KBG syndrome: Common and uncommon clinical features based on 31 new patients.

KBG syndrome (MIM #148050) is an autosomal dominant disorder characterized by developmental delay, intellectual disability, distinct craniofacial anomalies, macrodontia of permanent upper central incisors, skeletal abnormalities, and short stature. This study describes clinical features of 28 patients, confirmed by molecular testing of ANKRD11 gene, and three patients with 16q24 deletion encompassing ANKRD11 gene, diagnosed in a single center. Common clinical features are reported, together with uncommon findings, clinical expression in the first years of age, distinctive associations, and familial recurrences. Unusual manifestations emerging from present series include juvenile idiopathic arthritis, dysfunctional dysphonia, multiple dental agenesis, idiopathic precocious telarche, oral frenula, motor tics, and lipoma of corpus callosum, pilomatrixoma, and endothelial corneal polymorphic dystrophy. Facial clinical markers suggesting KBG syndrome before 6 years of age include ocular and mouth conformation, wide eyebrows, synophrys, long black eyelashes, long philtrum, thin upper lip. General clinical symptoms leading to early genetic evaluation include developmental delay, congenital malformations, hearing anomalies, and feeding difficulties. It is likely that atypical clinical presentation and overlapping features in patients with multiple variants are responsible for underdiagnosis in KBG syndrome. Improved knowledge of common and atypical features of this disorder improves clinical management.

Co-occurrence of mutations in KIF7 and KIAA0556 in Joubert syndrome with ocular coloboma, pituitary malformation and growth hormone deficiency: a case report and literature review.

BACKGROUND: Joubert syndrome is a recessive neurodevelopmental disorder characterized by clinical and genetic heterogeneity. Clinical hallmarks include hypotonia, ataxia, facial dysmorphism, abnormal eye movement, irregular breathing pattern cognitive impairment and, the molar tooth sign is the pathognomonic midbrain-hindbrain malformation on magnetic resonance imaging. The disorder is predominantly caused by biallelic mutations in more than 30 genes encoding proteins with a pivotal role in morphology and function of the primary cilium. Oligogenic inheritance or occurrence of genetic modifiers has been suggested to contribute to the variability of the clinical phenotype. We report on a family with peculiar clinical spectrum Joubert syndrome molecularly and clinically dissecting a complex phenotype, in which hypogonadism, pituitary malformation and growth hormone deficiency occur as major features. CASE PRESENTATION: A 7 year-old male was enrolled in a dedicated "Undiagnosed Patients Program" for a peculiar form of Joubert syndrome complicated by iris and retinochoroidal coloboma, hypogonadism pituitary malformation, and growth hormone deficiency. The molecular basis of the complex phenotype was investigated by whole exome sequencing. The concomitant occurrence of homozygosity for mutations in KIF7 and KIAA0556 was identified, and the assessment of major clinical features associated with mutations in these two genes provided evidence that these two independent events represent the cause underlying the complexity of the present clinical phenotype. CONCLUSION: Beside the clinical variability of Joubert syndrome, co-occurrence of mutations in ciliopathy-associated genes may contribute to increase the clinical complexity of the trait.

Exploiting novel tailored immunotherapies of type 1 diabetes: Short interfering RNA delivered by cationic liposomes enables efficient down-regulation of variant PTPN22 gene in T lymphocytes.

In autoimmune diseases as Type 1 diabetes, the actual treatment that provides the missing hormones is not able, however, to interrupt the underlining immunological mechanism. Importantly, novel immunotherapies are exploited to protect and rescue the remaining hormone producing cells. Among probable targets of immunotherapy, the C1858T mutation in the PTPN22 gene, which encodes for the lymphoid tyrosine phosphatase (Lyp) variant R620W, reveals an autoimmunity related pathophysiological role. Our scope was to establish new C1858T PTPN22 siRNA duplexes delivered by liposomal carriers (lipoplexes) to patients' PBMC. Following lipoplexes treatment, CD3+ and CD3- immunotypes were efficiently transfected; cell integrity and viability were preserved. Specific target mRNA down-modulation was observed. After T cell receptor stimulation, in lipoplexes-treated PBMC Lyp function was restored by increased release of IL-2 in cultures. Results set-up the stage for ultimate trials in the treatment of autoimmunity based on the specific inhibitory targeting of C1858T PTPN22 by lipoplexes.

