OBJECTIVE: Height age (HA) and bone age (BA) delay is well known in the patients with short stature. Therefore assessing pituitary hypoplasia based on chronological age (CA) might cause overdiagnosis of pituitary hypoplasia. We aimed to investigate the diagnostic and prognostic value of the PH and PV based on CA, HA, or BA in the patients with GHD.
METHODS: Fifty-seven patients with severe and 40 patients with partial GHD and 39 patients with ISS assigned to the study. For defining the most accurate diagnosis of pituitary hypoplasia, PH and PV were evaluated based on CA, BA and HA. The relationship of each method with clinical features was examined.
RESULTS: The mean PV was significantly larger in patients with ISS compared to the GH-deficient patients. PV was more correlated with clinical features including height SDS, stimulated GH concentration, IGF-1 and IGFBP-3 SDS, height velocity before and after rGH therapy. We found BA-based PV could discriminate GHD from ISS (Sensitivity: 17%, specificity: 98%, positive predictive value: 94%, negative predictive value: 39%), compared to the other methods based on PH or PV respect to CA and HA. 3% of patients with ISS, 17% of patients with GHD had pituitary hypoplasia based on PV-BA.
CONCLUSIONS: PV based on BA, has the most accurate diagnostic value for defining pituitary hypoplasia. But it should be kept in mind that there might be still misdiagnosed patients by this method. PV is also a significant predictor for the rGH response.

Objective. Idiopathic hypogonadotropic hypogonadism in children is a disease leading to a puberty absence. Some hypothalamic and pituitary defects cause hypogonadotropic hypogonadism. Pituitary magnetic resonance imaging is routinely performed in these patients. In our study, we provide an information about pituitary pathologies associated with an idiopathic hypogonado-tropic hypogonadism in childhood. Methods. Twenty-two patients, who were admitted to the pediatric endocrine outpatient clinic of our hospital because of their undeveloped secondary sex characteristics during adolescence, were included in our study. Age, gender, history, physical examination findings, and laboratory tests were recorded in patients. Pituitary magnetic resonance imaging results were examined. The criteria for the diagnosis of hypogonadism were: absence of puberty or delayed puberty, clinical signs or symptoms of hypogonadism, and presence of low or normal gonadotropin levels. Results. In the present study, 22 patients were diagnosed with hypogonadotropic hypogonadism. The mean age of the patients was 15.90±1.09 years. Basal and stimulated luteinizing hormone and follicular stimulating hormone levels of the patients were found to be low. Prolactin, cortisol, adrenocorticotropic hormone, free thyroxine, and thyroid stimulating hormone levels were within normal limits in all patients. The pituitary magnetic resonance imaging revealed six patients with pituitary adenoma, one with empty sella turcica, and five with pituitary hypoplasia. Conclusions. The present data showed that in the presence of hypogonadotropic hypogonadism, the hypothalamic-pituitary abnormalities are more likely to be present in the children compared to the adult population. Thus, it can be strongly emphasized the importance of the pituitary imaging examination, especially in the idiopathic hypogonadotropic hypogonadism cases.

Apart from stimulation of human growth and cell proliferation, growth hormone (GH) has pleiotropic metabolic effects in all periods of life. Severe GH deficiency is a common component of combined pituitary hormone deficiency (CPHD). CPHD may be caused by mutations in the genes encoding transcription factors and signaling molecules involved in normal pituitary development; however, often its genetic cause remains unknown. Symptoms depend on which hormone is deficient. The first symptom of GH or adrenocorticotropic hormone (ACTH) deficiency may be persistent hypoglycemia in apparently healthy newborns, which is often neglected. Diagnosing CPHD is based on decreased concentrations of hormones secreted by the anterior pituitary and peripheral endocrine glands. Findings in magnetic resonance imaging vary widely, including anterior pituitary hypoplasia/aplasia or pituitary stalk interruption syndrome (PSIS). Delayed diagnosis and treatment can be life-threatening. GH therapy is necessary to recover hypoglycemia and to improve auxological and psychomotor development. We present two girls, diagnosed and treated in our departments, in whom the diagnosis of CPHD was delayed, despite persistent neonatal hypoglycemia; and a review of similar cases, with attention paid to progress in the genetic assessments of such patients, since the introduction of whole exome sequencing that is especially important for PSIS.

Recent studies have indicated that heterozygous loss-of-function variants in fibroblast growth factor receptor 1 (FGFR1) are involved in the development of congenital hypogonadotropic hypogonadism and combined pituitary hormone deficiency (CPHD). We encountered a Japanese boy with short stature and pubertal failure. Endocrine studies showed GH, TSH, and LH/FSH deficiencies, and brain magnetic resonance imaging delineated hypoplastic anterior pituitary and ectopic posterior pituitary. The patient was treated with GH, l-thyroxine, and hCG/rFSH. Next-generation sequencing panel for pituitary dysfunction identified a probably weak disease-associated heterozygous missense variant in FGFR1 (NM_023110.3:c.176A>T:p.(Asp59Val)), together with a probably non-deleterious heterozygous missense variant in KISS1R (NM_032551.5:c.769G>C:p.(Val257Leu)). We also review six previously reported CHPD patients with probably deleterious FGFR1 variants. The data, in conjunction with the previously reported cases, argue for the relevance of FGFR1 variants to the development of CPHD.

