Prolactin Deficiency Research Articles

POU1F1 mutations in combined pituitary hormone deficiency: differing spectrum of mutations in a Western-Indian cohort and systematic analysis of world literature.

POU1F1 mutations are prevalent in Indian CPHD cohorts. Genotype-phenotype correlation is not well-studied. To describe phenotypic and genotypic spectrum of POU1F1 mutations in our CPHD cohort and present systematic review as well as genotype-phenotype analysis of all mutation-positive cases reported in world literature. Retrospective study of POU1F1 mutation-positive patients from a western-Indian center. PRISMA guidelines based pubmed search of published literature of all mutation-positive patients. Our cohort had 15 POU1F1 mutation-positive patients (9 index, 6 relatives). All had severe GH, TSH and prolactin deficiencies (GHD, TSHD and PD). TSHD was diagnosed earliest followed by GHD (median ages: TSHD-6months, GHD-3years), while PD was more variable. Two sisters had central precocious puberty at 7years of age. Pubic hair was deficient in all post-pubertal patients (females: P1-P2, males: P3-P4). Splice-site/intronic/frameshift mutations were most common, while missense/nonsense mutations were less frequent (33%). Review of world literature yielded 114 patients (82 index patients) from 58 studies. GHD was present in all patients. TSHD was spared in 12.5% and PD in 4.4% patients. Missense/nonsense mutations accounted for 75% of spectrum. Phenotype-genotype analysis revealed higher mean peak-GH levels (1.1 vs 0.2ng/ml, p = 0.008) and lower prevalence of anterior-pituitary hypoplasia (63.6% vs 86.3%, p = 0.03) in patients with heterozygous than homozygous and compound heterozygous mutations. We present largest series of POU1F1 mutation-positive patients. Precocious puberty and defective pubarche are lesser-appreciated phenotypic features. Our mutation spectrum is different from that of world literature. Patients with heterozygous mutations have milder phenotype.

Two Cases of anti–PIT-1 Hypophysitis Exhibited as a Form of Paraneoplastic Syndrome not Associated With Thymoma

Anti–pituitary-specific transcription factor 1 (PIT-1) hypophysitis (anti–PIT-1 antibody syndrome) is a thymoma-associated autoimmune disease characterized by acquired growth hormone (GH), prolactin (PRL), and thyrotropin (TSH) deficiencies due to autoimmunity against PIT-1. Ectopic expression of PIT-1 in the thymoma plays a causal role in development of the disease. Here, we report 2 cases of anti–PIT-1 hypophysitis exhibiting as a form of paraneoplastic syndrome with conditions other than thymoma. A 79-year-old woman (case 1) and an 86-year-old man (case 2) were referred with a suspicion of anti–PIT-1 hypophysitis because of acquired GH, PRL, and TSH deficiencies. Case 1 was complicated by diffuse large B-cell lymphoma (DLBCL) of the bladder and case 2 was diagnosed with malignancy with multiple metastases of unknown origin. Because circulating anti–PIT-1 antibody was detected, both patients were diagnosed with anti–PIT-1 hypophysitis. Circulating PIT-1–reactive T cells were detected in case 1 via enzyme-linked immunospot (ELISPOT) assay. Interestingly, the PIT-1 protein was ectopically expressed in the DLBCL cells of case 1, whereas DLBCL tissues derived from patients without anti–PIT-1 hypophysitis were negative for PIT-1. In case 2, the materials were not available because of best supportive care was under way. These data show that anti–PIT-1 hypophysitis is associated not only with thymoma but also with other malignancies. Additionally, the ectopic expression of PIT-1 in the DLBCL tissues and presence of PIT-1–reactive T cells suggested that the underlying mechanisms were similar to those observed in thymoma. Thus, anti–PIT-1 hypophysitis is defined as a form of paraneoplastic syndrome.

Correction: Systematic review and meta-analysis of prolactin and iron deficiency in peripartum cardiomyopathy.

