INTRODUCTION

Hutchinson-Gilford progeria syndrome (HGPS) is a well-characterized premature aging disorder caused by mutations in

, the gene encoding the nuclear scaffold proteins lamins A and C[1,2]. We have previously analyzed the clinical manifestations and imaging characteristics of this case[3]. HGPS is characterized by the presence of aging-associated symptoms, including lack of subcutaneous fat,alopecia, swollen veins, growth retardation, age spots, joint contractures, osteoporosis, cardiovascular pathology, and death due to heart attacks and strokes in childhood[4]. In this study, a heterozygous mutation of the

gene was found by high-throughput whole-exosome sequencing in a 2-year-old patient with an abnormal appearance, and growth and development lag behind those of children of the same age.

CASE PRESENTATION

Chief complaints

A boy was aged 2 years and 5 mo at the time of diagnosis of HGPS, by which time, he had an abnormal appearance and his growth and development lagged behind those of children of his age.

I pulled the boy up off the ground and helped him back to his house which was about two blocks down the street from the school building. When we reached his home his sister told me that her brother was deaf but that he was not dumb like the two bullies said. That he was very smart but could not say or hear anything. I told her that he did make a sound when the bully3 kicked him in the back. She told me that I must be mistaken because all her brother s vocal4 cords had been removed during an experimental surgery, which had failed.

History of present illness

In the past 6 mo, the weight of the child did not increase and remained at about 8 kg. The veins in the head of the child were clearly visible, his skin was lighter, and his hair was yellow and sparse, which were the main clinical manifestations of the disease. Peripheral blood DNA samples obtained from the patient and his parents were sequenced using high-throughput whole-exosome sequencing, which was verified by Sanger sequencing.

History of past illness

At birth, the parents found that the veins and blood vessels at the trunk of the child were obvious. At the age of 6 mo, the head and trunk veins were more apparent, and the skin pigment in the trunk was partially lost, presenting as spots. Around the age of 1 year, the scalp vein and skin had lost pigment,and his hair was relatively sparse. After 1 year of age, the increase in body weight was not obvious, and he was immediately taken to a local hospital. A diagnosis of rickets was considered, but the relevant treatment seemed useless.

Personal and family history

The child was born at 40 wk by cesarean section. He weighed 2650 g at birth and had no history of asphyxia rescue. After birth, he received artificial feeding. Milk and porridge were added as supplementary foods. He could raise up his head at 3 mo, turn over at 4-5 mo, and walk steadily at 11 mo. At the age of 1 year, he could shout “YeYe” and “NaNa”, and at 18 mo, continuous sentences could be spoken. He could express his needs. His neurological and mental development was the same as that of children of the same age. His parents were not consanguineous. There was no family history of familial genetic disease or infectious diseases.

31.Stately castle, the master of which was an ogre: In some versions of the tale, the cat finds a castle whose owner is away. He quickly outwits the guards and then gains admittance for the Marquis and his bride. The former owner inexplicably dies while away and never returns to claim his property. In other versions, the Marquis quickly buys property with the money he receives as a dowry. Return to place in story.

So be it, said the Wolf and beat his paw against the dry ground, and immediately he took the shape of the Horse with the Golden Mane, so like to that the Princess rode that no one could have told one from the other. Then Tsarevitch Ivan, leaving Helen the Beautiful on the green lawn with the real Horse with the Golden Mane, mounted arid39 rode to the Palace gate.

Physical examination

The child’s weight was 8 kg, head circumference 46.5 cm, and body length 81 cm, which were lower than those of children at the same age. There was no abnormal mental reaction. The skin was thin and had poor elasticity. The skin of the trunk showed spot-like depigmentation, and some superficial lymph nodes were swollen. It could also be seen that the hair was sparse and yellow, the veins of the scalp were clearly visible, and the anterior fontanel was not closed. His eyeballs were slightly prominent, the bridge of the nose was lower, and the face showed mandibuloacral dysplasia. The ear position was not low, and there was no penetrating palm. The chest circumference was 44 cm and the chest showed changes consistent with pigeon breast. There were no abnormalities in the auscultation of his heart and lungs. His knee and ankle joints were stiff, with poor mobility, his fingers and toes were slender, and his joints showed slight swelling, with clubbing fingers. Bilateral Babinski signs were positive.

