lNTRODUCTlON

Children often visit pediatric endocrinologists because of their short stature.However,the clinical definition and therapeutic regimen of pediatric growth disorders have been significantly changed by recent advances in genetic methodology.Idiopathic short stature and advanced bone age(BA),in the presence or absence of heterozygous aggrecan()mutation-induced early-onset osteoarthritis and/or osteochondritis dissecans exemplify these changes well.Herein,we presented the case and his affected members with symmetrical short stature,and a heterozygous variant of thegene was the disease-causing variant in this family.

CASE PRESENTATlON

Chief complaints

A 2-year-old boy with growth retardation for over 1 year.

History of present illness

This boy was born at 40 wk of gestation following a common pregnancy and parturition.At birth,his weight was 2.75 kg,while there was no specific body length measurement.At 2 years of age,the patient visited us due to his short stature.His height was 79 cm(-2.7 SD),with a bodyweight of 10 kg,and his occipitofrontal circumference was 49 cm.No dysmorphic features were detected.His mental and motor development were normal.

History of past illness

The patient was not associated with any previous illness.

Personal and family history

The height of his father and paternal grandmother was 152 cm(＜ -3.0 SD)and 138 cm(＜ -3.0 SD),respectively.

Physical examination

There are 19 exons in the humangene[11].The G1 region,interglobular domain,and G2 region are encoded by exons 3-6,exon 7,and exons 8-10,respectively.The GAG attachment region is encoded by exons 11 and 12,in which exon 11 encodes the first part of the KS-rich domain,and the large exon 12 encodes the remainder of the KS-rich domain as well as the CS1 and CS2 domains.The exons 13-19 encode the G3 region,exons 13 and 14 each encode an epidermal growth factor-like domain,exons 15-17 encode the lectin-like domain,and exon 18 encodes the complement regulatory protein-like domain.

Laboratory examinations

Watanabe[15]showed that heterozygotes have two obvious phenotypes: slight dwarfism and age-related hyperlordosis,the anterior concavity in the curvature of the spine.In the families analyzed by some studies[16-18],heterozygotes are detected in all affected members,who exhibit the clinical features of short stature and advanced BA.These data indicate that various pathogenic heterozygousvariants(Table 1)affect the chondrogenesis of the growth plate in a similar pattern.Therefore,the growth plate chondrogenesis is impaired by functional haploinsufficiency of ACAN rather than various mutation-specific mechanisms.However,a dysfunctional C-type lectin domain in the ACAN protein leads to a more severe phenotype,impairing the functions of the growth plate and articularcartilage.All these studies provide a reasonable explanation for why those families have short stature but no evidence of early-onset osteoarthritis.The proband and affected members of our case also presented with autosomal dominant short stature and no indications of chondrodysplasia.

Imaging examinations

His BA was evaluated as 3 years and 6 mo to 4 years(Figure 2).

FlNAL DlAGNOSlS

Short stature caused bymutation.

TREATMENT

Then one day, I met a girl, a wonderful girl, an army nurse, whose faith and stability were to change my whole life. As our acquaintance ripened16 into friendship, she discerned, behind a shell of gaiety, my recurring17 plateaus of depression. She said, Stop knocking on closed doors. Keep up your beautiful music. I know your opportunity will come. You’re trying too hard. Why don’t you relax, and have you ever tried praying?

OUTCOME AND FOLLOW-UP

The height of the patient was increased by about 1 cm per month after GH treatment.During the treatment,no adverse events were recorded.

DlSCUSSlON

Thegene encoding aggrecan is usually localized on chromosome 15q26[1,2].Its full-length clone has been obtained by Doege[3].The kernel protein of ACAN is composed of three disulfide-bonded globular domains(G1,G2,and G3)and intervening extended domains[4].The interglobular domain is a protruding site for breaking proteins into smaller polypeptides or amino acids,and many proteinases can cleave between the G1 and G2 domains[5,6].An extended GAG-attachment region separates the G2 and G3 domains,which is differentiated into three parts.The keratan sulfate(KS)-rich domain lies adjacent to the G2 domain.The KS-rich domain is likened to the chondroitin sulfate(CS)-rich domain,which is differentiated into two subdomains(CS1 and CS2),and the amino acid sequences of these two subdomains are different.The CS2 domain is connected to the G3 domain,which is located at the carboxy terminus of the core protein.The G3 region consists of two epidermal growth factor-like domains,one C-type lectin-like domain,and one complement regulatory protein-like domain[7].The G3 region plays a fundamental role in the normal trafficking of ACAN within the chondrocytes,and such a region is also involved in the release of ACAN into the extracellular matrix[8].In the extracellular matrix,the G3 domain is not detected in some ACAN molecules[9,10],which can probably be attributed to proteolytic cleavage.