Correction: Systematic review and meta-analysis of prolactin and iron deficiency in peripartum cardiomyopathy.

Mutations Within the Transcription Factor PROP1 in a Cohort of Turkish Patients with Combined Pituitary Hormone Deficiency

Objective:Mutations of the genes encoding transcription factors which play important roles in pituitary morphogenesis, differentiation and maturation may lead to combined pituitary hormone deficiency (CPHD). PROP1 gene mutations are reported as the most frequent genetic aetiology of CHPD. The aim of this study was to describe the phenotypes of Turkish CPHD patients and define the frequency of PROP1 mutations.Methods:Fifty-seven CPHD patients from 50 families were screened for PROP1 mutations. The patients were affected by growth hormone (GH) and additional anterior pituitary hormone deficiencies.Results:All patients had GH deficiency. In addition, 98.2% had central hypothyroidism, 45.6% had hypogonadotropic hypogonadism, 43.8% had adrenocorticotropic hormone deficiency and 7.1% had prolactin deficiency. Parental consanguinity rate was 50.9% and 14 cases were familial. Mean height standard deviation score (SDS) and weight SDS were -3.8±1.4 and -3.1±2.0, respectively. Of 53 patients with available pituitary imaging, 32 (60.4%) showed abnormalities. None had extra-pituitary abnormalities. Eight index patients had PROP1 gene mutations. Five sporadic patients were homozygous for c.301_302delAG (p.Leu102CysfsTer8) mutation, two siblings had exon 2 deletion, two siblings had complete gene deletion and two siblings were homozygous for the novel c.353A>G (p.Q118R) mutation. The frequency of the PROP1 mutations was 16% in our cohort. Mutation rate was significantly higher in familial cases compared to sporadic cases (42.8% vs 11.6%; p<0.01).Conclusion:Phenotype of patients regarding hormonal deficiencies, pituitary morphology, presence of extra-pituitary findings, family history of CPHD and parental consanguinity are important for deciding which pituitary transcription factor deficiency should be investigated. PROP1 mutation frequencies vary in different populations and its prevalence is high in Turkish CPHD patients.

Trpc5 deficiency causes hypoprolactinemia and altered function of oscillatory dopamine neurons in the arcuate nucleus

Dopamine neurons of the hypothalamic arcuate nucleus (ARC) tonically inhibit the release of the protein hormone prolactin from lactotropic cells in the anterior pituitary gland and thus play a central role in prolactin homeostasis of the body. Prolactin, in turn, orchestrates numerous important biological functions such as maternal behavior, reproduction, and sexual arousal. Here, we identify the canonical transient receptor potential channel Trpc5 as an essential requirement for normal function of dopamine ARC neurons and prolactin homeostasis. By analyzing female mice carrying targeted mutations in the Trpc5 gene including a conditional Trpc5 deletion, we show that Trpc5 is required for maintaining highly stereotyped infraslow membrane potential oscillations of dopamine ARC neurons. Trpc5 is also required for eliciting prolactin-evoked tonic plateau potentials in these neurons that are part of a regulatory feedback circuit. Trpc5 mutant females show severe prolactin deficiency or hypoprolactinemia that is associated with irregular reproductive cyclicity, gonadotropin imbalance, and impaired reproductive capabilities. These results reveal a previously unknown role for the cation channel Trpc5 in prolactin homeostasis of female mice and provide strategies to explore the genetic basis of reproductive disorders and other malfunctions associated with defective prolactin regulation in humans.

