IGSF1 Deficiency Syndrome Research Articles

Prolactin deficiency in the context of other pituitary hormone abnormalities : Special issue: hypoprolactinemia: a neglected endocrine disorder.

Prolactin deficiency is rare. It generally occurs when pituitary disorders, such as large pituitary tumors, pituitary apoplexy, and other conditions associated with sellar mass effect lead to global failure of pituitary function and hypopituitarism. In these situiations, prolactin is commonly the last pituitary hormone affected, after growth hormone and gonadotropins are lost and thyroid-stimulating hormone and adrenocorticotopic hormone secretion is impaired. Prolactin deficiency accompanies several congenital syndromes due to mutations in PROP1 and Pit1/ POU1F and in X-linked IGSF1 deficiency syndrome, and several aqcuired conditions including Sheehan syndrome, IgG4-related hypophysitis, and immune checkpoint-inhibitor-induced hypophysitis. In women, prolactin deficiency prevents lactation following childbirth among other symptoms associated with hypopituitarism. Human prolactin is not available commercially as replacement therapy. However, recombinant human prolactin administered daily to women with hypoprolactinemia and alactogenesis was found to lead to the production of significant milk volume sufficient for lactation.

Hepatomegaly and fatty liver disease secondary to central hypothyroidism in combination with macrosomia as initial presentation of IGSF1 deficiency syndrome.

IGSF1 deficiency syndrome (immunoglobulin superfamily member 1) is considered the most common sex-linked cause of secondary congenital hypothyroidism and is characterized by a wide variety of other clinical and biochemical features, including hypoprolactinemia, transient and partial growth hormone deficiency, early/normal timing of testicular enlargement but delayed testosterone rise in puberty, and adult macro-orchidism. Congenital central hypothyroidism is a rare disease (1:65,000 births); the detection of which may be delayed and missed by neonatal screening programs since most neonatal screening programs are based on TSH determination in dried blood spots only. Untreated hypothyroidism may cause abnormal liver biochemistry and non-alcoholic fatty liver disease. Our aim is to report a case of secondary hypothyroidism in an infant with an uncommon initial presentation. A 3-month-old male baby was referred to our hospital due to elevated alpha-fetoprotein levels, hypercholesterolemia, and macrosomia. Initial investigations revealed enlarged fatty liver and central hypothyroidism. Pituitary insufficiency was biochemically excluded and a pituitary MRI showed normal findings. Upon genetic analysis, a hemizygous variant NM_001170961.1:c.2422dup, p.(His808Profs*14), in IGSF1 gene was detected, establishing the diagnosis of the IGSF1 deficiency syndrome. In our patient, no other clinical findings were identified. Treatment with levothyroxine led to the remission of liver disease. Liver disease may be the initial presentation of secondary hypothyroidism in neonates and infants. Macrosomia in patients with isolated secondary central hypothyroidism is a strong indicator of IGSF1 syndrome.

SAT-057 A Novel IGSF1 Variant in a Boy with Central Hypothyroidism and Epiphyseal Dysplasia

