A Case of Functional Growth Hormone Deficiency and Early Growth Retardation in a Child With IFT172 Mutations

Lucas‐Herald, Angela K; Kinning, Esther; Iida, Aritoshi; Wang, Zheng; Miyake, Noriko; Ikegawa, Shiro; McNeilly, Jane; Ahmed, S Faisal

doi:10.1210/jc.2014-3852

Cited by 30 publications

(25 citation statements)

References 11 publications

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“…Mutations in genes encoding proteins of the SHH signaling pathway, such as SHH, the hedgehog receptor CDON (cell adhesion associated, oncogene regulated) and GLI2, have been reported to be causative of both disorders 8,11‐13 . Furthermore, other genes, encoding ciliary proteins, have been implicated in isolated and syndromic pituitary developmental anomalies 14‐16 …”

Section: Discussionmentioning

confidence: 99%

Pituitary stalk interruption syndrome broadens the clinical spectrum of the TTC26 ciliopathy

et al. 2020

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Ciliopathies are a heterogeneous group of disorders, related to abnormal ciliary function. Severe biliary ciliopathy, caused by bi‐allelic mutations in TTC26, has been recently described in the context of a syndrome of polydactyly and severe neonatal cholestasis, with brain, kidney and heart involvement. Pituitary involvement has not been previously reported for patients with this condition. Pituitary stalk interruption syndrome (PSIS) is a congenital anomaly of the pituitary gland, diagnosed by characteristic MRI findings. We now describe four patients with TTC26 ciliopathy due to a homozygous c.695A>G p.Asn232Ser mutation and delineate PSIS as a novel clinical feature of this disorder, highlighting an important role of TTC26 in pituitary development.

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Section: Discussionmentioning

confidence: 99%

Pituitary stalk interruption syndrome broadens the clinical spectrum of the TTC26 ciliopathy

et al. 2020

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“…However, in addition to the core Joubert features, both of our patients had growth hormone deficiency in association with structural abnormalities of the pituitary gland on brain MRI. Growth hormone deficiency occurs in a small number of patients with ciliopathies, including a family recently reported with KIAA0556 mutations (Parisi and Glass 1993; Sanders et al 2015), and an IFT172-related disorder (Lucas-Herald et al 2015), suggesting the potential importance of ciliary function in the development of the pituitary gland. Whether the pituitary defects in our patients were caused by the KIAA0753 defect remains uncertain; identification of other Joubert syndrome patients with defects in KIAA0753 will help to answer this question.…”

Section: Discussionmentioning

confidence: 99%

Mutations in KIAA0753 cause Joubert syndrome associated with growth hormone deficiency

et al. 2017

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Joubert syndrome and related disorders (JSRD) are a heterogeneous group of ciliopathies defined based on the mid-hindbrain abnormalities that result in the characteristic “molar tooth sign” on brain imaging. The core clinical findings of JSRD are hypotonia, developmental delay, abnormal eye movements and breathing abnormalities. To date, more than 30 JSRD genes that encode proteins important for structure and/or function of cilia have been identified. Here, we present 2 siblings with Joubert syndrome associated with growth hormone deficiency. Whole exome sequencing of the family identified compound heterozygous mutations in KIAA0753, i.e., a missense mutation (p.Arg257Gly) and an intronic mutation (c.2359-1G>C). The intronic mutation alters normal splicing by activating a cryptic acceptor splice site in exon 16. The novel acceptor site skips nine nucleotides, deleting three amino acids from the protein coding frame. KIAA0753 (OFIP) is a centrosome and pericentriolar satellite protein, previously not known to cause Joubert syndrome. We present comprehensive clinical descriptions of the Joubert syndrome patients as well as the cellular phenotype of defective ciliogenesis in the patients’ fibroblasts.

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“…Compound heterozygosity for a gene encoding a protein important for ciliary function (IFT172) can cause functional GHD, pituitary hypoplasia, and ectopic posterior pituitary (34), and also Alström syndrome, caused by a mutation of ALMS1 encoding a protein localized to the centrosomes and basal bodies of ciliated cells (35) is associated with GHD. GHD has also been documented in a congenital malformation syndrome associated with a paternal deletion of 6q24.2-q25.2 (36), complete generalized glucocorticoid resistance (37), and mitochondrial diseases (38).…”

Section: Gh Deficiencymentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

Wit

Oostdijk

Losekoot

et al. 2016

European Journal of Endocrinology

153

132

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The fast technological development, particularly single nucleotide polymorphism array, array-comparative genomic hybridization, and whole exome sequencing, has led to the discovery of many novel genetic causes of growth failure. In this review we discuss a selection of these, according to a diagnostic classification centred on the epiphyseal growth plate. We successively discuss disorders in hormone signalling, paracrine factors, matrix molecules, intracellular pathways, and fundamental cellular processes, followed by chromosomal aberrations including copy number variants (CNVs) and imprinting disorders associated with short stature. Many novel causes of GH deficiency (GHD) as part of combined pituitary hormone deficiency have been uncovered. The most frequent genetic causes of isolated GHD are GH1 and GHRHR defects, but several novel causes have recently been found, such as GHSR, RNPC3, and IFT172 mutations. Besides well-defined causes of GH insensitivity (GHR, STAT5B, IGFALS, IGF1 defects), disorders of NFkB signalling, STAT3 and IGF2 have recently been discovered. Heterozygous IGF1R defects are a relatively frequent cause of prenatal and postnatal growth retardation. TRHA mutations cause a syndromic form of short stature with elevated T 3 /T 4 ratio. Disorders of signalling of various paracrine factors (FGFs, BMPs, WNTs, PTHrP/IHH, and CNP/NPR2) or genetic defects affecting cartilage extracellular matrix usually cause disproportionate short stature. Heterozygous NPR2 or SHOX defects may be found in w3% of short children, and also rasopathies (e.g., Noonan syndrome) can be found in children without clear syndromic appearance. Numerous other syndromes associated with short stature are caused by genetic defects in fundamental cellular processes, chromosomal abnormalities, CNVs, and imprinting disorders.

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A Case of Functional Growth Hormone Deficiency and Early Growth Retardation in a Child With IFT172 Mutations

Cited by 30 publications

References 11 publications

Pituitary stalk interruption syndrome broadens the clinical spectrum of the TTC26 ciliopathy

Pituitary stalk interruption syndrome broadens the clinical spectrum of the TTC26 ciliopathy

Mutations in KIAA0753 cause Joubert syndrome associated with growth hormone deficiency

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

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