MON-434 Familial Alactogenesis Associated with a Prolactin Mutation

BACKGROUND: Isolated prolactin deficiency is a rare disorder manifesting as absence of puerperal lactation. We identified a family with multiple members who had alactogenesis and examined genetic causes. SUBJECTS: Three women in one family (proband, sister and niece) reported puerperal alactogenesis, i.e. no milk production postpartum. All the women had regular menstrual cycles during their reproductive years. The proband, currently 66 yrs, had 7 pregnancies and 2 live births. Prolactin level was 1.16 ng/mL (2.8-29.2 ng/mL) at the age of 47 yrs. The sister, currently 73 yrs, had 3 children. Her prolactin level was 1.4 ng/mL (2.8-29.2 ng/mL) at the age of 64 yrs. Both women had menopause before age 45 years. The niece, currently 43 years old, had infertility of unknown cause and conceived 2 children with fertility treatment. She had prolactin levels of 1.13 ng/mL, 0.618 ng/mL and 0.759 ng/mL at the age of 34-36 yrs. METHODS: DNA and mRNA were extracted from blood of all three women and a fertile control with a history of normal lactation. PRL exons 1-6 were Sanger sequenced from the DNA. cDNA was subjected to RT-PCR with primers spanning intron 5 and the terminal portion of exon 6. RT-PCR was analyzed using the 2-ΔΔCT method. Prolactin mRNA expression was compared among the affected women and the control subject. RESULTS: We identified a heterozygous mutation (c.658C>T) changing CGA (arginine) to TGA (stop codon) (p.Arg220Ter) in exon 6 of the prolactin gene. PRL mRNA expression (0.011±0.003 vs. 1.0±0.0; p<0.001) and terminal exon 6 expression (0.0027±0.0028 vs. 0.99±0.05; p<0.001) was decreased compared to control mRNA expression. DISCUSSION: We have identified a genetic cause of puerperal alactogenesis resulting from a stop-gain mutation in the prolactin gene (PRL). PRL mRNA expression is decreased in these subjects. These findings suggest that the mutated PRL may undergo nonsense decay. The low circulating prolactin resulted in inability to breastfeed. It may also be the cause of infertility and early menopause, but further studies are needed. CONCLUSION: We report a stop-gain mutation in exon 6 of the prolactin gene (PRL) resulting in familial puerperal alactogenesis.

Hypopituitarism After Cranial Irradiation for Meningiomas: A Single-Institution Experience

PurposePatients undergoing cranial irradiation are at high risk for development of subsequent pituitary deficiencies. Patients with meningiomas can expect to live many years after treatment and are therefore particularly vulnerable to long-term sequalae of radiation therapy (RT). The purpose of this study was to determine the rates and timing of onset of pituitary dysfunction across each hypothalamic-pituitary axis in patients with meningiomas in the sellar region. Methods and MaterialsData from 74 patients with meningiomas in the sellar or perisellar region who underwent RT between 2001 and 2017 at a single academic center were analyzed. Dose-volume histograms were generated to determine the dose of radiation to the pituitary gland. Pituitary function tests were evaluated before and after completion of RT. ResultsThere was a 20% risk for new hypopituitarism across any hypothalamic-pituitary axis after RT at a median follow-up of 43 months. Identified rates of dysfunction across each axis were 24% for thyroid and adrenal, 19% for growth hormone, and 10% for gonadal. Median time to develop deficiencies ranged from 11 months for growth hormone deficiency to 32 months for adrenal insufficiency. Deficiencies were likely to be correlated, with increased risk for thyroid dysfunction in patients with adrenal, gonadal, or prolactin deficiencies (P < .05). On univariate analysis, mean dose to the pituitary gland and male sex were associated with increased risk for post-RT thyroid deficiency (P = .01 and P = .004, respectively). There was no difference in rates of hypothyroidism after protons compared with photons (P = .14). ConclusionsCranial irradiation for sellar meningiomas carries a risk for subsequent hypopituitarism that appears to be dose dependent and may occur years after completion of RT. Growth hormone deficiency and gonadal dysfunction were likely underestimated here secondary to a lack of routine testing. Given the favorable tumor prognosis in this patient population, early and long-term endocrine follow-up is warranted.

Growth Hormone Deficiency: Health and Longevity.