Background: IGSF1 deficiency syndrome, also known as X-linked central hypothyroidism and testicular enlargement (CHTE) syndrome, is caused by mutations in the immunoglobulin superfamily, member 1 gene. Recently recognized as the most common genetic cause of isolated central hypothyroidism (CH), its cardinal features include CH and adult macroorchidism. We describe a boy with CH and epiphyseal dysplasia found to have a novel IGSF1 variant.Clinical case: A male with attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder, obsessive compulsive disorder and obesity was evaluated at age 9y for high total and LDL cholesterol and low T4 with normal TSH. He had short stature for family, high BMI, high sitting height ratio, and short arm span. Laboratory investigation revealed persistently mildly high total and LDL cholesterol, low T4, normal cortisol response to low-dose Cortrosyn stimulation, and normal IGF-1 and IGF-BP3. Bone age at 9y1m chronological age was 8y0m. Skeletal survey showed abnormal epiphyses of the femoral heads, knees, and humeral capitella suggesting primary epiphyseal dysplasia; he was referred to genetics. Growth improved after starting levothyroxine for CH. Multiple epiphyseal dysplasia gene panel (with reflex to clinical exome) did not find any variants known to be pathogenic for his condition. He was found to be a carrier of autosomal recessive Bartter syndrome. Heterozygous variants of unknown significance were found in RMRP, FGFR1, CDT1 and APOB. Whole exome sequencing showed hemizygosity for the p.Q743X (c.2227C>T) variant in IGSF1.Discussion: The p.Q743X IGSF1 variant has not been reported in the literature and is not present in population databases. It is predicted to cause loss of normal protein function and is considered pathogenic. CH is found in all males with IGSF1 deficiency syndrome. Macroorchidism, another defining feature, develops in adulthood; age of testicular growth onset is normal, but pubertal testosterone rise is delayed. Our patient remains prepubertal at age 11y. Other features sometimes present include hypoprolactinemia (which was found in this child) and transient partial GHD (not seen in this case). Overweight and the metabolic syndrome are common; this child’s cholesterol abnormalities may be due to weight and/or APOB variant found on genetic testing. ADHD has been seen in some patients with this syndrome; this child also has extensive psychiatric/behavioral problems, which have not been described. The skeletal findings in this case have not been previously noted in IGSF1 deficiency syndrome; whether this is a rare feature of IGSF1 deficiency syndrome or a separate entity is unclear. This case adds to the growing list of disease-causing variants in IGSF1. Endocrinologists should consider IGSF1 deficiency syndrome when diagnosing isolated CH in boys, as the characteristic macroorchidism is not present in childhood.

A novel IGSF1 mutation in a large Irish kindred highlights the need for familial screening in the IGSF1 deficiency syndrome.

SummaryObjectiveLoss‐of‐function mutations in IGSF1 result in X‐linked central congenital hypothyroidism (CeCH), occurring in isolation or associated with additional pituitary hormone deficits. Intrafamilial penetrance is highly variable and a minority of heterozygous females are also affected. We identified and characterized a novel IGSF1 mutation and investigated its associated phenotypes in a large Irish kindred.Design, Patients and MeasurementsA novel hemizygous IGSF1 mutation was identified by direct sequencing in two brothers with CeCH, and its functional consequences were characterized in vitro. Genotype‐phenotype correlations were investigated in the wider kindred.ResultsThe mutant IGSF1 protein (c.2318T > C, p.L773P) exhibited decreased plasma membrane expression in vitro due to impaired trafficking from the endoplasmic reticulum. Ten hemizygous males and 11 heterozygous females exhibited characteristic endocrine deficits. Ireland operates a TSH‐based CH screening programme, which does not detect CeCH; therefore, genetic ascertainment preceded biochemical diagnosis of moderate CH in five of seven boys as well as their 75‐year‐old grandfather. Clinical features potentially attributable to hypothyroidism were variable; normal free T3 (FT3) and low/low normal reverse T3 (rT3) concentrations suggested that preferential deiodination of FT4 to FT3 may help maintain tissue euthyroidism in some individuals. However, neonatal jaundice, delayed speech or growth, and obesity were observed in seven subjects in whom diagnosis was delayed.ConclusionsAs observed with other IGSF1 mutations, p.L773P results in variably penetrant IGSF1 deficiency syndrome. Our observations emphasize the need for multi‐generation genetic ascertainment in affected families, especially where TSH‐based CH screening programmes may fail to detect CeCH at birth.

A novel IGSF1 mutation in a large Irish kindred highlights the need for family screening in the IGSF1 deficiency syndrome

A novel IGSF1 mutation in a large Irish kindred highlights the need for family screening in the IGSF1 deficiency syndrome

A novel IGSF1 mutation in a large Irish kindred highlights the need for systematic familial endocrine screening in the IGSF1 deficiency syndrome

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Familial Central Hypothyroidism Caused by a Novel IGSF1 Gene Mutation.

