ESPE Abstracts (2023) 97 P1-524

ESPE2023 Poster Category 1 Growth and Syndromes (75 abstracts)

Two male siblings with extremely tall stature, moderate mental retardation and a deletion of ASH1L at chromosome 1q22.

Niels Birkebæk 1,2 & Dorte Lildballe 3

1Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark. 2Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark. 3Department of Molecular Medicin, Aarhus University Hospital, Aarhus, Denmark

Background: Several symmetric monogenic overgrowth syndromes with tall stature have been described, which is why children with syndromic tall stature should undergo comprehensive diagnostics. Tall stature has not been associated with chromosome 1.

Objective: To present height growth and diagnostics in two male siblings with extreme tall stature and moderate mental retardation. Both had a deletion of ASH1L at chromosome 1q22.

Case report: The siblings were born at term, with birth weight and length of 5220 g, 58 cm and 4820 g, 60 cm, respectively. Father’s, mother’s and sister’s height were 193, 168 and 177 cm, respectively. Sibling 1 was referred 10.3year old with height of 173 cm (+ 5SD), and sibling 2 was referred 6.3year old with height of 138 cm (+ 4SD). The children were not disproportionate, but they had discrete dysmorphic features with epicanthus and slight swan neck deformity of their fingers. Both were moderately mental retarded. Both had a male 46XY karyotype, normal hormonal axes, and a normal magnetic resonance imaging of the brain including normal hypothalamus and pituitary anatomy. Sibling 1 was treated with testosterone injections to accelerate closure of the growth zones -final height was 215 cm. Sibling 2 refrained from testosterone treatment and refrained also from epiphysiodesis -final height was 223 cm. An array comparative genomic hybridization (BAC array CGH) and analysis for fragile X were normal (year 2010). Using next generation sequencing, whole exome sequencing was carried out on both siblings and parents. The siblings were analyzed for causal variants in genes known to be associated with tall stature (human phenotype ontology 28/03/2019) without identification of pathogenic variants, but confirmed paternity. An 180K array CGH conducted in 2021 revealed a 68 kb deletion of chromosome 1q22 including ASH1L in both siblings, but not in their parents and sister.

Conclusion: The two extremely tall male siblings with moderate mental retardation both had a large deletion at chromosome 1q22, including ASH1L known to code for a histone methyl transferase involved in epigenetic modification of chromatin. Variants in ASH1L have previously been associated with mental retardation. Pathogenic variants in genes coding for methyl transferases have been associated with symmetric overgrowth syndromes – e.g variants in EXH2 at chromosome 7 causes Weavers syndrome and variants in NSDL1 at chromosome 5 causes Sotos syndrome. Therefore, the deletion of the ASH1L at chromosome 1 in the siblings may explain both their mental retardation and their extremely tall stature.

Volume 97

61st Annual ESPE (ESPE 2023)

The Hague, Netherlands
21 Sep 2023 - 23 Sep 2023

European Society for Paediatric Endocrinology 

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