The important role of GH in the control of mammalian longevity was first deduced from extended longevity of mice with genetic GH deficiency (GHD) or GH resistance. Mice with isolated GHD (IGHD) due to GHRH or GHRH receptor mutations, combined deficiency of GH, prolactin, and TSH, or global deletion of GH receptors live longer than do their normal siblings. They also exhibit multiple features of delayed and/or slower aging, accompanied by extension of healthspan. The unexpected, remarkable longevity benefit of severe endocrine defects in these animals presumably represents evolutionarily conserved trade-offs among aging, growth, maturation, fecundity, and the underlying anabolic processes. Importantly, the negative association of GH signaling with longevity extends to other mammalian species, apparently including humans. Data obtained in humans with IGHD type 1B, owing to a mutation of the GHRH receptor gene, in the Itabaianinha County, Brazil, provide a unique opportunity to study the impact of severe reduction in GH signaling on age-related characteristics, health, and functionality. Individuals with IGHD are characterized by proportional short stature, doll facies, high-pitched voices, and central obesity. They have delayed puberty but are fertile and generally healthy. Moreover, these IGHD individuals are partially protected from cancer and some of the common effects of aging and can attain extreme longevity, 103 years of age in one case. We think that low, but detectable, residual GH secretion combined with life-long reduction of circulating IGF-1 and with some tissue levels of IGF-1 and/or IGF-2 preserved may account for the normal longevity and apparent extension of healthspan in these individuals.

Isolated Prolactin Deficiency: A Possible Culprit in Lactation Failure

ABSTRACT Objective: To review a case of a woman with postpartum prolactin deficiency after each of 2 pregnancies. Methods: We discuss isolated prolactin deficiency in a patient who presented to the...

Increased environmental temperature normalizes energy metabolism outputs between normal and Ames dwarf mice.

Ames dwarf (Prop1df) mice possess a loss-of-function mutation that results in deficiency of growth hormone, prolactin, and thyroid-stimulating hormone, as well as exceptional longevity. Work in other laboratories suggests that increased respiration and lipid utilization are important for maximizing mammalian longevity. Interestingly, these phenotypes are observed in Ames dwarf mice. We recently demonstrated that Ames dwarf mice have hyperactive brown adipose tissue (BAT), and hypothesized that this may in part be due to their increased surface to mass ratio leading to increased heat loss and an increased demand for thermogenesis. Here, we used increased environmental temperature (eT) to interrogate this hypothesis. We found that increased eT diminished BAT activity in Ames dwarf mice, and led to the normalization of both VO2 and respiratory quotient between dwarf and normal mice, as well as partial normalization (i.e. impairment) of glucose homeostasis in Ames dwarf mice housed at an increased eT. Together, these data suggest that an increased demand for thermogenesis is partially responsible for the improved energy metabolism and glucose homeostasis which are observed in Ames dwarf mice.

A novel heterozygous mutation in POU1F1 is associated with combined pituitary hormone deficiency

Mutations in the POU1F1 gene (OMIM#613038) are a rare case of combined pituitary hormone deficiency (CPHD), which is characterized by deficiency of growth hormone, TSH, and prolactin. Brain mri reveals hypoplasia of the anterior lobe of the pituitary gland. The prevalence of this disease has not been fully studied, but it is reported that the incidence of mutations in the POU1F1 gene in patients with CPHD from nonrelated marriages is 3—7%, reaching 25—52% among familial cases. Both the autosomal dominant and the autosomal recessive inheritance patterns are possible. More than 30 mutations in POU1F1 have been described in patients with CPHD. One child in the family had a pronounced delay in physical and psychomotor development, characteristic signs of dysmorphogenesis, an extremely low IGF-1 level, low levels of ft4 and prolactin, and a normal cortisol level. Molecular genetic testing revealed a heterozygous mutation c.500a&gt; g: p.q167r in the POU1F1 gene. This mutation has never been previously described. The patient showed a good response to the recombinant GH (rhGH) therapy.

Pituitary microadenoma with prolactin, corticotropic and thyreotropic deficiency: from infertility to pregnancy : About a case.

