case_images: PMC6959155_01
case_images: (a and b) A1 aged 15 years. Facial profile demonstrating prominent forehead, high anterior hairline, and pointed chin.
case_images: CRIG2019-1398250.001.jpg
case_images: PMC6959155_01_CRIG2019-1398250.001.jpg
case_images: fig1
case_images: On examination she had a pointed chin (see Figure 1(a)) with small ears and a high anterior hairline. Her forehead was prominent (also present in her mother) as seen in Figures 1(a)and1(b).
case_images: (a and b) A1 with her maternal half-brother, B1. Note significant short stature (both <0.4th centile). A1 has lumbar lordosis.
case_images: CRIG2019-1398250.002.jpg
case_images: PMC6959155_01_CRIG2019-1398250.002.jpg
case_images: fig2
case_images: He is taller than A1 as shown in Figures 2(a) and 2(b) Human GH was administered from age 14 to 17 years under the SGA license (35 mug/kg daily) but with poor response.
case_images: (a and b) B1 (aged 21 years) facial front view and profile. Note prominent forehead and high anterior hairline.
case_images: CRIG2019-1398250.003.jpg
case_images: PMC6959155_01_CRIG2019-1398250.003.jpg
case_images: fig3
case_images: On examination he had a prominent forehead (although less than A1) (as seen in Figures 3(a) and 3(b), high anterior hairline, small hands, and feet, but nil else of particular note.
case_images: (a and b) Radiographs of A1's left hand and left forearm with changes described in the text.
case_images: CRIG2019-1398250.004.jpg
case_images: PMC6959155_01_CRIG2019-1398250.004.jpg
case_images: fig4
case_images: The skeletal survey performed aged 13 years showed subjective hypoplasia of the distal radial epiphyses (Figures 4(a) and 4(b)). The 4th and 5th metacarpals were bilaterally short (Figure 4(a)).
case_images: (a and b) B1 radiograph of right hand aged 15 years (a). B1 radiograph of right hand aged 3 years (b).
case_images: CRIG2019-1398250.005.jpg
case_images: PMC6959155_01_CRIG2019-1398250.005.jpg
case_images: fig5
case_images: B1's radiographs (hand and lower limb images) showed slight global bone age delay (age 6 years) and subjective smaller epiphyses (Figures 5(a) and 5(b)), with slight elongation of the fibula (Figure 6).
case_images: B1 radiograph of right lower limb (lateral and AP) aged 5 years.
case_images: CRIG2019-1398250.006.jpg
case_images: PMC6959155_01_CRIG2019-1398250.006.jpg
case_images: fig6
case_images: B1's radiographs (hand and lower limb images) showed slight global bone age delay (age 6 years) and subjective smaller epiphyses (Figures 5(a) and 5(b)), with slight elongation of the fibula (Figure 6).
case_images: Sanger sequence analysis for A1, B1, and their mother showing nucleotide change C>A, heterozygous.
case_images: CRIG2019-1398250.007.jpg
case_images: PMC6959155_01_CRIG2019-1398250.007.jpg
case_images: fig7
case_images: A heterozygous maternally inherited variant in the CDKN1C gene was identified; c.836G>T; p.(Arg279Leu) (NM_000076.2) as shown in Figure 7.
case_images: Focussed pedigree showing CDKN1C gene change; c.836G>T; p.(Arg279Leu) in A1, B1, and their mother.
case_images: CRIG2019-1398250.008.jpg
case_images: PMC6959155_01_CRIG2019-1398250.008.jpg
case_images: fig8
case_images: This was confirmed by Sanger sequencing in the local diagnostic lab (West Midlands Regional Genetics Laboratory) and confirmed in her mother and B1 (as illustrated in Figure 8).