Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations

Ciliopathies constitute heterogeneous disorders that result from mutations in ciliary proteins. These proteins play an important role in the development of organs, physiology, and signaling pathways, and sequence variations in the genes encoding these proteins are associated with multisystem disorders. In this study, we describe a severe ciliopathy disorder that segregates in an autosomal recessive manner in a nonconsanguineous Saudi family. The proband exhibited features such as cholestasis, cystic dilatation of intrahepatic biliary ducts, diabetes insipidus, dysmorphic facial features, optic atrophy, pituitary hypoplasia, hydrocephalus, aqueductal stenosis, hyperextensible knee joints, bilateral knee dislocation, polydactyly, and syndactyly. Whole-genome sequencing and Sanger sequencing revealed a homozygous splice site variant (c.4–1G&#x3e;C; NM_024926.3) in the tetratricopeptide repeat domain 26 (<i>TTC26</i>) gene located in chromosome 7q34, which cosegregated perfectly with the disease phenotype. qRT-PCR revealed a substantial decrease in the expression of the <i>TTC26</i> gene as compared to the normal control, suggesting the pathogenicity of the identified variant. This report further strengthens the evidence that homozygous variants in the <i>TTC26</i> gene cause severe ciliopathies with diverse phenotypes. We named this newly characterized condition as BRENS syndrome, which stands for biliary, renal, neurological, and skeletal features.

Pituitary Hypoplasia Is the Best MRI Predictor of the Severity and Type of Growth Hormone Deficiency in Children With Congenital Growth Hormone Deficiency

Background and Objectives: Congenital idiopathic growth hormone deficiency(GHD) is associated with various MRI abnormalities, including both sellar anomalies such as pituitary hypoplasia, ectopic pituitary, empty sella and abnormalities of the pituitary stalk and extrasellar abnormalities such as Arnold Chiari malformation, corpus callosum agenesis, arachnoid cyst, septum pellucidum agenesis, enlarged ventricles, vermis dysplasia, and sphenoid cyst. However, it remains contentious whether MRI brain findings could provide an additional avenue for precisely predicting the differentiation of GHD based on severity(severe or partial) and type(isolated GHD or multiple pituitary hormone deficiency MPHD). This study aimed to ascertain the abnormality that is the best predictor of severe GHD and type of GHD amongst the different MRI findings. Methods: This was an analytical cross-sectional study conducted from 2018-2020. During the study period, we included a total of 100 subjects diagnosed to have idiopathic GHD after the exclusion of syndromic causes, system illness, presence of pituitary mass, and those with h/o cranial irradiation. Patients were divided into severe GHD and partial GHD based on peak stimulated GH of &lt;5 ng/dl and ≥ 5 ng/dl respectively and into groups based on isolated GHD and MPHD. Patients were further divided into groups based on the presence of pituitary hypoplasia,extrasellar brain abnormalities (EBA), and presence of ectopic posterior pituitary and/or pituitary stalk abnormalities(EPP/PSA), respectively. Analyses were performed using SPSS version 24.0 software. Results: Amongst 100 subjects with idiopathic congenital GHD, 66 (66%) subjects had Isolated GHD while the remaining 34 (34%) had MPHD. 71 had severe GHD, and 29 had partial GHD. Amongst the MRI findings, pituitary hypoplasia was the most common finding observed in 53% of patients, while 23(23%) had EBA, and 25(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 (95% CI 3.38-29.6) followed by ectopic posterior pituitary /pituitary stalk abnormalities (OR =2.8, 95% CI 1.5-9.5) while the presence of extrasellar abnormalities was the weakest predictor (OR =1.8, 95% CI 1.05-3.2). Pituitary hypoplasia was the only finding to significantly predict MPHD (OR=9.2). On ROC analysis, a Pituitary height SDS of -2.03 had a 73.2 % sensitivity and specificity of 79.3%(AUC =0.787,95% CI 0.7-0.873) for severe GHD and a sensitivity of 88.2 % and specificity of 66.7% (AUC =0.745, 95% CI 0.68-0.877) for MPHD. Conclusion: 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.

Pituitary hypoplasia is the best MRI predictor of the severity and type of growth hormone deficiency in children with congenital growth hormone deficiency

Objectives 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.

Brain MRIs may be of low value in most children diagnosed with isolated growth hormone deficiency

Objectives Brain MRIs are considered essential in the evaluation of children diagnosed with growth hormone deficiency (GHD), but there is uncertainty about the appropriate cut-off for diagnosis of GHD and little data about the yield of significant abnormal findings in patients with peak growth hormone (GH) of 7–10 ng/mL. We aimed to assess the frequency of pathogenic MRIs and associated risk factors in relation to peak GH concentrations. Methods In this retrospective multicenter study, charts of patients diagnosed with GHD who subsequently had a brain MRI were reviewed. MRIs findings were categorized as normal, incidental, of uncertain significance, or pathogenic (pituitary hypoplasia, small stalk and/or ectopic posterior pituitary and tumors). Charges for brain MRIs and sedation were collected. Results In 499 patients, 68.1% had normal MRIs, 18.2% had incidental findings, 6.6% had uncertain findings, and 7.0% had pathogenic MRIs. Those with peak GH<3 ng/mL had the highest frequency of pathogenic MRIs (23%). Only three of 194 patients (1.5%) with peak GH 7–10 ng/mL had pathogenic MRIs, none of which altered management. Two patients (0.4%) with central hypothyroidism and peak GH<4 ng/mL had craniopharyngioma. Conclusions Pathogenic MRIs were uncommon in patients diagnosed with GHD except in the group with peak GH<3 ng/mL. There was a high frequency of incidental findings which often resulted in referrals to neurosurgery and repeat MRIs. Given the high cost of brain MRIs, their routine use in patients diagnosed with isolated GHD, especially patients with peak GH of 7–10 ng/mL, should be reconsidered.