Pituitary adenomas are benign tumors developed at the expense of different cellular populations of the pituitary gland. Within the pituitary gland, several cell populations may be involved, but the lactotropic cells remain the most frequently affected by this hyperplasia. For both sexes, the overall frequency of adenomas is 100 per million, of which 40% are prolactinomas. The stimulating effect of estrogens (combined oral contraceptives and pregnancy) on lactotropic cells has long been demonstrated, and in general, only large tumors (macroadenomas) have an evolving risk to be feared during pregnancy. The diagnosis rests on the one hand on the evidence of a hormonal hypersecretion of the cell population concerned as well as a hormonal deficiency of the other cell groups which can be compressed by the tumor. On the other hand, this diagnosis uses hypophyseal magnetic resonance imaging (MRI) to distinguish, according to their size, microadenomas (diameter less than 10 mm) from macroadenomas (diameter greater than 10 mm) pituitary. The risk of increasing the volume of the adenoma during pregnancy depends on the initial size of the tumor. This risk is evaluated at 2% for microadenoma and 15-35% for macroadenomas. However, the most severe complication during pregnancy remains paroxysmal acute growth or pituitary apoplexy by necrotic-haemorrhagic phenomena. The management is mainly based on prolactinoma on bromocryptin or cabergoline and sometimes surgery, urgently in the presence of a pituitary apoplexy or in the presence of an evolutionary macroadenoma.

A Novel Clinical Entity of Autoimmune Endocrinopathy: Anti-PIT-1 Antibody Syndrome.

Pituitary-specific transcription factor 1 (PIT-1; POU domain, class 1, transcription factor 1 (POU1F1)) is an essential transcription factor for the differentiation of somatotrophs, lactotrophs, and thyrotrophs, and for the expression of growth hormone (GH), prolactin (PRL), and thyroid-stimulating hormone (TSH). Mutations in PIT-1 cause congenital defects in GH and PRL secretion and severe TSH insufficiency. Anti-PIT-1 antibody syndrome, firstly reported in 2011, is characterized by acquired GH, PRL, and TSH deficiencies without PIT-1 mutation and is associated with the presence of the circulating antibody against PIT-1 protein as a marker. Various autoantibodies are detected with multiple endocrine organopathies in this syndrome; therefore, it meets the criteria of autoimmune polyglandular syndrome. Mechanistically, cytotoxic T lymphocytes specifically reacting with PIT-1 protein play an important role in the development of this syndrome.

Brown Adipose Tissue Function Is Enhanced in Long-Lived, Male Ames Dwarf Mice.

Ames dwarf mice (Prop1df/df) are long-lived due to a loss of function mutation, resulting in deficiency of GH, TSH, and prolactin. Along with a marked extension of longevity, Ames dwarf mice have improved energy metabolism as measured by an increase in their oxygen consumption and heat production, as well as a decrease in their respiratory quotient. Along with alterations in energy metabolism, Ames dwarf mice have a lower core body temperature. Moreover, Ames dwarf mice have functionally altered epididymal white adipose tissue (WAT) that improves, rather than impairs, their insulin sensitivity due to a shift from pro- to anti-inflammatory cytokine secretion. Given the unique phenotype of Ames dwarf epididymal WAT, their improved energy metabolism, and lower core body temperature, we hypothesized that Ames dwarf brown adipose tissue (BAT) may function differently from that of their normal littermates. Here we use histology and RT-PCR to demonstrate that Ames dwarf mice have enhanced BAT function. We also use interscapular BAT removal to demonstrate that BAT is necessary for Ames dwarf energy metabolism and thermogenesis, whereas it is less important for their normal littermates. Furthermore, we show that Ames dwarf mice are able to compensate for loss of interscapular BAT by using their WAT depots as an energy source. These findings demonstrate enhanced BAT function in animals with GH and thyroid hormone deficiencies, chronic reduction of body temperature, and remarkably extended longevity.

Original Research: Metabolic alterations from early life thyroxine replacement therapy in male Ames dwarf mice are transient.

