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A Novel IGSF1 Mutation in a Boy With Short Stature and Hypercholesterolemia: A Case Report.

ABSTRACT: Context:IGSF1 deficiency is a recently discovered syndrome consisting of congenital central hypothyroidism (CeH) and macroorchidism. Here, we report on a patient presenting with short stature, who was found to carry a pathogenic mutation in the IGSF1 gene. Case Description:A 14-year-old Israeli boy was referred to the Academic Medical Center in Amsterdam, The Netherlands, for follow-up on short stature ascribed to constitutional delay of growth and puberty, and familial hypercholesterolemia. Primary hypothyroidism had previously been excluded by a normal thyroid-stimulating hormone (TSH) concentration. However, in follow-up, plasma free thyroxine (FT4) concentrations were repeatedly low, and the patient was diagnosed with CeH. Because of coexistent relative macroorchidism, IGSF1 gene analysis was performed, revealing a mutation (c.2588C>G; p.Ser863Cys). The mutant IGSF1 protein was retained mainly in the endoplasmic reticulum and reached the plasma membrane with poor efficiency compared with wild-type protein. After starting thyroxine treatment, plasma cholesterol almost normalized. Conclusions:This case illustrates the necessity of measuring both FT4 and TSH when hypothyroidism is suspected, or needs to be ruled out. In addition, this case suggests that the presence of childhood hypercholesterolemia may be an indication of undiagnosed hypothyroidism.

SUBMITTER: Heinen CA

PROVIDER: S-EPMC5686658 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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A Novel <i>IGSF1</i> Mutation in a Boy With Short Stature and Hypercholesterolemia: A Case Report.

Heinen Charlotte A CA Zwaveling-Soonawala Nitash N Fliers Eric E Turgeon Marc-Olivier MO Bernard Daniel J DJ van Trotsenburg A S Paul ASP

Journal of the Endocrine Society 20170502 6

<h4>Context</h4>IGSF1 deficiency is a recently discovered syndrome consisting of congenital central hypothyroidism (CeH) and macroorchidism. Here, we report on a patient presenting with short stature, who was found to carry a pathogenic mutation in the <i>IGSF1</i> gene.<h4>Case description</h4>A 14-year-old Israeli boy was referred to the Academic Medical Center in Amsterdam, The Netherlands, for follow-up on short stature ascribed to constitutional delay of growth and puberty, and familial hyp ...[more]

PMID: 29264525

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Project description:BackgroundMutations in the aggrecan (ACAN) gene are identified in patients with: spondyloepiphyseal dysplasia, Kimberley type; short stature with advanced bone age (BA); in the presence or absence of heterozygous ACAN mutation-induced early-onset osteoarthritis and/or osteochondritis dissecans; and spondyloepimetaphyseal dysplasia, ACAN type. Heterozygous mutations contribute to spondyloepiphyseal dysplasia, Kimberley type (MIM#608361), which is a milder skeletal dysplasia. In contrast, homozygous mutations cause a critical skeletal dysplasia, which is called spondyloepimetaphyseal dysplasia, ACAN type (MIM#612813). Lately, investigations on exome and genome sequencing have shown that ACAN mutations can also lead to idiopathic short stature with or without an advanced BA, in the presence or absence of early-onset osteoarthritis and/or osteochondritis dissecans (MIM#165800). We herein reported a heterozygous defect of ACAN in a family with autosomal dominant short stature, BA acceleration, and premature growth cessation.Case summaryA 2-year-old male patient visited us due to growth retardation. The patient presented symmetrical short stature (height 79 cm, < -2 SD) without facial features and other congenital abnormalities. Whole-exome sequencing revealed a heterozygous pathogenic variant c. 871C>T (p. Gln291*) of ACAN, which was not yet reported in cases of short stature. This mutation was also detected in his father and paternal grandmother. According to the Human Gene Mutation Database, 67 ACAN mutations are registered. Most of these mutations are genetically inheritable, and very few children with short stature are associated with ACAN mutations. To date, heterozygous ACAN mutations have been reported in approximately 40 families worldwide, including a few individuals with a decelerated BA.ConclusionHeterozygous c. 871C>T (p. Gln291*) variation of the ACAN gene was the disease-causing variant in this family. Collectively, our newly discovered mutation expanded the spectrum of ACAN gene mutations.

Project description:BackgroundThe pathogenic mutation of short stature homeobox (SHOX) gene is one of the main genetic causes of short stature in children, with an incidence rate of 1/1000~1/2000 and the main clinical manifestations are short stature and (or) limb skeletal abnormalities. SHOX gene mutations are mostly large deletions of regulatory sequence genes, while exon mutations are relatively rare. The pathogenic rate of mutations occurring in exon 5 is only 1/50 000~1/100 000. This study reviewed the clinical data of a child with SHOX gene mutation in exon 5, and analyzed the clinical phenotype, pathogenesis, diagnosis, treatment and prognosis of SHOX gene mutation in combination with relevant literature at home and abroad.Case presentationThe patient was an 8-year-old girl with a height of 105.2 cm (-4.31 standard deviations). Her sitting height/height ratio was 56.8% (>55.5%), and she exhibited high-arched palate, irregular dentition, micrognathia, short fingers, and a normal growth hormone stimulation test. Whole-exome sequencing was performed, and Sanger sequencing was used for site validation. The sequencing results revealed a heterozygous mutation of c.577G > A in exon 5 of the SHOX gene, inherited from the father. The clinical symptoms of the proband were consistent with the phenotype of short stature idiopathic familial associated with SHOX gene mutations. The father, grandfather, uncle, and sister of the proband all had the c.577G > A heterozygous mutation. Therefore, the clinical diagnosis was childhood short stature caused by SHOX gene defects. The SHOX: c.577G > A mutation is likely to be the genetic etiology of familial idiopathic short stature in this family, and this novel mutation enriches the mutation spectrum of the SHOX gene.ConclusionThis is the first case report of familial idiopathic dwarfism caused by mutation at the c.577G > A locus of exon 5 of SHOX gene in the world. This novel mutation enriches the mutation spectrum of the SHOX gene. It is important to emphasize genetic testing, including the SHOX gene, in patients with familial idiopathic short stature and to provide timely growth hormone therapy to individuals with short stature caused by SHOX gene mutations in order to improve their adult height.

Dataset Information

A Novel IGSF1 Mutation in a Boy With Short Stature and Hypercholesterolemia: A Case Report.

Publications

A Novel <i>IGSF1</i> Mutation in a Boy With Short Stature and Hypercholesterolemia: A Case Report.

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