplasia cutis congenita (ACC) (61%) and ectrodactyly (37%). Early growth deficiency and neurodevelopmental delay were reported in 61% and 80% of affected individuals, respectively. More variable digital and skeletal abnormalities were also present (56%), which were sometimes subtle and included clinodactyly (62%), syndactyly (59%), camptodactyly (57%), and hip abnormality (35%). The most common craniofacial variations were tall forehead/high hairline (76%), downslanting palpebral fissures (47%), hypertelorism (62%), broad nasal root (81%), microcephaly (37%), and micrognathia (53%). In addition, other ectodermal variations (82%), ocular abnormalities (53%), and cardiac (43%), genital (50%, in males), and renal (36%) abnormalities were observed.

The transmission pattern of ACCES syndrome in the families reported by Wang et al. (2020) and Schnur et al. (2021) was consistent with autosomal dominant inheritance.

In a 2.5-year-old girl with scalp defects, high forehead, hip dysplasia, and fifth-finger clinodactyly, Marble et al. (2017) performed whole-exome sequencing (WES) and identified a heterozygous de novo missense mutation in the UBA2 gene (G24V; 613295.0001). The variant occurred at a highly conserved residue and was not found in public variant databases.

In a cohort of 7 Japanese families with syndromic or nonsyndromic split-hand/foot malformation (SHFM; see 183600), who were negative for mutation in known genes or CNVs, Yamoto et al. (2019) performed WES and identified a male proband (family 38) with bilateral ectrodactyly of the hands and feet as well as bilateral tibial deficiency and undermasculinized genitalia who was heterozygous for a de novo 1-bp duplication in the UBA2 gene (c.1324dupT; 613295.0002). The duplication was not found in an in-house database of 218 exomes or in public variant databases.

In a 4-year-old boy with ACC, ectrodactyly, tracheoesophageal fistula, and horseshoe kidney, who was negative for mutation in Adams-Oliver syndrome (see 100300)-related genes, Wang et al. (2020) performed WES and identified heterozygosity for a 1-bp deletion in the UBA2 gene (c.327delT; 613295.0003). His mother, who had isolated ACC, was also heterozygous for the deletion, which was not found in public variant databases.

In an 8-year-old boy with ectrodactyly of the feet, failure to thrive in infancy, and impaired intellectual development, Aerden et al. (2020) performed whole-genome sequencing and identified a de novo heterozygous 1-bp deletion in the UBA2 gene (c.612delA; 613295.0004). The authors reviewed previously published cases with intragenic UBA2 mutations or 19q13.11 microdeletions (see 613026) and noted significant overlap of clinical characteristics. Recurrent features in both groups included developmental delay, aplasia cutis, and hip dysplasia, but ectrodactyly was more specific to patients with intragenic UBA2 mutations.

Using GeneDx and GeneMatcher, Schnur et al. (2021) ascertained 16 patients from 7 families with ACC and/or ectodermal dysplasia, including a family (family 3) that was originally described by Marble and Pridjian (2002), who were heterozygous for frameshift, nonsense, or missense mutations in the UB2 gene (see, e.g., 613295.0005-613295.0008). The authors noted that reported human UBA2 variants were distributed across the gene. Given the highly variable expressivity of the human UBA2 phenotype, even within the same family, they suggested that there were likely other modifiers still to be identified.

By genome sequencing in a cohort of 69 patients with congenital limb malformations and no molecular diagnosis after standard clinical genetic testing, Elsner et al. (2021) identified 2 unrelated male patients (families 12 and 13) with isolated bilateral split-hand malformation and heterozygous frameshift mutations in the UBA2 gene. In family 12, the proband had a de novo 2-bp deletion, whereas in family 13, the proband had a 4-bp deletion that was inherited from his apparently unaffected mother. Limited clinical information was reported. Subsequent Sanger sequencing of the UBA2 gene in 24 unrelated families with ectrodactyly yielded a man (family 14) with unilateral split-hand malformation who was heterozygous for a missense mutation in UBA2 (D50G). His daughter and her son were reported to be affected but were not available for testing. None of the mutations were found in public variant databases.

Using CRISPR/Cas9-targeted deletion, Schnur et al. (2021) generated uba2 knockout zebrafish lines. The survival rate of uba2 -/- zebrafish was significantly lower than wildtype or heterozygotes, with uba2-null zebrafish showing a mortality rate of approximately 50% at 8 dpf and 100% at 12 dpf. Nullizygous fish exhibited a wide phenotypic range, including abnormal pectoral fins that were short and upright-oriented, with collapsed and irregular fin-fold edges. Quantification of defects at 8 dpf showed abnormalities involving the pectoral fin in 100% of mutant fish, swim bladder in 94%, brain size in 91%, tail fin in 25%, and craniofacial structures in 9%. Immunohistochemistry revealed that compared to wildtype controls, uba2-null fish had small heads, reduced midbrain size, and low nuclei cell count with high accumulation of actin signal, implying a decreased proportion of gray to white matter. In addition, uba2 -/- fish had smaller eyes, reduced retinal thickness, retinal laminations, and lens defects. Abnormal craniofacial development included jaw malformations as well as malformed and hypoplastic ventral and dorsal cartilage structures with lack of basihyal and hypohyal development. In summary, the uba2-null fish showed deficient growth, microcephaly, microphthalmia, mandibular hypoplasia, and abnormal fins, and the authors noted that total uba2 function loss recapitulated some tissue-level phenotypes and the variable expression observed in human UBA2-related phenotypes.