Ames dwarf mice are exceptionally long-lived due to a Prop1 loss of function mutation resulting in deficiency of growth hormone, thyroid-stimulating hormone and prolactin. Deficiency in thyroid-stimulating hormone and growth hormone leads to greatly reduced levels of circulating thyroid hormones and insulin-like growth factor 1, as well as a reduction in insulin secretion. Early life growth hormone replacement therapy in Ames dwarf mice significantly shortens their longevity, while early life thyroxine (T4) replacement therapy does not. Possible mechanisms by which early life growth hormone replacement therapy shortens longevity include deleterious effects on glucose homeostasis and energy metabolism, which are long lasting. A mechanism explaining why early life T4 replacement therapy does not shorten longevity remains elusive. Here, we look for a possible explanation as to why early life T4 replacement therapy does not impact longevity of Ames dwarf mice. We found that early life T4 replacement therapy increased body weight and advanced the age of sexual maturation. We also find that early life T4 replacement therapy does not impact glucose tolerance or insulin sensitivity, and any deleterious effects on oxygen consumption, respiratory quotient and heat production are transient. Lastly, we find that early life T4 replacement therapy has long-lasting effects on bone mineral density and bone mineral content. We suggest that the transient effects on energy metabolism and lack of effects on glucose homeostasis are the reasons why there is no shortening of longevity after early life T4 replacement therapy in Ames dwarf mice.

Delayed Adrenarche may be an Additional Feature of Immunoglobulin Super Family Member 1 Deficiency Syndrome.

Immunoglobulin super family member 1 (IGSF1) deficiency syndrome is characterized by central hypothyroidism, delayed surge in testosterone during puberty, macro-orchidism, and in some cases, hypoprolactinemia and/or transient growth hormone (GH) deficiency. Our patient was a 19-year-old male adolescent who had been treated since the age of 9 years with GH and thyroxine for an idiopathic combined GH, thyroid-stimulating hormone (TSH), and prolactin (PRL) deficiency. His GH deficiency proved to be transient, but deficiencies of TSH and PRL persisted, and he had developed macro-orchidism since the end of puberty. Brain magnetic resonance imaging and PROP1 and POU1F1 sequencing were normal. A disharmonious puberty (delayed genital and pubic hair development, bone maturation, and pubertal growth spurt, despite normal testicular growth) was observed as well as a delayed adrenarche, as reflected by very low dehydroepiandrosterone sulfate and delayed pubarche. Direct sequencing of the IGSF1 gene revealed a novel hemizygous mutation, c.3127T>C, p.Cys1043Arg. Pathogenicity of the mutation was demonstrated in vitro. Male children with an idiopathic combined GH, PRL, and TSH deficiency, showing persistent central hypothyroidism but transient GH deficiency upon retesting at adult height, should be screened for mutations in the IGSF1 gene, especially when macro-orchidism and/or hypoprolactinemia are present. We suspect that delayed adrenarche, as a consequence of PRL deficiency, might be part of the clinical phenotype of patients with IGSF1 deficiency.

IGSF1 Deficiency: Lessons From an Extensive Case Series and Recommendations for Clinical Management.

