Pituitary stalk interruption syndrome is characterized by genetic heterogeneity

Abstract

Pituitary stalk interruption syndrome is a rare disorder characterized by an absent or ectopic posterior pituitary, interrupted pituitary stalk and anterior pituitary hypoplasia, as well as in some cases, a range of heterogeneous somatic anomalies. A genetic cause is identified in only around 5% of all cases. Here, we define the genetic variants associated with PSIS followed by the same pediatric endocrinologist. Exome sequencing was performed in 52 (33 boys and 19 girls), including 2 familial cases single center pediatric cases, among them associated 36 (69.2%) had associated symptoms or syndromes. We identified rare and novel variants in genes (37 families with 39 individuals) known to be involved in one or more of the following—midline development and/or pituitary development or function (BMP4, CDON, GLI2, GLI3, HESX1, KIAA0556, LHX9, NKX2-1, PROP1, PTCH1, SHH, TBX19, TGIF1), syndromic and non-syndromic forms of hypogonadotropic hypogonadism (CCDC141, CHD7, FANCA, FANCC, FANCD2, FANCE, FANCG, IL17RD, KISS1R, NSMF, PMM2, SEMA3E, WDR11), syndromic forms of short stature (FGFR3, NBAS, PRMT7, RAF1, SLX4, SMARCA2, SOX11), cerebellum atrophy with optic anomalies (DNMT1, NBAS), axonal migration (ROBO1, SLIT2), and agenesis of the corpus callosum (ARID1B, CC2D2A, CEP120, CSPP1, DHCR7, INPP5E, VPS13B, ZNF423). Pituitary stalk interruption syndrome is characterized by a complex genetic heterogeneity, that reflects a complex phenotypic heterogeneity. Seizures, intellectual disability, micropenis or cryptorchidism, seen at presentation are usually considered as secondary to the pituitary deficiencies. However, this study shows that they are due to specific gene mutations. PSIS should therefore be considered as part of the phenotypic spectrum of other known genetic syndromes rather than as specific clinical entity.

Exome sequencing of families from Ghana reveals known and candidate hearing impairment genes

“…Ccdc141 - deficient mice exhibited impaired recognition memory and spatial reference memory 66 . In human, biallelic variants in CCDC141 was associated with pituitary stalk interruption syndrome (a rare disorder characterized by an absent or ectopic posterior pituitary, interrupted pituitary stalk, and anterior pituitary hypoplasia) 67 ; and in normonosmic or anosmic hypogonadotropic hypogonadism, due to neuronal migration disorders the results in a defect in the development of the GnRH and the olfactory system 68 – 70 .…”

Diagnosis and Management of Central Congenital Hypothyroidism

“…It was first described in 1987 in a series of ten patients with “idiopathic pituitary dwarfism” showing an ectopic pituitary lobe and transection of the pituitary stalk upon magnetic resonance imaging (MRI) ( 69 ). Since then, there have been many reports on PSIS and a broad clinical, radiological and genetic heterogeneity has become apparent ( 70 – 72 ). The classic triad may not always be complete, but cardinal features include either interrupted/absent pituitary stalk or ectopic posterior pituitary.…”

Truncating and zinc‐finger variants in GLI2 are associated with hypopituitarism

“…We reviewed the literature for comprehensive phenotypic descriptions of individuals with confirmed pathogenic (a) intragenic GLI2 variants and (b) chromosome 2q14.2 deletions encompassing only GLI2 . We re‐evaluated the pathogenicity of previously published GLI2 missense variants (Table 2) (Arnhold et al, 2015; Babu et al, 2019; Bear et al, 2014; Bertolacini et al, 2012; Brauner et al, 2020; Flemming et al, 2013; França et al, 2013; Gregory et al, 2015; Juanes et al, 2016; Meng et al, 2019; Rahimov et al, 2006; Vaaralahti et al, 2012; Vishnopolska et al, 2021). This re‐evaluation was primarily based on population variant frequency in the gnomAD database (Karczewski et al, 2020).…”