What can be the reason for such a crowd close by the pigsty? said theEmperor, who happened just then to step out on the balcony; he rubbed hiseyes, and put on his spectacles. They are the ladies of the court; I must godown and see what they are about! So he pulled up his slippers at the heel,for he had trodden them down.

Laboratory examinations

We carried out tests on the patient’s blood: Leukocyte count 7.9 × 10

/L, hemoglobin 130 g/L, platelet count 339 × 10

/L, neutrophils 32.4%, lymphocytes 58.3%, and calcitonin 0.00 mg/L. The results of thyroid function tests were: Serum total triiodothyronine (T3) 3.29 nmol/L, total serum thyroxine 86.00 nmol/L, free T3 7.03 pmol/L, thyroid-stimulating hormone 1.93 mIU/L, and parathyroid hormone 0.21 pmol/L. Liver and kidney function tests, electrolytes, blood gas analysis, copper blue analysis, urine and feces analysis, coagulation function tests, and erythrocyte sedimentation rate showed no obvious abnormalities.

Imaging examinations

The results of electroencephalography and blood/urine tandem mass spectrometry were normal. Color Doppler echocardiography showed mild tricuspid regurgitation. The liver, bile, pancreas, and spleen were examined by color Doppler ultrasonography, and the results showed no abnormalities. The testicular color ultrasound examination showed a fluid dark area around the right testicle, which could be considered as a testicular hydrocele. No abnormal acoustic images were found in the testicle and epididymis on both sides. Chest radiographs showed normal cardiopulmonary septum. Spina bifida of the second sacral vertebral body was possible. Three-dimensional cranial reconstruction showed a lowdensity lesion in the white matter space of the right parietal lobe. On November 29, 2019, nuclear magnetic resonance imaging of the head revealed a partial perivascular space, with localized keratinosis in bilateral parietal lobes, accompanied by thickening of the maxillary sinus mucosa on the right side,suggesting irregular tooth arrangement.

High throughput whole-exome sequencing and mitochondrial sequencing

Whole-exome sequencing (WES) and whole-genome sequencing analyses of copy number variants were performed to seek for genetic counseling and clarify the etiology of the child’s condition. Informed consent was obtained from the parents on behalf of the proband for WES and mitochondrial sequencing and for publication of photographs. DNA was obtained from peripheral blood samples from the patient and his parents. Statistical analysis of the data on single nucleotide polymorphisms (SNPs) and insertion deletion mutations (indels) was conducted. The SNPs and indels were screened using the Database of Single Nucleotide Polymorphisms (dbSNP), 1000 Genomes, and ExAC database. Application of the human Online Mendelian Genetic Database (OMIM) confirmed the reported pathogenic gene locus. The American College of Medical Genetics and Genomics (ACMG) sequence variation interpretation standards and guidelines were used for a comprehensive evaluation of the pathogenicity of mutation sites.

We report a case of synonymous heterozygous mutation in the

gene (C.1824 C>T; P.G608G).This variant belongs to a spontaneous mutation, whose parent gene has no variation at this locus, and the genetic mode belongs to the autosomal dominant inheritance[4,5]. As for the function of the mutation, the observed mutations improve the match to a consensus splice donor, suggesting that it activates a cryptic splice site. It shows that 150 nucleotides within exon 11 are missing. This abnormal transcript would be expected to code for a protein with an internal deletion of 50 amino acids near the C terminus of lamin A[10-13].

Gene detection results and pathogenicity analysis

All the authors of this article have no conflict of interest to disclose.

