Inositol 1,4,5-triphosphate receptor type 1 (ITPR1) is an endoplasmic reticulum-bound intracellular inositol triphosphate receptor involved in the regulation of intracellular calcium. Pathogenic variants in ITPR1 are associated with spinocerebellar ataxia (SCA) types 15/16 and 29 and have recently been implicated in a facial microsomia syndrome. In this report, we present a family with three affected individuals found to have a heterozygous missense c.800C > T (predicted p.Thr267Met) who present clinically with a SCA29-like syndrome. All three individuals presented with varying degrees of ataxia, developmental delay, and apparent intellectual disability, as well as craniofacial involvement-an uncommon finding in patients with SCA29. The variant was identified using clinical exome sequencing and validated with Sanger sequencing. It is presumed to be inherited via parental germline mosaicism. We present our findings to provide additional evidence for germline mosaic inheritance of SCA29, as well as to expand the clinical phenotype of the syndrome.

OBJECTIVE: To investigate the association between certain intracranial masses (meningioma and arachnoid cyst) and the incidence of Pneumosinus Dilatans (PSD) - including whether the size of the mass correlates with severity of the condition.
METHODS: A review of the available case reports on PSD was performed. Clinical data was extracted from 111 case reports for analysis. A further case-control study was performed using CT Head datasets to investigate the aetiological relationship between intracranial masses and PSD. Cases included patients with confirmed arachnoid cyst or meningioma. Controls included patients with no intracranial masses.
RESULTS: PSD is most common in the frontal (48%) and sphenoid sinuses (43%). Men are twice as likely to be affected as women. 58% of cases occur in patients aged 35 or under. The most common symptoms reported are facial deformities (39%), headache (24%) and visual loss (15%). Unexplained visual changes (e.g. diplopia, reduced visual acuity) are strongly correlated with sphenoid sinus involvement. PSD is more common in patients with skull-base meningioma (OR 5.67) and middle cranial fossa arachnoid cysts (OR 10.00). Mean sinus volume in patients with PSD can increase by up to 4 times.
CONCLUSIONS: We present the first direct investigation into the relationship between meningioma, arachnoid cyst and Pneumosinus Dilatans. There is a statistical correlation between skull-base meningioma and middle cranial fossa arachnoid cysts and the incidence of PSD. This specific anatomical relation suggests that local factors contribute to the pathogenesis of the condition. Alterations in intracranial pressure due to mass effect or vascular occlusion, in addition to the localised release of bone growth factors (IGF-1, IGF-2, PDGF), are possible mechanisms for this. The first peak in incidence of PSD coincides with the completion of normal sinus pneumatisation, which raises the further possibility that predisposing genetic factors also contribute.

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.

We describe two unrelated patients, a 12-yr-old female and a 6-yr-old male, with congenital contractures and severe congenital muscular atrophy. Exome and genome sequencing of the probands and their unaffected parents revealed that they have the same de novo deletion in BICD2 (c.1636_1638delAAT). The variant, which has never been reported, results in an in-frame 3-bp deletion and is predicted to cause loss of an evolutionarily conserved asparagine residue at position 546 in the protein. Missense mutations in BICD2 cause autosomal dominant spinal muscular atrophy, lower-extremity predominant 2 (SMALED2), a disease characterized by muscle weakness and arthrogryposis of early onset and slow progression. The p.Asn546del clusters with four pathogenic missense variants in a region that likely binds molecular motor KIF5A. Protein modeling suggests that removing the highly conserved asparagine residue alters BICD2 protein structure. Our findings support a broader phenotypic spectrum of BICD2 mutations that may include severe manifestations such as cerebral atrophy, seizures, dysmorphic facial features, and profound muscular atrophy.