Congenital hypothyroidism of central origin (CH-C) is a rare disease in which thyroid hormone deficiency is caused by insufficient thyrotropin stimulation of a normal thyroid gland. A recently described syndrome of isolated CH-C and macroorchidism was attributed to loss-of-function mutations of the immunoglobulin superfamily, member 1 gene (IGSF1). CH-C was diagnosed in three siblings. The TRH, TRHR, and TSHB genes were sequenced followed by whole-exome sequencing in the proband. A mutation identified in IGSF1 was analyzed by direct PCR sequencing in family members. The effects of the mutation were assessed by in vitro studies in HEK293 cells. The index case was negative for mutations in TRH, TRHR, and TSHB. Whole-exome sequencing revealed a novel insertion mutation in IGSF1, c.2284_2285insA, p.R762QfsX7, which was confirmed by direct PCR sequencing and was identified in six additional family members. The mutation introduces a frame-shift and premature stop codon in the seventh Ig loop, thereby truncating IGSF1. In vitro studies revealed that the mutated IGSF1-R762QfsX7 migrates as a doublet at ∼28 kDa, which is far smaller than the wild type protein (130-140 kDa). Both bands were endonuclease H sensitive, indicating immature glycosylation and failure of the protein to traffic out of the endoplasmic reticulum to the plasma membrane. Further phenotypic findings in the family included macroorchidism and infertility in the uncle and mild neurological phenotypes in the affected males, such as hypotonia, delayed psychomotor development, clumsy behavior, and attention deficit disorder. We identified a novel insertion mutation in the IGSF1 gene and further delineated the phenotype of the IGSF1-deficiency syndrome. Our findings indicate a possible association between an IGSF1 mutation and neurological phenotypes.

Mild deficits in attentional control in patients with the IGSF1 deficiency syndrome.

Male patients with the X-linked IGSF1 deficiency syndrome are characterized by central hypothyroidism, delayed pubertal testosterone rise, adult macroorchidism, variable prolactin deficiency and occasionally transient partial growth hormone deficiency. Thyroid hormone plays a vital role in brain development and functioning, and while most patients receive adequate replacement therapy starting shortly after birth, it is unknown whether this syndrome is accompanied by long-term impaired cognitive functioning. We therefore assessed cognitive functioning in male patients with IGSF1 deficiency. Fifteen adult male patients with IGSF1 deficiency participated in neuropsychological assessment of executive functioning and memory, and completed validated questionnaires on health-related quality of life (HRQoL), mood and fatigue. Results were compared to data from previous studies by our department: 54 healthy controls (76 for the attention task) for the test battery and 191 healthy controls for the questionnaires. All patients had central hypothyroidism, and twelve were treated with levothyroxine. Patients performed worse than controls in tasks that required attentional control (Trail Making Test, Letter-Digit Substitution Test, and Sustained Attention to Response Task) (all P < 0·001). Memory was unaffected. In addition, patients reported more mental fatigue and reduction of activity (Multidimensional Fatigue Inventory) (both P < 0·01), while HRQoL and mood reports were not different from controls. Age at the start of replacement therapy and current thyroxine levels were not related to outcome. Adult male patients with IGSF1 deficiency exhibit mild deficits in attentional control on formal testing. This finding was not related to the age at start of replacement therapy, or current levothyroxine treatment.

Pituitary hormone secretion profiles in IGSF1 deficiency syndrome

Pituitary hormone secretion profiles in IGSF1 deficiency syndrome

IGSF1 deficiency syndrome: A newly uncovered endocrinopathy.

A recently uncovered X-linked syndrome, caused by loss-of-function of IGSF1, is characterized by congenital central hypothyroidism and macroorchidism, variable prolactin deficiency, occasional growth hormone deficiency, delayed pubertal testosterone secretion and obesity. We propose to call this endocrinopathy “IGSF1 deficiency syndrome.” Based on an estimated incidence of isolated congenital central hypothyroidism of 1:65,000, we predict that the incidence of IGSF1 deficiency related hypothyroidism is approximately 1:100,000. IGSF1 encodes a plasma membrane immunoglobulin superfamily glycoprotein that is highly expressed in pituitary and testis, but is of unknown function. The variable profile of pituitary dysfunction suggests that IGSF1 may play a role in pituitary paracrine regulation. The clinical significance of the syndrome, particularly the clinical consequences of untreated hypothyroidism, justifies screening family members of patients with IGSF1 mutations for carriership and to study potential carriers of IGSF1 mutations, including patients with idiopathic central hypothyroidism, combined GH and TSH deficiency, macroorchidism or delayed puberty.