Short Stature in Klinefelter Syndrome From Aggrecan Mutation

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Abstract

Despite tall stature being a characteristic feature of Klinefelter syndrome, occasional cases of short stature have been reported. These cases are often attributed to GH deficiency. This case report details a unique case of a 16-year-old male with Klinefelter syndrome exhibiting proportionate short stature resulting from a heterozygous, likely pathogenic, variant in the ACAN gene c.7141G > A (p.Asp2381Asn). This specific variant, previously identified once in a family with a recessive inheritance pattern is reported here for the first time in an individual with Klinefelter syndrome. This report emphasizes the importance of a thorough evaluation and consideration of genetic testing for an underlying diagnosis in short-statured individuals with Klinefelter syndrome. Timely detection would enable appropriate therapeutic interventions.

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Clinical review: Klinefelter syndrome--a clinical update.

Kristian Groth, Anne Skakkebæk, Christian Høst … (2013)

Recently, new clinically important information regarding Klinefelter syndrome (KS) has been published. We review aspects of epidemiology, endocrinology, metabolism, body composition, and neuropsychology with reference to recent genetic discoveries. PubMed was searched for "Klinefelter," "Klinefelter's," and "XXY" in titles and abstracts. Relevant papers were obtained and reviewed, as well as other articles selected by the authors. KS is the most common sex chromosome disorder in males, affecting one in 660 men. The genetic background is the extra X-chromosome, which may be inherited from either parent. Most genes from the extra X undergo inactivation, but some escape and serve as the putative genetic cause of the syndrome. KS is severely underdiagnosed or is diagnosed late in life, roughly 25% are diagnosed, and the mean age of diagnosis is in the mid-30s. KS is associated with an increased morbidity resulting in loss of approximately 2 yr in life span with an increased mortality from many different diseases. The key findings in KS are small testes, hypergonadotropic hypogonadism, and cognitive impairment. The hypogonadism may lead to changes in body composition and a risk of developing metabolic syndrome and type 2 diabetes. The cognitive impairment is mainly in the area of language processing. Boys with KS are often in need of speech therapy, and many suffer from learning disability and may benefit from special education. Medical treatment is mainly testosterone replacement therapy to alleviate acute and long-term consequences of hypogonadism as well as treating or preventing the frequent comorbidity. More emphasis should be placed on increasing the rate of diagnosis and generating evidence for timing and dose of testosterone replacement. Treatment of KS should be a multidisciplinary task including pediatricians, speech therapists, general practitioners, psychologists, infertility specialists, urologists, and endocrinologists.

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A recessive skeletal dysplasia, SEMD aggrecan type, results from a missense mutation affecting the C-type lectin domain of aggrecan.

Stuart W J Tompson, Barry Merriman, Vincent Funari … (2009)

Analysis of a nuclear family with three affected offspring identified an autosomal-recessive form of spondyloepimetaphyseal dysplasia characterized by severe short stature and a unique constellation of radiographic findings. Homozygosity for a haplotype that was identical by descent between two of the affected individuals identified a locus for the disease gene within a 17.4 Mb interval on chromosome 15, a region containing 296 genes. These genes were assessed and ranked by cartilage selectivity with whole-genome microarray data, revealing only two genes, encoding aggrecan and chondroitin sulfate proteoglycan 4, that were selectively expressed in cartilage. Sequence analysis of aggrecan complementary DNA from an affected individual revealed homozygosity for a missense mutation (c.6799G --> A) that predicts a p.D2267N amino acid substitution in the C-type lectin domain within the G3 domain of aggrecan. The D2267 residue is predicted to coordinate binding of a calcium ion, which influences the conformational binding loops of the C-type lectin domain that mediate interactions with tenascins and other extracellular-matrix proteins. Expression of the normal and mutant G3 domains in mammalian cells showed that the mutation created a functional N-glycosylation site but did not adversely affect protein trafficking and secretion. Surface-plasmon-resonance studies showed that the mutation influenced the binding and kinetics of the interactions between the aggrecan G3 domain and tenascin-C. These findings identify an autosomal-recessive skeletal dysplasia and a significant role for the aggrecan C-type lectin domain in regulating endochondral ossification and, thereby, height.

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Clinical Characterization of Patients With Autosomal Dominant Short Stature due to Aggrecan Mutations.

Alexandra Gkourogianni, Melissa Andrew, Leah Tyzinski … (2016)

Heterozygous mutations in the aggrecan gene (ACAN) cause autosomal dominant short stature with accelerated skeletal maturation.

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Author and article information

Contributors

Antoinette Farrell:

ORCID: https://orcid.org/0009-0002-9180-9691

Sunitha R Sura

Journal

Journal ID (nlm-ta): JCEM Case Rep

Journal ID (iso-abbrev): JCEM Case Rep

Journal ID (publisher-id): jcemcr

Title: JCEM Case Reports

Publisher: Oxford University Press (US )

ISSN (Electronic): 2755-1520

Publication date Collection: October 2024

Publication date (Electronic): 03 October 2024

Publication date PMC-release: 03 October 2024

Volume: 2

Issue: 10

Electronic Location Identifier: luae170

Affiliations

Department of Pediatrics, University of Connecticut School of Medicine , Hartford, CT 06106, USA

Department of Pediatrics, University of Connecticut School of Medicine, Hartford , CT 06106, USA

Division of Pediatric Endocrinology & Diabetes, Connecticut Children's , Farmington, CT 06032, USA

Author notes

Correspondence: Antoinette Farrell, MD, Department of Pediatrics, University of Connecticut School of Medicine, 282 Washington St., Hartford, CT 06106, USA, Email: aafarrell26@ 123456gmail.com .

Author information

Antoinette Farrell https://orcid.org/0009-0002-9180-9691

Article

Publisher ID: luae170

DOI: 10.1210/jcemcr/luae170

PMC ID: 11447372

PubMed ID: 39364324

SO-VID: 7522e4e5-507e-4564-9493-02c4c6550906

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History

Date received : 04 June 2024

Date: 10 September 2024

Date: 03 October 2024

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Pages: 4

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Short Stature in Klinefelter Syndrome From Aggrecan Mutation

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Most cited references 10

Clinical review: Klinefelter syndrome--a clinical update.

A recessive skeletal dysplasia, SEMD aggrecan type, results from a missense mutation affecting the C-type lectin domain of aggrecan.

Clinical Characterization of Patients With Autosomal Dominant Short Stature due to Aggrecan Mutations.

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