Mutations in the immunoglobulin superfamily, member 1 (IGSF1) gene cause the X-linked IGSF1 deficiency syndrome consisting of central hypothyroidism, delayed pubertal testosterone rise, adult macroorchidism, variable prolactin deficiency, and occasionally transient partial GH deficiency. Since our first reports, we discovered 20 new families with 18 new pathogenic IGSF1 mutations. We aimed to share data on the largest cohort of patients with IGSF1 deficiency to date and formulate recommendations for clinical management. We collected clinical and biochemical characteristics of 69 male patients (35 children, 34 adults) and 56 female IGSF1 mutation carriers (three children, 53 adults) from 30 unrelated families according to a standardized clinical protocol. At evaluation, boys were treated with levothyroxine in 89%, adult males in 44%, and females in 5% of cases. Additional symptoms in male patients included small thyroid gland volume (74%), high birth weight (25%), and large head circumference (20%). In general, the timing of pubertal testicular growth was normal or even premature, in contrast to a late rise in T levels. Late adrenarche was observed in patients with prolactin deficiency, and adult dehydroepiandrosterone concentrations were decreased in 40%. Hypocortisolism was observed in 6 of 28 evaluated newborns, although cortisol concentrations were normal later. Waist circumference of male patients was increased in 60%, but blood lipids were normal. Female carriers showed low free T4 (FT4) and low-normal FT4 in 18% and 60%, respectively, delayed age at menarche in 31%, mild prolactin deficiency in 22%, increased waist circumference in 57%, and a negative correlation between FT4 concentrations and metabolic parameters. IGSF1 deficiency represents the most common genetic cause of central hypothyroidism and is associated with multiple other characteristics. Based on these results, we provide recommendations for mutational analysis, endocrine work-up, and long-term care.

Failure of postpartum lactogenesis due to isolated prolactin deficiency

Objective: To review a case of a postpartum female with lactation failure due to isolated prolactin deficiency. Methods: We describe the presentation of isolated prolactin deficiency, found during the evaluation of a postpartum woman withabsence of postpartum lactogenesis. Results: A 31-year-old G1P1 female five weeks post-partum presented for evaluation of lactation failure. She had an uncomplicatedpregnancy and delivery, with no retained placental fragments. The patient was unable to lactate despite regularbreast stimulation through early and regular infant latch and subsequent bilateral breast pumping. The patient had a historyof Hashimoto’s thyroiditis, but was otherwise healthy. There was no history of alcohol abuse or breast disease. A prolactinlevel measured after a session of breast pumping was 12.4 ng/ml (reference range 122-370 ng/ml). Evaluation of other pituitaryhormones was normal. An MRI of the pituitary was unremarkable. Conclusion: Isolated prolactin deficiency is a rare disorder, presenting postpartum with lack of breast milk production. The causeof this condition is unclear, but may be related to autoimmune destruction of lactotrophs in some patients. In the future, treatmentwith recombinant human prolactin may be used to treat this rare disorder.

Central Hypothyroidism in Miniature Schnauzers.

BackgroundPrimary hypothyroidism is a common endocrinopathy in dogs. In contrast, central hypothyroidism is rare in this species.ObjectivesThe objective of this article is to describe the occurrence and clinical presentation of central hypothyroidism in Miniature Schnauzers. Additionally, the possible role of the thyroid‐stimulating hormone (TSH)‐releasing hormone receptor (TRHR) gene and the TSHβ (TSHB) gene was investigated.AnimalsMiniature Schnauzers with proven central hypothyroidism, based on scintigraphy, and the results of a 3‐day‐TSH‐stimulation test, or a TSH‐releasing hormone (TRH)‐stimulation test or both, presented to the Department of Clinical Sciences of Companion Animals at Utrecht University or the Department of Medicine and Clinical Biology of Small Animals at Ghent University from 2008 to 2012.MethodsRetrospective study. Pituitary function tests, thyroid scintigraphy, and computed tomography (CT) of the pituitary area were performed. Gene fragments of affected dogs and controls were amplified by polymerase chain reaction (PCR). Subsequently, the deoxyribonucleic acid (DNA) sequences of the products were analyzed.ResultsCentral hypothyroidism was diagnosed in 7 Miniature Schnauzers. Three dogs had disproportionate dwarfism and at least one of them had a combined deficiency of TSH and prolactin. No disease‐causing mutations were found in the TSHB gene and the exons of the TRHR gene of these Schnauzers.Conclusions and clinical importanceCentral hypothyroidism could be underdiagnosed in Miniature Schnauzers with hypothyroidism, especially in those of normal stature. The fact that this rare disorder occurred in 7 dogs from the same breed suggests that central hypothyroidism could have a genetic background in Miniature Schnauzers.

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.