• MSS is a rare genetic disorder. • Cardiac findings in MSS include ASD, VSD, PDA, and aortic root dilation. • MS reported here could likely represent an expanding phenotype of MSS. • Formal cardiac evaluation is warranted in MSS given the reported cardiac findings. [Figure: see text]

Malan syndrome, an overgrowth disorder caused by pathogenic NFIX gene variants, is characterized by macrocephaly, distinct facial features, and intellectual disability. This case highlights the associated ophthalmologic features of this rare condition. We describe a young Spanish white man with progressive vision loss in the setting of a prior clinical diagnosis of Sotos syndrome, accompanied by developmental delay and epilepsy. Ophthalmic examination and imaging studies revealed visual acuity of 20/50 in each eye and bilateral optic atrophy. Genetic testing identified a heterozygous pathogenic NFIX variant, confirming Malan syndrome rather than NSD1-related Sotos syndrome. This case underscores the importance of genetic testing in patients with syndromic features, highlighting Malan syndrome as a differential diagnosis in cases of optic atrophy with overgrowth phenotypes.

Excessive growth syndromes are a heterogeneous group of rare congenital disorders characterized by increased body size from the neonatal period or early childhood. In addition to accelerated growth, these conditions frequently co-occur with dysmorphic features and other medical problems, including intellectual disability, organ defects, and an increased risk of cancer. The objective of this study is to present a comprehensive overview of selected dysmorphic syndromes associated with excessive growth, with particular emphasis on syndromes with confirmed or strongly suspected monogenic etiology. The following aspects are discussed in this text: the pathogenesis of the condition, its inheritance, the characteristic clinical symptoms, the diagnostic approach, and the potential treatment options. A comprehensive analysis of data pertaining to syndromes of excessive growth, accompanied by either a recognized or postulated monogenic basis, was conducted based on scientific literature. A particular emphasis was placed on the examination of endocrinological, oncological, and prognostic aspects. The usefulness of genetic testing in the diagnostic process was also evaluated. A number of excessive growth syndromes were identified, including Sotos syndrome, Beckwith-Wiedemann syndrome, Simpson-Golabi-Behmel syndrome, Bannayan-Riley-Ruvalcaba syndrome, Marshall-Smith syndrome, Weaver syndrome, Nevo syndrome, and Elejalde syndrome. Clinical symptoms, prevalence of endocrine disorders, and risk of developing cancer were meticulously documented. Following a thorough analysis, a set of diagnostic schemes and indications for monitoring selected complications were proposed. The diagnosis of overgrowth syndromes is a complex process that requires a meticulous clinical evaluation and the application of contemporary genetic methodologies. Early identification of characteristic phenotypic and molecular features facilitates prompt implementation of appropriate treatment and monitoring of complications. The adaptation of therapeutic strategies to a specific syndrome and patient is pivotal to improving prognosis. Zespoły nadmiernego wzrostu to heterogenna grupa rzadkich wad wrodzonych, charakteryzujących się zwiększoną wielkością ciała już od okresu noworodkowego lub wczesnego dzieciństwa. Oprócz przyspieszonego wzrostu, często współwystępują z cechami dysmorfii oraz innymi problemami medycznymi, takimi jak niepełnosprawność intelektualna, wady narządowe czy zwiększone ryzyko rozwoju nowotworów. Celem niniejszej pracy jest przedstawienie przeglądu wybranych zespołów dysmorficznych związanych z nadmiernym wzrostem, ze szczególnym uwzględnieniem zespołów o potwierdzonej lub silnie podejrzewanej etiologii monogenowej. Omówiono ich patogenezę, dziedziczenie, charakterystyczne objawy kliniczne, podejście diagnostyczne oraz potencjalne możliwości leczenia. Analizie poddano dostępne w literaturze naukowej dane dotyczące zespołów nadmiernego wzrostu o znanym lub postulowanym podłożu jednogenowym. Szczególną uwagę poświęcono aspektom endokrynologicznym, onkologicznym i rokowniczym. Oceniono również przydatność badań genetycznych w procesie diagnostycznym. Zidentyfikowano szereg zespołów nadmiernego wzrostu, takich jak: zespół Sotos, Beckwitha-Wiedemanna, Simpsona-Golabiego-Behmela, Bannayana-Rileya-Ruvalcaby, Marshalla-Smitha, Weavera, Nevo oraz Elejalde. W każdym z nich opisano charakterystyczne objawy kliniczne, częstość występowania zaburzeń endokrynologicznych oraz ryzyko rozwoju nowotworów. Na podstawie analizy zaproponowano schematy diagnostyczne i wskazania do monitorowania wybranych powikłań. Rozpoznanie zespołów nadmiernego wzrostu wymaga uważnej oceny klinicznej oraz zastosowania nowoczesnych metod genetycznych. Wczesna identyfikacja charakterystycznych cech fenotypowych i molekularnych umożliwia szybsze wdrożenie odpowiedniego leczenia i monitorowania powikłań. Indywidualizacja opieki, w tym dostosowanie strategii terapeutycznych do konkretnego zespołu i pacjenta, jest kluczowa dla poprawy rokowania.

