Stiff skin syndrome (SSS) is a rare connective tissue disease manifesting as a progressive, non-inflammatory fibrosis that causes the skin and soft tissues to harden. It can result in restricted joint movement, particularly affecting the shoulder and pelvic girdle. A segmental variant with a better prognosis has been described. Due to its similarity in presentation to other scleroderma-like conditions, this case report will discuss it as a diagnostic challenge.

Stiff skin syndrome (SSS) is a rare, non-inflammatory skin disease with a pronounced restriction in joint mobility. In this study, we aim to report Chinese pediatric patients with SSS in our center and summarize the clinical features of the disease through literature review. A retrospective study was conducted on 16 pediatric patients diagnosed with SSS at Peking Union Medical College Hospital between January 2014 and January 2024, based on clinical manifestations, laboratory tests, and skin biopsy findings. Among these cases, two were classified as widespread SSS, and 14 as segmental SSS. Additionally, a review of relevant literature published between January 2000 and January 2024 involving 138 cases of pediatric SSS was also conducted. The clinical characteristics, treatment, and prognosis of these 154 patients were summarized. The age of onset in patients was 2.0(0.5, 4.8) years, with an average age at diagnosis being 9.0(5.0, 13.0) years. Thigh skin sclerosis (81, 52.6%) was the most common manifestation observed in these patients. Joint restriction was present in 55(35.7%) patients. Patients with joint contractures had longer diagnostic delays compared with those without joint contractures. Patients were primarily treated with physical therapy, while some patients received medications such as mycophenolate mofetil (MMF), losartan, and secukinumab. However, the prognosis varied. The diagnosis of SSS should involve a thorough investigation of family history, detailed physical examination, comprehensive pathological assessment, genetic testing when applicable, and careful exclusion of other scleroderma-like diseases. Currently, there is limited evidence supporting the use of systemic treatment options targeting the transforming growth factor-β or interleukin-17 pathways (such as MMF, losartan, and secukinumab) to slow disease progression. However, these treatments are not capable of reversing established skin lesions, and further investigations are imperative to assess their therapeutic efficacy in SSS.

The Thing is a Marvel Comics superhero who sports rocklike skin. This contribution describes The Thing's cutaneous features and explores similar rocky exteriors in the Stone Giants and other stony creatures described in legends, folklore, and fiction. In the real world, some animals resemble rocks and stones, such as the rock hyrax, stone fish, Pyura chilensis, and common toad. There are also children suffering from stiff skin syndrome, a rare genetic disorder that causes their skin to become stony-hard. The clinical features of this syndrome are highlighted in this contribution.

Stiff skin syndrome is a very rare non-inflammatory reactive skin disease, characterized by skin sclerosis and limited joint mobility. The paper reports one case of child with stiff skin syndrome and treated with combined therapy of acupuncture and cupping. Acupuncture was used at the lateral line 1 of vertex (MS8) on the right side, Jiaji (EX-B2) of L2 to L4, Huantiao (GB30), ashi point, Juliao (GB29), Fengshi (GB31), Weizhong (BL40), and etc. on the left side. After deqi, the electrodes of KWD-808Ⅰimpulse electronic therapeutic device were attached to Jiaji (EX-B2) of L4 and Huantiao (GB30), Fengshi (GB31) and Yanglingquan (GB34) on the left side respectively, at disperse-dense wave, a frequency of 2 Hz/100 Hz, and a current of 2 mA. The needles were retained for 20 min. Acupuncture was operated once every 2 days, 3 interventions a week. When acupuncture was completed in each intervention, moving cupping was followed till the skin turned to be red, along the distribution of the governor vessel, foot-shaoyang gallbladder meridian and foot-taiyang bladder meridian on the left side, of the lumbar region and leg. Moving cupping was delivered once every 2 days, 3 times a week. Once a week, after moving cupping, the cups were retained on the areas with skin stiffness for 8 min to 10 min. One course of the combined therapy of acupuncture and cupping was composed of 6 treatments. After 2 courses of treatment, the skin stiffness on the left buttock region and the lateral side of the lower limb was ameliorated, the swelling on the left lower limb relieved and the walking improved; and the patient could walk continuously for 2 000 m. The combined therapy of acupuncture and cupping provides a new idea for the clinical treatment of stiff skin syndrome. 皮肤僵硬综合征（SSS）是一种极为罕见的非炎性反应性皮肤病，其特征是皮肤硬化和关节活动受限。本文报道了1例SSS患儿，予针刺联合火罐治疗，针刺穴取右侧顶旁1线，左侧L2-L4夹脊穴、环跳、阿是穴、居髎、风市、委中等，针刺得气后，左侧L4夹脊穴和环跳、风市和阳陵泉分别连接一组KWD-808Ⅰ脉冲电疗仪电极，采用疏密波，频率2 Hz/100 Hz，电流2 mA，留针20 min，隔日1次，每周3次；针刺结束后行火罐疗法，沿督脉及左侧足少阳胆经、足太阳膀胱经在腰腿部循行线上走罐，至局部皮肤潮红为度，隔日1次，每周3次，并在皮肤僵硬部位留罐8~10 min，每周1次。针刺联合火罐治疗6次为一疗程，治疗2个疗程后，患儿左侧臀部及下肢外侧皮肤僵硬好转，左侧下肢肿胀缓解，行走明显好转，可连续行走约2 000 m。针刺、拔罐联合疗法，为SSS的临床治疗提供了新的思路。.

Stereotyped mutations in NOTCH3 drive CADASIL, the leading inherited cause of stroke and vascular dementia. The vast majority of these mutations result in alterations in the number of cysteines in the gene product. However, non-cysteine-altering pathogenic mutations have also been identified, making it challenging to discriminate pathogenic from benign NOTCH3 sequence variants. Here, we present a method for quantitative assessment of NOTCH3 mutants, the light chain split luciferase (LSL) assay. In LSL, NOTCH3 mutant fragments, cloned between a split luciferase open reading frame, are transfected into cells, producing secreted luciferase activity that is dependent on the normal structure of NOTCH3. Insertion of point mutants that cause CADASIL results in significantly lower activity. Using a panel of 47 sequences, we determined the sensitivity and specificity of LSL for pathogenic NOTCH3 mutation discrimination to be 100% and 93%. LSL was also modestly successful in differentiating pathogenic proteins responsible for Marfan's disease and Stiff Skin Syndrome. Two additional parameters from the LSL analysis (TCEP rescue of activity and secretion index) were also shown to be useful in characterizing NOTCH3 mutants. We show that the spacing and primary sequence of the light chain module is an important component of the LSL assay, as a single light chain cysteine is critical for pathogenic sequence discrimination. Furthermore, we show that the activity of CADASIL mutant reporters is amplified by the application of cysteine-reactive iodoacetamide, suggesting that LSL may be deployed to screen for novel compounds that suppress pathogenic conformations of NOTCH3.