Ramakrishnan Anand, Popat Dillon, Purushothaman Preetha, Chan Li F, Gevers Evelien F
Department of Paediatric Endocrinology, Barts Health NHS Trust-Royal London Children's Hospital, Whitechapel Road, London E1 1FR, UK.
Centre for Endocrinology, William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, EC1M 6BQ, London, UK.
JCEM Case Rep. 2024 Aug 5;2(8):luae125. doi: 10.1210/jcemcr/luae125. eCollection 2024 Aug.
variants were recently described in 1% of patients not known to have pseudohypoparathyroidism/inactivating PTH/PTHrP signalling disorder 2 in the UK Genetics of Obesity Study. We describe a new missense variant, c.791A > C, p.(Asp264Thr), in a family with obesity, hyperphagia and mild PTH resistance. A 6-year-old female (body mass index +4.3 SD score [SDS], height +1.9 SDS) presented with hyperphagia and obesity from age 3 years. She had subtle brachydactyly, macrocephaly, and mildly delayed development. The 12-year-old brother (height +2.1 SDS, body mass index +2.9 SDS) had hyperphagia, obesity, mildly delayed development, and autism. He had subtle brachydactyly, as did the affected mother. We assessed the functional effect of the mutant, measuring cAMP production in cells transfected with wild type and mutant GNAS after ligand stimulation. Cells with the mutant GNAS showed impaired cAMP generation through melanocortin receptor 4, GH releasing hormone receptor, and PTH receptor. These cases demonstrate the clinical heterogeneity of monogenic disease, suggesting a need to test for PHP1A in children with obesity even without classical signs of PHP1A.
在英国肥胖遗传学研究中，最近在1%的无假甲状旁腺功能减退症/失活性甲状旁腺激素/甲状旁腺激素相关蛋白信号传导障碍2的患者中发现了变异体。我们在一个患有肥胖症、食欲亢进和轻度甲状旁腺激素抵抗的家庭中描述了一种新的错义变异体，即c.791A>C，p.(Asp264Thr)。一名6岁女性（体重指数+4.3标准差评分[SDS]，身高+1.9 SDS）从3岁起就出现食欲亢进和肥胖。她有轻微的短指畸形、巨头畸形和轻度发育迟缓。12岁的哥哥（身高+2.1 SDS，体重指数+2.9 SDS）有食欲亢进、肥胖、轻度发育迟缓和自闭症。他有轻微的短指畸形，患病的母亲也有。我们评估了该突变体的功能效应，在配体刺激后测量了用野生型和突变型GNAS转染的细胞中cAMP的产生。携带突变型GNAS的细胞通过黑皮质素受体4、生长激素释放激素受体和甲状旁腺激素受体显示出cAMP生成受损。这些病例证明了单基因疾病的临床异质性，表明即使没有假甲状旁腺功能减退症1A型的典型体征，肥胖儿童也需要检测假甲状旁腺功能减退症1A型。