OBJECTIVE: Few studies have focused on thyroid function in children with isolated pituitary hypoplasia (IPH). The purpose of this study was to investigate thyroid function in children with short stature accompanied by IPH and evaluate the values of thyroid function for the diagnosis of IPH.
METHODS: This was a retrospective observational study. A total of 100 children with short stature accompanied by IPH were enrolled. Among them, 68 children presenting with isolated growth hormone deficiency (IGHD) were chosen as the IPH group. Sixty-eight age-matched and sex-matched IGHD children without pituitary abnormalities were chosen as the control group. Clinical, hormonal, and imaging parameters were analyzed. The diagnostic value of thyroid function for IGHD children with IPH was evaluated.
RESULTS: Children in the IPH group had significantly lower height standard deviation score (HSDS), HSDS-target height standard deviation score (THSDS), free thyroxine (FT4), insulin-like growth factor-1 standard deviation score (IGF-1SDS), and pituitary height than the control subjects (p = 0.027, p = 0.033, p < 0.001, p = 0.03, and p < 0.001, respectively). The value of the area under the curve (AUC) was 0.701 (95% CI 0.614-0.788, p < 0.001) when the cut-off value for FT4 was ≤ 16.43 pmol/L and the sensitivity and specificity were 72.1 and 61.8%, respectively. FT4 levels were positively correlated with FT3, GH peak, and IGF-1 SDS levels in all children with short stature accompanied by IPH (p < 0.001, p = 0.009, and p = 0.01, respectively).
CONCLUSIONS: IGHD children with IPH had lower FT4 levels than IGHD children without pituitary abnormalities. FT4 levels may have diagnostic value for IGHD children with IPH.

UNASSIGNED: Pycnodysostosis is commonly associated with growth hormone (GH) deficiency and responds well to GH therapy with achievement of normal or near-normal height and restoration of body proportions.
UNASSIGNED: A 22-month-old extremely short (-4.05 height standard deviation score) disproportionate boy with skeletal dysplasia presented to clinic. Skeletal survey, genetic panel, magnetic resonance imaging, and an insulin-like growth factor generation tests were performed.
UNASSIGNED: Skeletal survey showed increased bone density with classic features of pycnodysostosis, subsequently confirmed to be due to a deleterious homozygous frameshift mutation in CTSK. Uniquely among skeletal dysplasias, GH deficiency is a common association, secondary to pituitary hypoplasia. Magnetic resonance imaging confirmed pituitary hypoplasia and he subsequently underwent an insulin-like growth factor generation test that demonstrated biochemical responsiveness to GH therapy. This was thought to be safer than a classic GH stimulation test, in view of his very small size. Subsequently, his height has markedly improved on GH therapy. His height is now -2.25 SD, with an annualized growth velocity of 9.65 cm/y over a period of 18 months .
UNASSIGNED: It is important to consider GH therapy in children with pycnodysostosis, with the greatest benefit seen in children started at a young age.

OBJECTIVE: Congenital idiopathic growth hormone deficiency (GHD) is associated with various MRI abnormalities, including sellar and extrasellar abnormalities. However, it remains contentious whether MRI brain findings could provide an additional avenue for precisely predicting the differentiation of GHD based on severity and type {isolated GHD or multiple pituitary hormone deficiencies (MPHD)}. This study aimed to ascertain the abnormality that is the best predictor of severity and type of GHD amongst the different MRI findings.
METHODS: We conducted an analytical cross-sectional study, including 100 subjects diagnosed with idiopathic GHD. Patients were grouped into severe GHD, partial GHD, and MPHD and into groups based on the presence of pituitary hypoplasia, extrasellar brain abnormalities (EBA), and presence of ectopic posterior pituitary or pituitary stalk abnormalities (EPP/PSA) or both.
RESULTS: Sixty six percentage of subjects had isolated GHD, 34% had MPHD, 71% had severe GHD, and 29% had partial GHD. Pituitary hypoplasia was the most common finding, observed in 53% of patients, while 23% had EBA, and 25% had EPP/PSA. Pituitary hypoplasia was observed to be the best predictor of severity of GHD with an odds ratio (OR) of 10.8, followed by EPP/PSA (OR=2.8), and EBA was the weakest predictor (OR=1.8). Pituitary hypoplasia was the only finding to predict MPHD (OR=9.2) significantly. On ROC analysis, a Pituitary height SDS of -2.03 had the best detection threshold for both severe GHD and MPHD.
CONCLUSIONS: We observed Pituitary hypoplasia to be not only the most frequent MRI abnormality but also the best predictor of severe GHD and MPHD amongst various sellar and extrasellar abnormalities.

