Department of Paediatrics, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czechia.
Department of Paediatrics, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czechia,
Horm Res Paediatr. 2024;97(2):203-210. doi: 10.1159/000531996. Epub 2023 Aug 23.
The SALL4 gene encodes a transcription factor that is essential for early embryonic cellular differentiation of the epiblast and primitive endoderm. It is required for the development of neural tissue, kidney, heart, and limbs. Pathogenic SALL4 variants cause Duane-radial ray syndrome (Okihiro syndrome), acro-renal-ocular syndrome, and Holt-Oram syndrome. We report a family with vertical transmission of a SALL4 pathogenic variant leading to radial hypoplasia and kidney dystopia in several generations with additional growth hormone deficiency (GHD) in the proband.
Our male proband was born at the 39th week of gestation. He was born small for gestational age (SGA; birth weight 2,550 g, -2.2 SDS; length 47 cm, -2.0 SDS). He had bilateral asymmetrical radial ray malformation (consisting of radial hypoplasia, ulnar flexure, and bilateral aplasia of the thumb) and pelvic kidney dystopia, but no cardiac malformations, clubfoot, ocular coloboma, or Duane anomaly. He was examined for progressive short stature at the age of 3.9 years, where his IGF-1 was 68 μg/L (-1.0 SD), and growth hormone (GH) after stimulation 6.2 μg/L. Other pituitary hormones were normal. A brain CT revealed normal morphology of the cerebral midline and the pituitary. He had a dental anomaly - a central mandibular ectopic canine. MRI could not be done due to the presence of metal after multiple corrective plastic surgeries of his hands. His mother's and father's heights are 152.3 cm (-2.4 SD) and 177.8 cm (-0.4 SD), respectively. His father has a milder malformation of the forearm. The affected paternal grandfather (height 164 cm; -2.3 SD) has a radial ray defect with missing opposition of the thumb. The family reports a similar phenotype of radial dysplasia in the paternal grandfather's mother. The proband started GH therapy at age 6.5 years when his height was 109 cm (-2.8 SDS) and he experienced catch-up growth as expected in GHD. Puberty started spontaneously at the age of 12.5 years. At age 13, his height was 158.7 cm (-0.2 SDS). Whole-exome sequencing revealed a nonsense variant in the SALL4 gene c.1717C>T (p.Arg573Ter) in the proband, his father, and paternal grandfather.
This is the first observation of a patient with a congenital upper limb defect due to a pathogenic SALL4 variant who has isolated GHD with no apparent cerebral or facial midline anomaly and has been successfully treated with growth hormone.
SALL4 基因编码一种转录因子，对于胚胎外胚层和原始内胚层的早期细胞分化至关重要。它是神经组织、肾脏、心脏和四肢发育所必需的。致病性 SALL4 变体可导致 Duane-radial ray 综合征（Okihiro 综合征）、acro-renal-ocular 综合征和 Holt-Oram 综合征。我们报告了一个家族，其 SALL4 致病性变体垂直传递，导致几代人出现桡骨发育不良和肾脏异位，先证者还伴有生长激素缺乏症（GHD）。
我们的男性先证者于孕 39 周时出生。他是小于胎龄儿（SGA；出生体重 2550g，-2.2 SDS；身长 47cm，-2.0 SDS）。他双侧桡骨射线不对称畸形（包括桡骨发育不良、尺骨弯曲和双侧拇指缺如）和骨盆肾异位，但无心脏畸形、马蹄内翻足、眼裂畸形或 Duane 异常。他在 3.9 岁时因进行性身材矮小接受检查，其 IGF-1 为 68μg/L（-1.0 SDS），GH 刺激后为 6.2μg/L。其他垂体激素正常。脑 CT 显示大脑中线和垂体形态正常。他有一个牙齿异常——下颌中央异位犬齿。由于手部多次矫形手术后存在金属，无法进行 MRI 检查。他母亲的身高为 152.3cm（-2.4 SDS），父亲的身高为 177.8cm（-0.4 SDS）。他的父亲前臂畸形较轻。受影响的祖父（身高 164cm；-2.3 SDS）有桡骨射线缺陷，拇指无对掌。家族报告称，祖父的母亲也有类似的桡骨发育不良表型。先证者在 6.5 岁时开始接受 GH 治疗，当时他的身高为 109cm（-2.8 SDS），并按预期在 GHD 中经历了追赶生长。青春期自发开始于 12.5 岁。13 岁时，他的身高为 158.7cm（-0.2 SDS）。全外显子组测序显示，先证者、他的父亲和祖父均携带 SALL4 基因 c.1717C>T（p.Arg573Ter）的无意义变异。
这是首例因致病性 SALL4 变体导致先天性上肢缺陷的患者，该患者孤立性 GHD 无明显脑或面部中线异常，并成功接受生长激素治疗。