This article reports on the clinical and genetic characteristics of monozygotic twins with Marshall-Smith syndrome (MRSHSS) due to a mutation in the NFIX gene, along with a review of related literature. Both patients presented with global developmental delays, a prominent forehead, shallow eye sockets, and pectus excavatum. Genetic testing revealed a heterozygous splicing site mutation c.697+1G>A in both children, with parents showing wild-type at this locus. According to the guidelines of the American College of Medical Genetics and Genomics, this mutation is considered likely pathogenic and has not been previously reported in the literature. A review of the literature identified 32 MRSHSS patients with splicing/frameshift mutations. Accelerated bone maturation and moderate to severe global developmental delay/intellectual disability are the primary clinical manifestations of patients with MRSHSS. Genetic testing results are crucial for the diagnosis of this condition. 该文报道了一对NFIX基因变异导致Marshall-Smith综合征（Marshall-Smith syndrome, MRSHSS）的同卵双胞胎临床及遗传学特点并对相关文献进行复习。2例患儿均表现为全面发育落后、高额头、浅眼眶、漏斗胸。基因检测提示2例患儿均存在NFIX杂合剪接位点变异c.697+1G>A，父母该位点为野生型，根据美国医学遗传学与基因组学学会指南判定为可能致病性变异，该位点突变既往未见文献报道。复习文献共发现32例MRSHSS患者，突变类型为剪切/移码突变。骨骼成熟加速、中至重度全面发育迟缓/智力障碍是MRSHSS患者最主要的临床表现。基因检测结果是该病重要的诊断依据。.

Several small genetic association studies have been conducted for atypical femur fracture (AFF) without replication of results. We assessed previously implicated and novel genes associated with AFFs in a larger set of unrelated AFF cases using whole exome sequencing (WES). We performed gene-based association analysis on 139 European AFF cases and 196 controls matched for bisphosphonate use. We tested all rare, protein-altering variants using both candidate gene and hypothesis-free approaches. In the latter, genes suggestively associated with AFFs (uncorrected p-values <.01) were investigated in a Swedish whole-genome sequencing replication study and assessed in 46 non-European cases. In the candidate gene analysis, PLOD2 showed a suggestive signal. The hypothesis-free approach revealed 10 tentative associations, with XRN2, SORD, and PLOD2 being the most likely candidates for AFF. XRN2 and PLOD2 showed consistent direction of effect estimates in the replication analysis, albeit not statistically significant. Three SNPs associated with SORD expression according to the GTEx portal were in linkage disequilibrium (R2 ≥ 0.2) with an SNP previously reported in a genome-wide association study of AFF. The prevalence of carriers of variants for both PLOD2 and SORD was higher in Asian versus European cases. While we did not identify genes enriched for damaging variants, we found suggestive evidence of a role for XRN2, PLOD2, and SORD, which requires further investigation. Our findings indicate that genetic factors responsible for AFFs are not widely shared among AFF cases. The study provides a stepping-stone for future larger genetic studies of AFF. We investigated the genetic factors contributing to atypical femur fractures (AFF), which are rare and unusual fractures in the thigh bone. These fractures are related to the use of bisphosphonates (BP), which are prescribed to prevent fractures caused by osteoporosis. Previous studies suggested potential genetic links, but their findings were not confirmed in larger groups. To address this, we analyzed genetic data from 139 European individuals with AFF and 196 individuals without AFF, all of whom used BP, using a genetic technique called whole exome sequencing. Our results suggested three genes—XRN2, SORD, and PLOD2—might be linked to AFF, although the evidence was not conclusive. Importantly, our findings suggest that AFF may be caused by different genes in different individuals. A much larger sample size is now needed to fully understand the genetic architecture of AFF. These findings may guide future research into the genetic causes of AFF.