IHH Gene Mutations Causing Short Stature With Nonspecific Skeletal Abnormalities and Response to Growth Hormone Therapy

Vasques, Gabriela A; Funari, Mariana F A; Ferreira, Frederico Moraes; Aza‐Carmona, Miriam; Sentchordi-Montané, Lucía; Barraza-García, Jimena; Lerário, Antônio Marcondes; Yamamoto, Guilherme Lopes; Naslavsky, Michel Satya; Duarte, Yeda A. O.; Bertola, Débora Romeo; Heath, Karen E.; Jorge, Alexander A L

doi:10.1210/jc.2017-02026

Cited by 57 publications

(52 citation statements)

References 30 publications

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“…The only recurrent radiological finding observed was a varying degree of shortening of the middle phalanx of the 5 th finger ( Figure 2B), which is the defining feature of Brachymesophalangia -V (BMP-V). BMP-V was observed in 64.3% hand radiographs from individuals with heterozygous mutations in IHH in our cohort, which was significantly higher than that observed in a population study (12.1%) (15). Four probands were born small for gestational age considering only length at birth.…”

Section: Ihhcontrasting

confidence: 79%

“…In 2018, we described heterozygous IHH mutations as a cause of the growth impairment in an ISS cohort (frequency of 3.4%) (15). Our patients with heterozygous IHH variants did not present classical features of BDA1.…”

Section: Ihhmentioning

confidence: 56%

“…For example, there are short stature individuals harboring pathogenic variants in genes responsible for the Noonan syndrome who do not present any of the other phenotypic alterations that would allow the recognition of this condition clinically (11). Additionally, genes that regulate the growth plate and that had already been associated with skeletal dysplasias were recently pointed as responsible for some cases of ISS (12)(13)(14)(15)(16). This review provides an update on monogenic causes of isolated short stature.…”

Section: Introductionmentioning

confidence: 99%

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Genetic causes of isolated short stature

Vasques¹,

Andrade²,

Jorge³

2019

Archives of Endocrinology and Metabolism

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Short stature is a common feature, and frequently remains without a specific diagnosis after conventional clinical and laboratorial evaluation. Longitudinal growth is mainly determined by genetic factors, and hundreds of common variants have been associated to height variability among healthy individuals. Although isolated short stature may be caused by the combination of variants, with a deleterious impact on the growth of individuals with polygenic inheritance, recent studies have pointed out some monogenic defects as the cause of the growth disorder observed in nonsyndromic children. The majority of these defects are in genes related to the growth plate cartilage and in the growth hormone (GH) -insulin-like growth factor 1 (IGF-1) axis. Affected patients usually present the mildest spectrum of some forms of skeletal dysplasia, or subtle abnormalities of laboratory tests, suggesting hormonal resistance or insensibility. The lack of specific characteristics, however, does not allow formulation of a definitive diagnosis without the use of broad genetic studies. Thus, molecular genetic studies including panels of genes or exome analysis will become essential in investigating and identifying the causes of isolated short stature in children, with a crucial impact on treatment and follow-up.

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Section: Ihhcontrasting

confidence: 79%

Section: Ihhmentioning

confidence: 56%

Section: Introductionmentioning

confidence: 99%

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Genetic causes of isolated short stature

Vasques¹,

Andrade²,

Jorge³

2019

Archives of Endocrinology and Metabolism

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“…14 IHH pathogenic variants have been reported to be association with BD [11][12][13][14][ figure 4A], and the variants are restricted to the N-terminal active fragment, and exhibit a variable outcome [4]. Variants associated with brachydactyly type A1 are known to predominantly affect codon 95, 100, 131, and 154 [3,[15][16].…”

Section: Discussionmentioning

confidence: 99%

“…In particular, p.D100E had been shown to affect IHH interaction with PTCH1 and HIP1, reducing its capacity to induce cellular differentiation [16], whereas p.D100E was shown to change the Hh local tertiary structure and intracellular fate [5] [3,[20][21]. Not all DBA1 individuals with these pathogenic variants exhibited short stature, but they were shorter than non-carrier family members [3,[19][20][21], suggesting variants at this mutational hotspot can affect the growth to various degree but with reduced penetrance for short stature. In this Chinese family with a novel variant at residue 100, short stature was not 100% penetrant: the proband (Ⅳ-2), proband's uncle (III-4) and cousin (Ⅳ-5) had short stature, whereas her father (III-2) and uncle (III-5)'s height had normal stature.…”

Section: Discussionmentioning

confidence: 99%

A novel pathogenic variant of IHH for Brachydactyly type A1

Yang¹,

Wang²,

Tian³

et al. 2019

Preprint

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Brachydactyly type A1 (BDA-1, MIM 112500) is a genetically heterogeneous autosomal-dominant disorder mainly characterized by shortening or missing of the middle phalanges. Brachydactyly type A1 (BDA-1) is caused by heterozygous pathogenic variants in a specific region of the N-terminal active fragment of Indian Hedgehog (IHH). In this study, we reported a Chinese family with 8 members affected with Brachydactyly type A1. After performing whole-exome sequencing in the proband, we identified a novel heterozygous missense variant c.299A>G (p.D100G) at the mutational hotspot of IHH gene. The variant co-segregated with BDA-1 in the pedigree, showed 100% penetrance for phalange phenotype with variable expressivity. This finding expanded the Brachydactyly type A1-related mutational spectrum of IHH gene.

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Hedgehog acyl‐transferase‐related multiple congenital anomalies: Report of an additional family and delineation of the syndrome

Pande

Radhakrishnan

Shetty³

et al. 2021

American J of Med Genetics Pt A

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This study includes previous reports of four affected individuals from two unrelated families with hedgehog acyl-transferase (HHAT)-related multiple congenital anomaly syndrome. Microcephaly, small cerebellar vermis, holoprosencephaly, agenesis of corpus callosum, intellectual disability, short stature, skeletal dysplasia, microphthalmiaanophthalmia, and sex reversal constitute the phenotypic spectrum of this condition with variable expression. We report an additional family with three affected conceptuses: two abortuses and one living proband. We did proband-parents trio exome sequencing and identified a biallelic in-frame deletion c.365_367del; (p.Thr122del) in exon 5 of HHAT. With this report, we delineate the phenotype and allelic heterogeneity of the HHAT-related multiple congenital anomaly syndrome.

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IHH Gene Mutations Causing Short Stature With Nonspecific Skeletal Abnormalities and Response to Growth Hormone Therapy

Abstract: Our study demonstrated the association of pathogenic variants in IHH with short stature with nonspecific skeletal abnormalities and established a frequent cause of growth disorder, with a preliminary good response to rhGH.

Cited by 57 publications

References 30 publications

Genetic causes of isolated short stature

Genetic causes of isolated short stature

A novel pathogenic variant of IHH for Brachydactyly type A1

Hedgehog acyl‐transferase‐related multiple congenital anomalies: Report of an additional family and delineation of the syndrome

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