Pituitary stalk interruption syndrome is characterized by genetic heterogeneity

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.

Evidence of Pituitary Hypoplasia Associated with Partial Central Diabetes Insipidus in a Young Persian Cat

Background: Congenital anomalies are an uncommon pituitary hypofunction cause associated to multiple hormone deficiencies. Congenital hyposomatotropism is often related to an inherited anomaly, characterized mainly by delayed growth. It is not uncommon to find associated thyroid-stimulating hormone and gonadotropin deficiencies. Pituitary malformation may be associated to progressive cystic lesion expansion. Central diabetes insipidus (CDI) is another rare disease associated to polyuria (PU) and polydipsia (PD) secondary to antidiuretic hormone (ADH) deficient secretion. The aim of this report is to describe a likely case of pituitary hypoplasia, associated with partial CDI in a cat.Case: A 9-month-old unneutered male Persian cat weighing 2 kg was presented due to severe polyuria and polydipsia associated with growth deficit when compared with its sibling. After clinical and laboratory evaluations during the months in which the patient was monitored, a reduced serum concentration of insulin-like growth factor-1 (IGF-1), thyroid-stimulating hormone (TSH), thyroid hormones, and testosterone was documented, confirming the diagnosis of hyposomatotropism, hypogonadism, and secondary hypothyroidism. Furthermore, therapeutic diagnosis with desmopressin revealed partial central diabetes insipidus (CDI). As the sibling showed normal development aging 13-months, a radiographic examination of the forelimb (carpus) was performed on both cats. There was lack of growth plate fusion in the patient, without any other evidence of dysgenesis, whereas complete epiphyseal closure was observed in the sibling. Despite desmopressin and levothyroxine therapeutic prescription the owners refuse further follow-up to the case.Discussion: Notwhistanding neuroimaging was not available for investigation of pituitary aspect in this particular case, the clinical symptoms added to the results of the complementary tests were consistent with pituitary hypoplasia, associated with hyposomatotropism, secondary hypothyroidism, hypogonadism, and partial CDI. Hyposomatotropism was presumably diagnosed based on the patient’s clinical characteristics, which included proportional growth delay, delayed tooth eruption, delayed growth plate fusion, associated with serum reduced IGF-1 results in comparison with its sibling. The report of low free T4 by equilibrium dialysis and of low total T4 levels, associated with low TSH levels, was considered compatible with secondary hypothyroidism. TRH stimulation test is considered the gold standard for secondary hypothyroidism diagnosis since low TSH could be secondary to assay´s low sensibility. However, normal TSH and thyroid hormone results in the sibling results ruled out this possible dismissed diagnose. The patient’s lack of sexual interest, associated with hypotestosteronemia and underdeveloped genitals (absence of penile spines and testicular hypoplasia), indicates hypogonadism. Finally, partial CDI diagnosis was demonstrated by cat´s partial ability to increase urinary specific gravity under water deprivation often made by the owners, as well as the response pattern to desmopressin therapy. Owing the lack of neurological signs expected to be associated with neoplastic or traumatic hypopituitarism etiology, hypoplasia hypothesis was raised. Quite often, patients with pituitary hypoplasia develop Rathke cleft cysts that might expand over time. In the present case, partial CDI is likely to be caused by the compression of the neurohypophysis by cyst formation secondary to adenohypophyseal hypoplasia since this kind of pituitary congenital anomaly does not justify per se neurohypophysis implications.

MITOL dysfunction causes dwarfism with anterior pituitary hypoplasia

In mitochondrial disorders, short stature and growth failure are common symptoms, but their underlying mechanism remains unknown. In this study, we examined the cause of growth failure of mice induced by nestin promoter-driven knockout of the mitochondrial ubiquitin ligase MITOL (MARCH5), a key regulator of mitochondrial function. MITOL-knockout mice have congenital hypoplasia of the anterior pituitary caused by decreased expression of pituitary transcript factor 1 (Pit1). Consistently, both mRNA levels of growth hormone (GH) and prolactin levels were markedly decreased in the anterior pituitary of mutant mice. Growth failure of mutant mice was partly rescued by hypodermic injection of recombinant GH. To clarify whether this abnormality was induced by the primary effect of MITOL knockdown in the anterior pituitary or a secondary effect of other lesions, we performed lentiviral-mediated knockdown of MITOL on cultured rat pituitary GH3 cells, which secrete GH. GH production was severely compromised in MITOL-knockdown GH3 cells. In conclusion, MITOL plays a critical role in the development of the anterior pituitary; therefore, mice with MITOL dysfunction exhibited pituitary dwarfism caused by anterior pituitary hypoplasia. Our findings suggest that mitochondrial dysfunction is commonly involved in the unknown pathogenesis of pituitary dwarfism.