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Hearing loss is more common among adults with skeletal dysplasias than children with these conditions, Tunkel et al (p. 1551, DOI: 10.1002/ajmg.a.35373) write.

While hearing loss is frequent in both age groups, little research highlights differences in their hearing screening results. To measure the prevalence of hearing loss and middle ear dysfunction in both age groups and to determine the feasibility of evaluations in a nonclinical setting, the researchers administered hearing screenings to 110 attendees of a national meeting of the Little People of America. These subjects ranged in age from 10 months to 65 years. Of these, 51.8% were children, 65.2% had achondroplasia, 30.4% had one of 11 other diagnoses, and 4.4% were undiagnosed.

Adults were more likely to fail hearing screens than children, with 46.3% of the adults doing so, versus 25.8% of the children. Just over 55% of adults and 25% of children with achondroplasia failed the screening. Majorities of patients with spondyloepiphyseal dysplasia congenita, diastrophic dysplasia, and Morquio had abnormal hearing, while those with hypochondroplasia, pseudoachondroplasia, andmicrocephalic osteodysplastic primordial dwarfism had normal hearing.

Abnormal tympanometry is associated with failed hearing screens in children with skeletal dysplasias, the researchers write. Just over 53% of children and 38.5% of adults had abnormal tympanometry, which in the absence of functioning tympanostomy tubes was associated with 9.5 times greater odds of hearing loss in children and 2.8 times greater odds of hearing loss in the total cohort.

Hearing screening is feasible at national meetings of skeletal dysplasia patient organizations, the researchers note.


Multiple maternal hypomethylation syndrome (MMHS) should be considered in atypical patients with suspected imprinting disorders, Niederhoffer et al (p. 1662, DOI: 10.1002/ajmg.a.35377rpar; write. They highlight the complexity of genetic mechanisms underlying both MMHs and Beckwith-Wiedemann syndrome (BWs) and related, genetically heterogeneous imprinting disorders.

The researchers characterized the genomic DNA of two brothers with BWs. Their DNA displayed discordant loss of methylation at several differentially methylated regions (DMRs), including imprinting center 2 (IC2) on chromosome band 11p15.5, which is often hypomethylated in BWS.

In keeping with MMHS, the older child had hypomethylation of the SGCE, PLAGL1, and IC2 genes, while the younger brother had no methylation loss at these DMRs. Although this discordance is consistent with previous observations that 15% to 20% of people with BWS do not have detectable genetic or epigenetic alterations of 11p15.5, this is the first report of familial recurrence of BWS with discordance for chromosomal 11p15.5 alterations.

The researchers hypothesize that apparent discordance might arise from mosaicism precluding identification of IC2 hypomethylation in blood, buccal mucosa DNA of the younger child, or from hypomethylation at a site unexplored by molecular studies.

The brothers demonstrate the importance of further characterizing the prenatal natural history of BWS as well as recognition of the full phenotypic spectrum, including the syndrome's association with MMHS.fx1

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Figure 2. sagittal 2D (a) and 3D (b) prenatal ultrasound examinations at 35 weeks gestation demonstrated macroglossia and visceromegaly including hepatomegaly (c) in Patient 2.


Research by Izumi et al (p. 1535, DOI: 10.1002/ajmg.a.35368) diminishes the genomic region responsible for a part of the Braddock-Carey syndrome (BCS) phenotype.

BCS involves Pierre Robin sequence, agenesis of the corpus callosum, facial dysmorphisms, developmental delay, and congenital thrombocytopenia.

The syndrome has emerged as a contiguous gene deletion syndrome following discovery of a causal chromosomal microdeletion in 21q22, including the RUNX1 gene. Its haploinsufficiency is responsible for thrombocytopenia phenotype.

The researchers describe an infant with Pierre Robin sequence, facial anomalies, congenital heart defects, hypotonia, and no thrombocytopenia. They found a 1.9 Mb microdeletion within the BCS contiguous deletion syndrome region. This deletion spares the RUNX1 gene.

The microdeletion disrupted 30 genes in the patient, but researchers were unable to determine which play an important role in her phenotype. The researchers call for more research on the genes located within 21q22 in the pathogenesis of BCS.fx2

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Figure 2. Facial appearances of the proposita. Note low anterior hairline, sparse eyebrows, downslanted palpebral fissures, and micrognathia.