背景:细胞周期蛋白依赖性激酶抑制剂1C(CDKN1C)是一种细胞增殖抑制剂,可通过G1细胞周期停滞调节细胞周期和细胞生长。CDKN1C突变可导致IMAGe综合征(CDKN1C等位基因功能获得突变导致宫内生长受限,干phy端发育不良,先天性肾上腺发育不全,和泌尿生殖系统畸形)。我们提出了一个银-罗素综合征(SRS)家系,这是由于错义突变影响相同的氨基酸位置,279,在CDKN1C基因中,导致氨基酸取代p.Arg279His(c.836G>A)。受影响的家庭成员具有SRS表型,但没有肢体不对称或肾上腺功能不全。该特定区域中的氨基酸变化位于狭窄的功能区域中,该区域包含先前与IMAGe综合征相关的突变。在家族性SRS患者中,应分析CDKN1C的PCNA区。在所有具有功能性CDKN1C变体的患者中,应排除肾上腺功能不全。
方法:我们描述了一个8岁女孩最初表现为身材矮小的案例。她的身高是91.6厘米,她的体重是10.2公斤。体检显示她的头比较大,倒三角形的脸,突出的前额,低耳位,凹陷的眼窝,牙齿不规则破裂,但没有肢体不对称。家族史:女孩的母亲,曾祖母,祖母的哥哥也有一个突出的额头,三角形的脸,严重比例侏儒症,但没有肢体不对称或肾上腺功能不全。该女孩的外显子组测序揭示了一个新的杂合CDKN1C(NM_000076。2)c.836G>A突变,产生一种变体,该变体具有被组氨酸取代的预测的进化上高度保守的精氨酸(p。Arg279His)。在两个先证者的母亲中发现了相同的致病突变,曾祖母,和祖母的兄弟,有相似表型的人。到目前为止,我们发现了一个SRS谱系,这是由于影响相同氨基酸位置的错义突变,279,在CDKN1C基因中,导致氨基酸取代p.Arg279His(c.836G>A)。尽管SRS相关的CDKN1C突变位于IMAGe相关突变热点区域[增殖细胞核抗原(PCNA)结构域],在这个SRS家系中没有肾上腺功能不全的报道.原因可能是基因组突变的位置和错义突变的类型决定了表型。先证用重组人生长激素(rhGH)处理。rhGH治疗1年后,先证者的身高标准差分数增加了0.93标准差分数,生长速度为8.1厘米/年。无不良反应,如血糖异常,被发现了。
结论:CDKN1C的功能性突变可导致无肢体不对称的家族性SRS,一些患者可能有葡萄糖异常。在家族性SRS患者中,应分析CDKN1C的PCNA区。在所有具有功能性CDKN1C变体的患者中,应排除肾上腺功能不全。
BACKGROUND: Cyclin-dependent kinase inhibitor 1C (CDKN1C) is a cell proliferation inhibitor that regulates the cell cycle and cell growth through G1 cell cycle arrest. CDKN1C mutations can lead to IMAGe syndrome (CDKN1C allele gain-of-function mutations lead to intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenital, and genitourinary malformations). We present a Silver-Russell syndrome (SRS) pedigree that was due to a missense mutation affecting the same amino acid position, 279, in the CDKN1C gene, resulting in the amino acid substitution p.Arg279His (c.836G>A). The affected family members had an SRS phenotype but did not have limb asymmetry or adrenal insufficiency. The amino acid changes in this specific region were located in a narrow functional region that contained mutations previously associated with IMAGe syndrome. In familial SRS patients, the PCNA region of CDKN1C should be analysed. Adrenal insufficiency should be excluded in all patients with functional CDKN1C variants.
METHODS: We describe the case of an 8-year-old girl who initially presented with short stature. Her height was 91.6 cm, and her weight was 10.2 kg. Physical examination revealed that she had a relatively large head, an inverted triangular face, a protruding forehead, a low ear position, sunken eye sockets, and irregular cracked teeth but no limb asymmetry. Family history: The girl\'s mother, great-grandmother, and grandmother\'s brother also had a prominent forehead, triangular face, and severely proportional dwarfism but no limb asymmetry or adrenal insufficiency. Exome sequencing of the girl revealed a new heterozygous CDKN1C (NM_000076. 2) c.836G>A mutation, resulting in a variant with a predicted evolutionarily highly conserved arginine substituted by histidine (p.Arg279His). The same causative mutation was found in both the proband\'s mother, great-grandmother, and grandmother\'s brother, who had similar phenotypes. Thus far, we found an SRS pedigree, which was due to a missense mutation affecting the same amino acid position, 279, in the CDKN1C gene, resulting in the amino acid substitution p.Arg279His (c.836G>A). Although the SRS-related CDKN1C mutation is in the IMAGe-related mutation hotspot region [the proliferating cell nuclear antigen (PCNA) domain], no adrenal insufficiency was reported in this SRS pedigree. The reason may be that the location of the genomic mutation and the type of missense mutation determines the phenotype. The proband was treated with recombinant human growth hormone (rhGH). After 1 year of rhGH treatment, the height standard deviation score of the proband increased by 0.93 standard deviation score, and her growth rate was 8.1 cm/year. No adverse reactions, such as abnormal blood glucose, were found.
CONCLUSIONS: Functional mutations in CDKN1C can lead to familial SRS without limb asymmetry, and some patients may have glucose abnormalities. In familial SRS patients, the PCNA region of CDKN1C should be analysed. Adrenal insufficiency should be excluded in all patients with functional CDKN1C variants.