Keppen-Lubinsky syndrome is caused by mutations in the inwardly rectifying K+ channel encoded by KCNJ6.

Keppen-Lubinsky syndrome (KPLBS) is a rare disease mainly characterized by severe developmental delay and intellectual disability, microcephaly, large prominent eyes, a narrow nasal bridge, a tented upper lip, a high palate, an open mouth, tightly adherent skin, an aged appearance, and severe generalized lipodystrophy. We sequenced the exomes of three unrelated individuals affected by KPLBS and found de novo heterozygous mutations in KCNJ6 (GIRK2), which encodes an inwardly rectifying potassium channel and maps to the Down syndrome critical region between DIRK1A and DSCR4. In particular, two individuals shared an in-frame heterozygous deletion of three nucleotides (c.455_457del) leading to the loss of one amino acid (p.Thr152del). The third individual was heterozygous for a missense mutation (c.460G>A) which introduces an amino acid change from glycine to serine (p.Gly154Ser). In agreement with animal models, the present data suggest that these mutations severely impair the correct functioning of this potassium channel. Overall, these results establish KPLBS as a channelopathy and suggest that KCNJ6 (GIRK2) could also be a candidate gene for other lipodystrophies. We hope that these results will prompt investigations in this unexplored class of inwardly rectifying K(+) channels.

Case Report: Precision COVID-19 Immunization Strategy to Overcome Individual Fragility: A Case of Generalized Lipodystrophy Type 4.

A 48-year-old patient affected with congenital generalized lipodystrophy type 4 failed to respond to two doses of the BNT162b2 vaccine, consisting of lipid nanoparticle encapsulated mRNA. As the disease is caused by biallelic variants of CAVIN1, a molecule indispensable for lipid endocytosis and regulation, we complemented the vaccination cycle with a single dose of the Ad26.COV2 vaccine. Adenovirus-based vaccine entry is mediated by the interaction with adenovirus receptors and transport occurs in clathrin-coated pits. Ten days after Ad26.COV2 administration, S- and RBD-specific antibodies and high-affinity memory B cells increased significantly to values close to those observed in Health Care Worker controls.

Final height in girls with central idiopathic precocious puberty treated with gonadotropin-releasing hormone analog and oxandrolone.

CONTEXT: GnRH analogs (GnRHa) are considered the treatment of choice for central precocious puberty (CPP). During GnRHa administration, the suppression of the pituitary-gonadal axis results in decreased rates of linear growth and skeletal maturation and in improved adult height. However, in some patients, the growth deceleration is so marked that the expected improvement in predicted adult height is not achieved. OBJECTIVE: The objective of this study was to assess whether the addition of oxandrolone (Ox) may affect the height outcome of patients with CPP and growth deceleration during GnRHa treatment. DESIGN: This was an open-label, clinical study. SETTING: The study was performed at a pediatric endocrinology referral clinic. PATIENTS: Twenty patients with CPP and marked growth deceleration during GnRHa treatment were studied. INTERVENTIONS: Treatment consisted of GnRHa (Leuprorelina, 3.75 mg im every 28 d) alone (10 patients) or in combination with Ox (0.06 mg/kg.d by mouth) (10 patients). MAIN OUTCOME MEASURE: The main outcome measure was the patients' adult height. RESULTS: The adult height of the patients treated with GnRHa plus Ox was significantly higher than pretreatment predicted adult height (162.6 +/- 2.3 vs. 154.8 +/- 1.7 cm, mean +/- sem; P < 0.05) and target height (162.6 +/- 2.3 vs. 158.0 +/- 1.9; P > 0.05). Patients treated with GnRHa alone reached an adult height similar to the pretreatment predicted adult height (151.9 +/- 1.2 vs. 155.4 +/- 2.1 cm) but significantly lower than target height (151.9 +/- 1.2 vs. 156.6 +/- 1.4 cm; P < 0.005). No side effects were recorded in either group of patients. CONCLUSIONS: Combined GnRHa and Ox therapy is a viable treatment option for children with CPP and marked growth deceleration during treatment with GnRHa alone.