The physical test showed retarded growth(height,79 cm;weight,10 kg).He presented symmetrical short stature without facial features and other congenital abnormalities.

They loosened their moorings, and made for the middle of the stream, and when they were at some distance from the bank, the hare took his oar37, and struck such a heavy blow at the other boat, that it broke in two

ACAN is the main proteoglycan of the extracellular matrix of the growth plate cartilage[12].Mutations inare associated with growth defects[13].The research of Gleghorn[14]first reported anmutation that causes human disease.They have identified the heterozygosity for a 1-bp insertion in thegene with spondyloepiphyseal dysplasia,Kimberley type-affected members.This mutation can forecast the synthesis of a truncated protein that is about 60% of the normal size.The truncated protein lacks half of the CS1 domain,the complete CS2 domain,and the G3 domain,while it includes a novel sequence of 212 aa.

One day she gave Helena twelve pounds of mixed feathers and bade her separate them all before evening, threatening her with heavy punishment if she failed to do so

The peripheral blood was collected from the patient and his family members,followed by DNA extraction.Whole-exome sequencing was performed using an xGen Exam research panel v1.0(IDT)on a HiSeq 4000(Illumina).Any known disease associations were determined using the Online Mendelian Inheritance of Man(http://www.omim.org)database.A heterozygous mutation in(NM_013227.3)was identified in all affected individuals.Thismutation was predicted to cause the resultant termination at codon 291(c.871C＞T;p.Gln291*)(Figure 1).

There the Gray Wolf stopped. Well, Tsarevitch Ivan, he said, I have paid for thy horse, and have served thee in faith and truth. Get down now; I am no longer thy servant.

The combination of short stature and advanced BA is rare.Most known causative mutations either impair proteoglycan synthesis[19-21]or reduce signaling through the cAMP-protein kinase A signaling pathway[22-24].

The authors declare that there was no conflict of interest to report.

The patient received growth hormone(GH)treatment.

“Even though I died right there in prison, I want to tell you something. The reason I need to talk to you today. I have risen again, just like in the Bible. I am reborn. One day a woman came in and told me to write. And I had never written before, but I did it anyway. I sat for eight ours in a chair and focused the way I have never focused before. I could never even sit still before! I wrote out my ugly life, and then I was able to finally feel something. To feel pity. For myself. When no one else was ever able to feel it. And I felt something else. I felt joy. I was writing, and what I was writing was good. I was a writer! And I was going to get up in front of all those men in that class, and I would say that this . . .” At these words he held up his little manuscript. This is more important to me than any drug. What I wanted to tell you was that I died a drug addict16, and I was reborn as a writer.”

CONCLUSlON

What a man! My husband understands my past. He s been beside me as I ve grown from an unsure young girl to a confident woman, mother, speaker and author.

ACKNOWLEDGEMENTS

We gratefully acknowledge the kind cooperation of the patient,the family members,and the staff from the unit for their assistance in conducting this study.

In the present study,a heterozygous mutation in thegene was identified in a Chinese family with short stature.We hypothesized that this mutation could induce early truncation of the ACAN protein.Genetic testing is important for diagnosis and treatment.

FOOTNOTES

Yin LP and Zheng HX collected the medical records of the patient,reviewed the literature,and drafted the manuscript;Zhu H revised the manuscript;all authors agreed to submit the final version.

The patient signed the informed consent and permitted publication of his information and any accompanying images.

In the clinical studies ofpatients,the length in the lower part of most heterozygous carriers ofvariants show a normal range at birth,while some of them are born short for gestational age[25].Some researchers have suggested that individuals treated with GH have an improvement in adult height.In addition to GH treatment,some patients also simultaneously receive treatment with gonadotropin-releasing hormone analogue.This treatment can be given to patients after the administration of an aromatase inhibitor,which can successfully postpone bone maturation,and such therapy can benefit those carrying confirmedmutations[26-31].

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

The young man did as he was bid, and when the lion was made the old woman hid the youth in it, and brought it to the king, who was so delighted with it that he wanted to buy it

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China

Li-Ping Yin 0000-0002-5965-037X;Hong-Xue Zheng 0000-0003-0929-6621;Hong Zhu 0000-0001-5078-1288.

Liu JH

I began to dread2 going to math. I was tired of their swear words, their stories of drugs and violence, and their negative attitudes. Some days they would come into the room in such a bad mood that everyone could feel it. I began to resent the fact that I had to be there. One girl in particular began to eat away at my nerves. Some days I wanted to hide under my desk.

Filipodia

Liu JH