Clinical and biochemical characteristics of 69 male patients and 56 female IGSF1 mutation carriers were collected, providing recommendations for mutational analysis, endocrine work-up, and long-term care.

In male patients, the X-linked IGSF1 deficiency syndrome is characterized by CeH, hypoprolactinemia, delayed puberty, macro-orchidism, and increased body weight. A subset of female carriers also exhibits CeH.

Context:Isolated congenital central hypothyroidism (CeH) can result from mutations in TRHR, TSHB, and IGSF1, but its etiology often remains unexplained. We identified a missense mutation in the transducin β-like protein 1, X-linked (TBL1X) gene in three relatives diagnosed with isolated CeH. TBL1X is part of the thyroid hormone receptor-corepressor complex.Objective:The objectives of the study were the identification of TBL1X mutations in patients with unexplained isolated CeH, Sanger sequencing of relatives of affected individuals, and clinical and biochemical characterization; in vitro investigation of functional consequences of mutations; and mRNA expression in, and immunostaining of, human hypothalami and pituitary glands.Design:This was an observational study.Setting:The study was conducted at university medical centers.Patients:Nineteen individuals with and seven without a mutation participated in the study.Main Outcome Measures:Outcome measures included sequencing results, clinical and biochemical characteristics of mutation carriers, and results of in vitro functional and expression studies.Results:Sanger sequencing yielded five additional mutations. All patients (n = 8; six males) were previously diagnosed with CeH (free T4 [FT4] concentration below the reference interval, normal thyrotropin). Eleven relatives (two males) also carried mutations. One female had CeH, whereas 10 others had low-normal FT4 concentrations. As a group, adult mutation carriers had 20%–25% lower FT4 concentrations than controls. Twelve of 19 evaluated carriers had hearing loss. Mutations are located in the highly conserved WD40-repeat domain of the protein, influencing its expression and thermal stability. TBL1X mRNA and protein are expressed in the human hypothalamus and pituitary.Conclusions:TBL1X mutations are associated with CeH and hearing loss. FT4 concentrations in mutation carriers vary from low-normal to values compatible with CeH.

BackgroundThe combination of developmental delay, facial characteristics, hearing loss and abnormal fat distribution in the distal limbs is known as Pierpont syndrome. The aim of the present study was to detect and study the cause of Pierpont syndrome.MethodsWe used whole-exome sequencing to analyse four unrelated individuals with Pierpont syndrome, and Sanger sequencing in two other unrelated affected individuals. Expression of mRNA of the wild-type candidate gene was analysed in human postmortem brain specimens, adipose tissue, muscle and liver. Expression of RNA in lymphocytes in patients and controls was additionally analysed. The variant protein was expressed in, and purified from, HEK293 cells to assess its effect on protein folding and function.ResultsWe identified a single heterozygous missense variant, c.1337A>C (p.Tyr446Cys), in transducin β-like 1 X-linked receptor 1 (TBL1XR1) as disease-causing in all patients. TBL1XR1 mRNA expression was demonstrated in pituitary, hypothalamus, white and brown adipose tissue, muscle and liver. mRNA expression is lower in lymphocytes of two patients compared with the four controls. The mutant TBL1XR1 protein assembled correctly into the nuclear receptor corepressor (NCoR)/ silencing mediator for retinoid and thyroid receptors (SMRT) complex, suggesting a dominant-negative mechanism. This contrasts with loss-of-function germline TBL1XR1 deletions and other TBL1XR1 mutations that have been implicated in autism. However, autism is not present in individuals with Pierpont syndrome.ConclusionsThis study identifies a specific TBL1XR1 mutation as the cause of Pierpont syndrome. Deletions and other mutations in TBL1XR1 can cause autism. The marked differences between Pierpont patients with the p.Tyr446Cys mutation and individuals with other mutations and whole gene deletions indicate a specific, but as yet unknown, disease mechanism of the TBL1XR1 p.Tyr446Cys mutation.

BackgroundFour genetic causes of isolated congenital central hypothyroidism (CeH) have been identified, but many cases remain unexplained. We hypothesised the existence of other genetic causes of CeH with a Mendelian inheritance pattern.MethodsWe performed exome sequencing in two families with unexplained isolated CeH and subsequently Sanger sequenced unrelated idiopathic CeH cases. We performed clinical and biochemical characterisation of the probands and carriers identified by family screening. We investigated IRS4 mRNA expression in human hypothalamus and pituitary tissue, and measured serum thyroid hormones and Trh and Tshb mRNA expression in hypothalamus and pituitary tissue of Irs4 knockout mice.ResultsWe found mutations in the insulin receptor substrate 4 (IRS4) gene in two pairs of brothers with CeH (one nonsense, one frameshift). Sequencing of IRS4 in 12 unrelated CeH cases negative for variants in known genes yielded three frameshift mutations (two novel) in three patients and one male sibling. All male carriers (n=8) had CeH with plasma free thyroxine concentrations below the reference interval. MRI of the hypothalamus and pituitary showed no structural abnormalities (n=12). 24-hour thyroid-stimulating hormone (TSH) secretion profiles in two adult male patients showed decreased basal, pulsatile and total TSH secretion. IRS4 mRNA was expressed in human hypothalamic nuclei, including the paraventricular nucleus, and in the pituitary gland. Female knockout mice showed decreased pituitary Tshb mRNA levels but had unchanged serum thyroid hormone concentrations.ConclusionsMutations in IRS4 are associated with isolated CeH in male carriers. As IRS4 is involved in leptin signalling, the phenotype may be related to disrupted leptin signalling.

Loss-of-function mutations in the immunoglobulin superfamily member 1 (IGSF1) gene cause an X-linked syndrome of central hypothyroidism, macroorchidism, variable prolactin and GH deficiency, delayed pubertal testosterone rise, and obesity. To understand the pathophysiology of this syndrome, knowledge on IGSF1's place in normal development is imperative. Therefore, we investigated spatial and temporal protein and mRNA expression of IGSF1 in rats using immunohistochemistry, real-time quantitative PCR (qPCR), and in situ hybridization. We observed high levels of IGSF1 expression in the brain, specifically the embryonic and adult choroid plexus and hypothalamus (principally in glial cells), and in the pituitary gland (PIT1-lineage of GH, TSH, and PRL-producing cells). IGSF1 is also expressed in the embryonic and adult zona glomerulosa of the adrenal gland, islets of Langerhans of the pancreas, and costameres of the heart and skeletal muscle. IGSF1 is highly expressed in fetal liver, but is absent shortly after birth. In the adult testis, IGSF1 is present in Sertoli cells (epithelial stages XIII-VI), and elongating spermatids (stages X-XII). Specificity of protein expression was corroborated with Igsf1 mRNA expression in all tissues. The expression patterns of IGSF1 in the pituitary gland and testis are consistent with the pituitary hormone deficiencies and macroorchidism observed in patients with IGSF1 deficiency. The expression in the brain, adrenal gland, pancreas, liver, and muscle suggest IGSF1's function in endocrine physiology might be more extensive than previously considered.

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Systemic TRH administration can increase the activity of cold-stimulated BAT in adult men. These findings may assist developing pharmacological strategies for modulating BAT activity in the management of obesity.