Serial assessments of anterior pituitary hormones in a case of mixed histiocytosis representing Langerhans cell histiocytosis overlapping with Erdheim–Chester disease

Summary A 61-year-old man developed central diabetes insipidus caused by mixed histiocytosis (MH) representing Langerhans cell histiocytosis overlapping with Erdheim–Chester disease. Bone, skin, vascular, and retroperitoneal involvements were also observed. Dynamic hormonal testing showed normal responses for anterior pituitary hormones, except for impaired secretion of growth hormone (GH). MRI of the brain showed thickening of the pituitary stalk with slightly reduced signal hyperintensity in the posterior pituitary lobe on T1-weighted imaging. During 2 years of follow-up without radical treatment for MH, imaging studies suggested extension of vascular and retroperitoneal involvements. In contrast, brain MRI did not show any particular interval changes, except for the disappearance of hyperintense signalling in the posterior pituitary lobe. Moreover, no other anterior pituitary dysfunctions beyond GH deficiency emerged during the 2 years of follow-up. The natural history of MH in this case is described, focusing on serial assessments of pituitary functions using dynamic tests. Learning points Erdheim–Chester disease and Langerhans cell histiocytosis overlapping as MH was described, focusing on pituitary functions. MH caused both GH deficiency and central diabetes insipidus. Despite a lack of radical therapy for MH, no other anterior pituitary dysfunctions emerged for 2 years. Radiological images showed no particular interval changes in pituitary stalk lesions, while vascular and retroperitoneal involvements extended.

MON-234 síNdrome de InterrupcióN del Tallo Pituitario Que Se Presenta Como Amenorrea Primaria

Pituitary stalk interruption syndrome presenting as primary amenorrhea. The pituitary stalk interruption syndrome is a rare congenital defect that is characterized by the absence or thinning of the pituitary stalk, an absent or ectopic posterior pituitary lobe, and hypoplasia or aplasia of the anterior lobe. The clinical presentation is variable. It is usually diagnosed in the neonatal period due to the clinical manifestations that arise as a consequence of hormonal deficiencies. However some patients are diagnosed at a latter stage in life. Growth hormone deficiency it is observed in virtually all patients and can be associated to other anterior pituitary hormonal deficiencies. There is a high frequency of associated extra-pituitary malformations including those involving the central nervous system and the craniofacial structures. We report the case of a 19-year-old woman with primary amenorrhea, lack of secondary sexual characteristics, short stature, low body mass index due to hypergonadotropic hypogonadism and growth hormone deficiency. The remaining pituitary hormones were normal. A pelvic ultrasound revealed orthotopic ovaries and uterus that were decreased in size. Her karyotype was normal. An MRI of the sellar region revealed an ectopic posterior pituitary lobe, and anterior pituitary hypoplasia with a thin pituitary stalk. The patient was treated with estradiol valerate and norgestrel as well as with growth hormone. In conclusion, the pituitary stalk interruption syndrome is a rare form of congenital hypopituitarism that should be considered in cases of growth hormone deficiency and primary amenorrhea particularly in the presence of extra pituitary malformations involving the central nervous system.

Clues for Polygenic Inheritance of Pituitary Stalk Interruption Syndrome From Exome Sequencing in 20 Patients

Context Pituitary stalk interruption syndrome (PSIS) consists of a small/absent anterior pituitary lobe, an interrupted/absent pituitary stalk, and an ectopic posterior pituitary lobe. Mendelian forms of PSIS are detected infrequently (<5%), and a polygenic etiology has been suggested. GLI2 variants have been reported at a relatively high frequency in PSIS. Objective To provide further evidence for a non-Mendelian, polygenic etiology of PSIS. Methods Exome sequencing (trio approach) in 20 patients with isolated PSIS. In addition to searching for (potentially) pathogenic de novo and biallelic variants, a targeted search was performed in a panel of genes associated with midline brain development (223 genes). For GLI2 variants, both (potentially) pathogenic and relatively rare variants (<5% in the general population) were studied. The frequency of GLI2 variants was compared with that of a reference population. Results We found four additional candidate genes for isolated PSIS (DCHS1, ROBO2, CCDC88C, and KIF14) and one for syndromic PSIS (KAT6A). Eleven GLI2 variants were present in six patients. A higher frequency of a combination of two GLI2 variants (M1352V + D1520N) was found in the study group compared with a reference population (10% vs 0.68%). (Potentially) pathogenic variants were identified in genes associated with midline brain anomalies, including holoprosencephaly, hypogonadotropic hypogonadism, and absent corpus callosum and in genes involved in ciliopathies. Conclusion Combinations of variants in genes associated with midline brain anomalies are frequently present in PSIS and sustain the hypothesis of a polygenic cause of PSIS.

Role of GLI2 in hypopituitarism phenotype

GLI2 is a zinc-finger transcription factor involved in the Sonic Hedgehog pathway. Gli2 mutant mice have hypoplastic anterior and absent posterior pituitary glands. We reviewed the literature for patients with hypopituitarism and alterations in GLI2. Twenty-five patients (16 families) had heterozygous truncating mutations, and the phenotype frequently included GH deficiency, a small anterior pituitary lobe and an ectopic/undescended posterior pituitary lobe on magnetic resonance imaging and postaxial polydactyly. The inheritance pattern was autosomal dominant with incomplete penetrance and variable expressivity. The mutation was frequently inherited from an asymptomatic parent. Eleven patients had heterozygous non-synonymous GLI2 variants that were classified as variants of unknown significance, because they were either absent from or had a frequency lower than 0.001 in the databases. In these patients, the posterior pituitary was also ectopic, but none had polydactyly. A third group of variants found in patients with hypopituitarism were considered benign because their frequency was ≥0.001 in the databases. GLI2 is a large and polymorphic gene, and sequencing may identify variants whose interpretation may be difficult. Incomplete penetrance implies in the participation of other genetic and/or environmental factors. An interaction between Gli2 mutations and prenatal ethanol exposure has been demonstrated in mice dysmorphology. In conclusion, a relatively high frequency of GLI2 mutations and variants were identified in patients with congenital GH deficiency without other brain defects, and most of these patients presented with combined pituitary hormone deficiency and an ectopic posterior pituitary lobe. Future studies may clarify the relative role and frequency of GLI2 alterations in the aetiology of hypopituitarism.