Pituitary pseudotumor (pituitary thyrotroph hyperplasia) caused by unrecognized and untreated hypothyroidism has been described as a rare condition, mostly in adults. There are only a few reports on this condition in children. Here we describe an unusual association of pituitary pseudotumor with hypothyroidism, vaginal bleeding, and growth retardation in a girl at an early stage of puberty. Hormonal testing showed low thyroxine and high TSH levels, hyperprolactinemia, low growth hormone levels and prepubertal levels of gonadotrophins. Ovarian cyst was detected by ultrasound. A large intrasellar mass expanding beyond the sella turcica was detected on MRI. Homogeneous contrast enhancement confirmed pituitary hyperplasia. Therapy with L-thyroxine resulted in rapid improvement of the clinical signs, normalization of the hormone levels, and resolution of the pituitary hyperplasia on MRI within 40 days. In children, prolonged unrecognized primary hypothyroidism might be accompanied by growth deficiency and pubertal disharmony. Pituitary hyperplasia should be sought in these cases. KEY WORDSpituitary pseudotumor, primary hypothyroidism, hyperprolactinemia, ovarian cyst

BackgroundThe Dandy-Walker malformation (DWM) is one of the commonest congenital cerebellar defects, and can be associated with multiple congenital anomalies and chromosomal syndromes. The occurrence of overlapping 3q deletions including the ZIC1 and ZIC4 genes in few patients, along with data from mouse models, have implicated both genes in the pathogenesis of DWM.Methods and resultsUsing a SNP-array approach, we recently identified three novel patients carrying heterozygous 3q deletions encompassing ZIC1 and ZIC4. Magnetic resonance imaging showed that only two had a typical DWM, while the third did not present any defect of the DWM spectrum. SNP-array analysis in further eleven children diagnosed with DWM failed to identify deletions of ZIC1-ZIC4. The clinical phenotype of the three 3q deleted patients included multiple congenital anomalies and peculiar facial appearance, related to the localization and extension of each deletion. In particular, phenotypes resulted from the variable combination of three recognizable patterns: DWM (with incomplete penetrance); blepharophimosis, ptosis, and epicanthus inversus syndrome; and Wisconsin syndrome (WS), recently mapped to 3q.ConclusionsOur data indicate that the 3q deletion is a rare defect associated with DWM, and suggest that the hemizygosity of ZIC1-ZIC4 genes is neither necessary nor sufficient per se to cause this condition. Furthermore, based on a detailed comparison of clinical features and molecular data from 3q deleted patients, we propose clinical diagnostic criteria and refine the critical region for WS.

USP9X is an X-chromosome gene that escapes X-inactivation. Loss or compromised function of USP9X leads to neurodevelopmental disorders in males and females. While males are impacted primarily by hemizygous partial loss-of-function missense variants, in females de novo heterozygous complete loss-of-function mutations predominate, and give rise to the clinically recognisable USP9X-female syndrome. Here we provide evidence of the contribution of USP9X missense and small in-frame deletion variants in USP9X-female syndrome also. We scrutinise the pathogenicity of eleven such variants, ten of which were novel. Combined application of variant prediction algorithms, protein structure modelling, and assessment under clinically relevant guidelines universally support their pathogenicity. The core phenotype of this cohort overlapped with previous descriptions of USP9X-female syndrome, but exposed heightened variability. Aggregate phenotypic information of 35 currently known females with predicted pathogenic variation in USP9X reaffirms the clinically recognisable USP9X-female syndrome, and highlights major differences when compared to USP9X-male associated neurodevelopmental disorders.

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