In this case report, we present a novel mutation in Lim-homeodomain (LIM-HD) transcription factor, LHX3, manifesting as combined pituitary hormone deficiency (CPHD). This female patient was originally diagnosed in Egypt during infancy with Diamond Blackfan Anemia (DBA) requiring several blood transfusions. Around 10 months of age, she was diagnosed and treated for central hypothyroidism. It was not until she came to the United States around two-and-a-half years of age that she was diagnosed and treated for growth hormone deficiency. Her response to growth hormone replacement on linear growth and muscle tone were impressive. She still suffers from severe global development delay likely due to delay in treatment of congenital central hypothyroidism followed by poor access to reliable thyroid medications. Her diagnosis of DBA was not confirmed after genetic testing in the United States and her hemoglobin normalized with hormone replacement therapies. We will review the patient\'s clinical course as well as a review of LHX3 mutations and the associated phenotype. Learning points: Describe an unusual presentation of undertreated pituitary hormone deficiencies in early life Combined pituitary hormone deficiency due to a novel mutation in pituitary transcription factor, LHX3 Describe the clinical phenotype of combined pituitary hormone deficiency due to LHX3 mutations.

Kallmann syndrome is a genetically heterogeneous form of hypogonadotropic hypogonadism caused by gonadotropin-releasing hormone deficiency and characterized by anosmia or hyposmia due to hypoplasia of the olfactory bulbs; osteoporosis and metabolic syndrome can develop due to longstanding untreated hypogonadism. Kallmann syndrome affects 1 in 10 000 men and 1 in 50 000 women. Defects in 17 genes, including KAL1, have been implicated. Kallmann syndrome can be associated with X-linked ichthyosis, a skin disorder characterized by early onset dark, dry, irregular scales affecting the limb and trunk, caused by a defect of the steroid sulfatase gene (STS). Both KAL1 and STS are located in the Xp22.3 region; therefore, deletions in this region cause a contiguous gene syndrome. We report the case of a 32-year-old man with ichthyosis referred for evaluation of excessive height (2.07 m) and weight (BMI: 29.6 kg/m2), microgenitalia and absence of secondary sex characteristics. We diagnosed Kallmann syndrome with ichthyosis due to a deletion in Xp22.3, a rare phenomenon. Learning points: Kallmann syndrome is a genetically heterogeneous disease characterized by hypogonadotropic hypogonadism with anosmia or hyposmia associated with defects in the production or action of gonadotropin-releasing hormone (GnRH) and hypoplasia of the olfactory bulbs. Several genes have been implicated in Kallmann syndrome, including KAL1, located in the Xp22.3 region, which is responsible for X-linked Kallmann syndrome. KAL1 encodes the protein anosmin-1. X-linked ichthyosis is caused by deficiency of the steroid sulfatase enzyme, encoded by STS, which is also located in the Xp22.3 region. Deletions involving this region can affect both genes and result in contiguous gene syndromes. Phenotype can guide clinicians toward suspicion of a specific genetic mutation. KAL1 mutations are mostly related to microgenitalia, unilateral renal agenesis and synkinesia, although patients need not present all these abnormalities. Longstanding untreated hypogonadism is associated with poor sexual health, osteoporosis and metabolic syndrome with the concomitant risk of developing type 2 diabetes mellitus and obesity. Treatment aims to promote the development of secondary sex characteristics, build and sustain normal bone and muscle mass and restore fertility. Treatment can also help minimize some psychological consequences. Treatments available for patients with congenital GnRH deficiency such as Kallmann syndrome include gonadal steroid hormones, human gonadotropins and GnRH. The choice of therapy depends on the goal or goals.

Growth failure and pubertal abnormalities are not uncommon in chronic uncontrolled metabolic diseases like diabetes mellitus. We present a young girl with uncontrolled type 1 diabetes mellitus, who presented with short stature and primary amenorrhea, and on evaluation was found to have anterior pituitary hypoplasia. In addition to uncontrolled diabetes mellitus, she presented with early onset growth failure and lack of spontaneous secondary sexual characteristics. She had central hypothyroidism and inappropriately normal gonadotropin levels. However her serum cortisol levels were normal. MRI of the sellar-suprasellar region revealed a small anterior pituitary gland with thinning of the pituitary stalk consistent with pituitary hypoplasia. While uncontrolled type 1 diabetes itself may cause growth retardation and pubertal abnormalities, this girl had coexisting pituitary maldevelopment - a rare co-existence of two major illnesses of unrelated etiologies. The partial pituitary hormonal deficiency, which spared the hypothalamo-pituitary-adrenal axis, may be due to a transcription factor defect.