FINAL DIAGNOSIS

Sanger sequencing showed that there was a spontaneous and synonymous heterozygous mutation of C.1824 C>T (P. G608G) in the

gene. Due to the mutation of this gene, the child was diagnosed with HGPS.

TREATMENT

According to the clinical manifestations, laboratory tests, and gene sequencing results, the clinical phenotype of the patient was HGPS. The patient was treated with vitamin A/D, calcium supplement,and other drugs.

OUTCOME AND FOLLOW-UP

We would like to thank the child and his family members for agreeing to participate in this study.

DISCUSSION

HGPS (OMIM: 176670) is an autosomal dominant genetic disease that causes a remarkable phenotype resembling many aspects of aging[1,5]. The disease was first reported by general practitioner Jonathan Hutchinson in 1886, and was subsequently refined and supplemented[6]. The main first symptoms in typical childhood-onset phenotype include postnatal growth retardation (55%), alopecia (40%), absence of subcutaneous fat (28%), and lipodystrophy (20%)[1,7]. The following symptoms also exist: Midface hypoplasia, micrognathia, osteoporosis, low body weight, decreased joint mobility, and premature aging.

With respect to the small molecule treatment, significant progress has been made in the enzyme isoprenylcysteine carboxylmethyltransferase inhibitors and the interaction between progerin and lamin A[18]. Regarding the biological therapy, antisense oligonucleotides have shown encouraging results in progeria.

The

(OMIM: 150330) gene is located on chromosome 1q22, and different sets of mutations in the

and genes coding for interacting proteins, give rise to a variety of genetic disorders collectively called laminopathies[10].

codes for two major, alternatively spliced transcripts that give rise to lamin A and lamin C proteins, which are generated by use of an alternative 50 splice site in exon 10. Unlike lamin C, lamin A is translated as prelamin A and undergoes post-translational processing steps at the C-terminal CaaX motif[9,11].

The three days passed; then the riddle was asked: What did the rose do to the cypress? The prince had an eloquent48 tongue, which could split a hair, and without hesitation49 he replied to her with a verse: Only the Omnipotent50 has knowledge of secrets; if any man says, I know do not believe him

With that, the man darted7 across the floor and out the door, leaving the lady in much bewilderment. He finally realized that he had already found his dream girl, and she was... the Vancouver girl all along! The drunken lady had said something that awoken him.

In the present case, obvious veins and blood vessels at the trunk were found. At the age of 6 mo, these were more apparent, and more typical symptoms appeared: Postnatal growth retardation, lipodystrophy, beak-like nose, micrognathia, and spotty skin pigment loss. Around the age of 1 year, his hair volume was sparse and he had a tendency to alopecia. The joints of the whole body, including the fingers and toes, were stiff, but there was no abnormal function of the circulation and digestive system.The child had normal intelligence and was born with low body weight, but had no history of feeding difficulties. Growth and development before 1 year were basically normal.Initially, the patient’s clinical manifestations were squared skull, pigeon breast, and alopecia, in line with the clinically typical phenotype of rickets, so vitamin A/D and calcium treatment were given, but the ideal treatment effect was not obtained. In order to determine the cause of the disease, after obtaining informed consent from the patients, we used high-throughput WES and identified a synonymous heterozygous mutation of the

gene[2].

We followed this patient for 18 mo, and found that his height and weight did not improve. This shows that most of the disease manifestations are determined by genetic mutations, so the support therapy does not improve quality of life[4,9,14].

People's cognition of the disease has been gradually deepened, prompting further exploration of the treatment for progeria. The main treatment strategies include gene therapy, biological therapy, and small molecule treatment[15,16]. Gene therapy can directly repair pathogenic mutations; although this therapy still has many limitations and is not commonly used currently, it is anticipated to be a valuable treatment in the future.

