A number sign (#) is used with this entry because of evidence that Adams-Oliver syndrome-4 (AOS4) is caused by homozygous mutation in the EOGT gene (614789) on chromosome 3p14.

Adams-Oliver syndrome (AOS) is a rare congenital disorder characterized by aplasia cutis congenita and terminal transverse limb defects. Additional abnormalities may be present in other organs, e.g., heart, brain, and/or eyes (summary by Shaheen et al., 2013).

For a discussion of genetic heterogeneity of Adams-Oliver syndrome, see AOS1 (100300).

Shaheen et al. (2013) studied 5 affected children from 3 consanguineous Arab families who had Adams-Oliver syndrome. All patients displayed typical features of AOS, including cutis aplasia of the scalp and terminal transverse digit defects of the feet, with hypoplastic or absent nails and variably absent distal phalanges. The probands from 2 families also had cardiac defects, including an atrial and a ventricular septal defect and patent ductus arteriosus that resolved; the 3 affected individuals from the third family had no cardiac defects, and none of the 5 patients exhibited microphthalmia.

Schroder et al. (2019) reported a Turkish father and son with AOS4. The son was born at the 3rd percentile for height and weight and had a parietooccipital scalp defect with a bony defect and herniation of brain. He had corrective surgery at several weeks of age. Clinical examination at 10 years of age showed a hairless scarred area on his scalp, small fingernails and toenails, and small tapered toes. His father had a large area of alopecia on his head and no limb abnormalities. Both patients had normal intellectual development and neither had neurologic deficits or ocular abnormalities. Schroder et al. (2019) also reported a 24-year-old German man who was found at birth to have a large area of cutis aplasia from his occiput to forehead with an underlying bony defect. The cutaneous lesion on his scalp healed by the age of 2 years, but the bony defect remained until he was 17 years of age. At age 24, he had a hairless scarred area on his scalp and mildly hypoplastic terminal phalanges and nails of his index fingers. He had no ocular abnormalities. Head MRI showed a focal thickening of the falx and a Rathke cleft cyst.

In affected members of 3 consanguineous Arab families with Adams-Oliver syndrome in whom no mutation in the DOCK6 gene (614194) was detected, Shaheen et al. (2013) found autozygome overlap on a previously unreported 2,744,933-bp locus at Chr3:66,612,406-69,357,338 (GRCh37). Linkage analysis confirmed the locus, with a single peak that corresponded to the same critical region of homozygosity highlighted by autozygome analysis, yielding a lod score of approximately 3.7.

The transmission pattern of AOS4 in the family reported by Shaheen et al. (2013) was consistent with autosomal recessive inheritance.

In a 5-week-old girl from a consanguineous Arab family with AOS mapping to chromosome 3, Shaheen et al. (2013) performed exome sequencing and identified a homozygous missense mutation in the EOGT gene (W207S; 614789.0001), located within the critical locus. Sanger sequencing confirmed the homozygous mutation in the proband and showed that her unaffected parents were heterozygous carriers of the mutation. Screening of EOGT in 4 affected members from 2 more consanguineous Arab families revealed homozygosity for a 1-bp deletion (614789.0002) and for a missense mutation (R377Q; 614789.0003) that segregated with disease in both families, respectively. None of the variants were found in 230 Saudi exomes, the 1000 Genomes Project, or the NHLBI Exome Variant Server.

In a Turkish boy and his father with AOS4 from a multiconsanguineous family, Schroder et al. (2019) identified a homozygous missense mutation in the EOGT gene (C135Y; 614789.0004). Schroder et al. (2019) also identified a homozygous splicing mutation (614789.0005) in the EOGT gene in a German man with AOS4; the man's parents were heterozygous for the mutation.