Modern studies suggest that lonafarnib, although unable to cure the disease, is able to improve some clinical symptoms of the disease and, therefore, can be a target for further research. Kang

[17]reported that progerinin may be an efficient, stable, and safe treatment.

Children affected with HGPS typically appear normal at birth, but within a year the characteristic features of failure to thrive, delayed dentition, alopecia, and sclerodermatous skin changes begin to appear. Mean age at diagnosis is 2.9 years[8,9]. Median life expectancy is about 13 years, with most dying from complications associated with atherosclerosis. The most common mutation in HGPS, C.1824 C>T (P. G608G), is a synonymous substitution.

ABE variants were reported to have higher editing activity than ABE7.10max by Koblan

[19].They suggest that ABE editing has the potential to cooperate with emerging premature treatments,including farnesyltransferase inhibitors, other small molecule drugs, or antisense oligonucleotides targeting the mutant

allele.

CONCLUSION

We report a case of synonymous heterozygous mutation in the

gene (C.1824 C>T; P.G608G). This variant belongs to a spontaneous mutation, whose parent gene has no variation at this locus, and the genetic mode belongs to the autosomal dominant inheritance. After 18 mo of treatment, the symptoms did not improve. Neither height nor weight have changed significantly. Up to now, the gene therapy is still in the developmental stage, so there are many unknown areas of the disease to be further investigated.

Taken together, although there are multiple obstacles to overcome before HGPS can be cured,effective treatments are only a matter of time as the molecular mechanisms of the disease are continuously understood and the exploration of therapeutic strategies continues[20].

ACKNOWLEDGEMENTS

After 18 mo of treatment, the symptoms did not improve. Neither height nor weight have changed significantly since the age of 2 years.

FOOTNOTES

Zhang SL and Lin SZ collected and analyzed all clinical data and wrote the manuscript; Zhou YQ and Wang C participated in the collation of the literature and the chart research; Pang QM was involved in the genetic diagnosis and treatment of the patient; Lin SZ, Zhou YQ, Wang WQ, and Li JY substantially participated in drafting and revising the important intellectual content of the manuscript; all authors involved have read and approved the final manuscript.

Hainan Province Clinical Medical Center, No. (2021)75 and No. (2021)276.

Informed consent was obtained from the patient’s parents for the publication of this article.

WES showed that there was a synonymous heterozygous variation of the

gene in this patient,one of which was a spontaneous and synonymous mutation C.1824 C>T (P. G608G), which may lead to a change of gene function (Figure 1). No anomalies were found in the child’s father and mother as revealed by WES (Figures 2 and 3). The frequency of the variation in the normal population is unknown,it is a low-frequency variation, and the results of protein function prediction are unknown. According to Sanger sequencing, there was no variation in this locus of parental genes, and the inheritance mode was autosomal dominant inheritance. According to ACMG guidelines, the mutation was suspected to be pathogenic.

Indeed she was on the point of falling over in reality with the chair on which she sat; but she was so startledand alarmed that she could not remember what she had dreamed, onlythat it was something very dreadful

The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).

We scoured12 the beach, enjoying the cool ocean breeze and the feel of the ocean mist on our bodies. Although we still exchanged no words, we became friends through our daily enterprise.

There she was to go to my true friend, Henry Wilson ,who would give her money and make arrangements for her to follow her lover to Cape26 Town and from there to England , where, my love, we can he be married at once

This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BYNC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is noncommercial. See: https://creativecommons.org/Licenses/by-nc/4.0/

China

Su-Li Zhang 0000-0001-5887-1026; Shuang-Zhu Lin 0000-0001-5333-2138; Yan-Qiu Zhou 0000-0001-6834-1723; Wan-Qi Wang 0000-0002-8247-7616; Jia-Yi Li 0000-0002-7729-4479; Cui Wang 0000-0003-2723-5929; Qi-Ming Pang 0000-0002-9501-1700.

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Gao CC

Wang TQ

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