Increasing histone acetylation improves sociability and restores learning and memory in KAT6B-haploinsufficient mice.

Mutations in genes encoding chromatin modifiers are enriched among mutations causing intellectual disability. The continuing development of the brain postnatally, coupled with the inherent reversibility of chromatin modifications, may afford an opportunity for therapeutic intervention following a genetic diagnosis. Development of treatments requires an understanding of protein function and models of the disease. Here, we provide a mouse model of Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) (OMIM 603736) and demonstrate proof-of-principle efficacy of postnatal treatment. SBBYSS results from heterozygous mutations in the KAT6B (MYST4/MORF/QFK) gene and is characterized by intellectual disability and autism-like behaviors. Using human cells carrying SBBYSS-specific KAT6B mutations and Kat6b heterozygous mice (Kat6b+/-), we showed that KAT6B deficiency caused a reduction in histone H3 lysine 9 acetylation. Kat6b+/- mice displayed learning, memory, and social deficits, mirroring SBBYSS individuals. Treatment with a histone deacetylase inhibitor, valproic acid, or an acetyl donor, acetyl-carnitine (ALCAR), elevated histone acetylation levels in the human cells with SBBYSS mutations and in brain and blood cells of Kat6b+/- mice and partially reversed gene expression changes in Kat6b+/- cortical neurons. Both compounds improved sociability in Kat6b+/- mice, and ALCAR treatment restored learning and memory. These data suggest that a subset of SBBYSS individuals may benefit from postnatal therapeutic interventions.

Topical trametinib for epidermal and sebaceous nevi in a child with Schimmelpenning-Feuerstein-Mims syndrome.

We present the case of a 20-month-old girl with Schimmelpenning-Feuerstein-Mims (SFM) syndrome with extensive head, neck, and torso skin involvement successfully managed with topical trametinib. Trametinib interferes downstream of KRAS and HRAS in the MAPK signaling pathway, of which KRAS was implicated in our child's pathogenic variant. Although other dermatologic conditions have shown benefit from oral trametinib, its topical use has not been well reported. Our patient showed benefit from the use of twice-daily topical trametinib, applied to the epidermal and sebaceous nevi over a 16-month period, leading to decreased pruritus and thinning of the plaques.

Kansl1 haploinsufficiency impairs autophagosome-lysosome fusion and links autophagic dysfunction with Koolen-de Vries syndrome in mice.

Koolen-de Vries syndrome (KdVS) is a rare disorder caused by haploinsufficiency of KAT8 regulatory NSL complex subunit 1 (KANSL1), which is characterized by intellectual disability, heart failure, hypotonia, and congenital malformations. To date, no effective treatment has been found for KdVS, largely due to its unknown pathogenesis. Using siRNA screening, we identified KANSL1 as an essential gene for autophagy. Mechanistic study shows that KANSL1 modulates autophagosome-lysosome fusion for cargo degradation via transcriptional regulation of autophagosomal gene, STX17. Kansl1+/- mice exhibit impairment in the autophagic clearance of damaged mitochondria and accumulation of reactive oxygen species, thereby resulting in defective neuronal and cardiac functions. Moreover, we discovered that the FDA-approved drug 13-cis retinoic acid can reverse these mitophagic defects and neurobehavioral abnormalities in Kansl1+/- mice by promoting autophagosome-lysosome fusion. Hence, these findings demonstrate a critical role for KANSL1 in autophagy and indicate a potentially viable therapeutic strategy for KdVS.

A detailed regimen of isotretinoin for the successful treatment of severe keratosis pilaris.

Although a well-known recommended treatment option, there are currently no studies that describe the detailed regimen of isotretinoin for the treatment of primary keratosis pilaris. Based on previous studies involving other hyperkeratotic disorders, this report describes a safe and effective treatment course of isotretinoin for severe keratosis pilaris.

A Potential Treatment of Congenital Sodium Diarrhea in Patients With Activating GUCY2C Mutations.

INTRODUCTION: Gain-of-function mutations in guanylyl cyclase C (GCC) result in persistent diarrhea with perinatal onset. We investigated a specific GCC inhibitor, SSP2518, for its potential to treat this disorder. METHODS: We investigated the effect of SSP2518 on GCC-mediated intracellular cyclic guanosine monophosphate (cGMP) levels and on GCC-mediated chloride secretion in intestinal organoids from 3 patients with distinct activating GCC mutations and from controls, with and without stimulation of GCC with heat-stable enterotoxin. RESULTS: Patient-derived organoids had significantly higher basal cGMP levels than control organoids, which were lowered by SSP2518 to levels found in control organoids. In addition, SSP2518 significantly reduced cGMP levels and chloride secretion in patient-derived and control organoids (P < 0.05 for all comparisons) after heat-stable enterotoxin stimulation. DISCUSSION: We reported in this study that the GCC inhibitor SSP2518 normalizes cGMP levels in intestinal organoids derived from patients with GCC gain-of-function mutations and markedly reduces cystic fibrosis transmembrane conductance regulator-dependent chloride secretion, the driver of persistent diarrhea.

Rhabdomyolysis due to rosuvastatin in a patient with ROHHAD syndrome.

We report a 13-year-old female with rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome, panhypopituitarism, dyslipidemia, type 2 diabetes mellitus, and nonalcoholic fatty liver disease, who developed rhabdomyolysis and acute kidney injury, two weeks after switching from lovastatin to rosuvastatin. She had been on lovastatin for eight years without any adverse effects.

Follow-Up Study of Growth Hormone Therapy in Children with Kabuki Syndrome: Two-Year Treatment Results.

INTRODUCTION: Kabuki syndrome (KS) is a genetic disorder with characteristic facial dysmorphisms, short stature, hypertension, and obesity later in life. The aim of this study was to evaluate catch-up growth and cardiovascular markers before and during growth hormone (rhGH) treatment in KS children. METHODS: This prospective study included 18 children whose KS was genetically established. Each KS subject received rhGH for a period of 2 years. Several measurements were performed before and during treatment: anthropometry, glucose metabolism, lipid profile, markers for endothelial function, and low-grade inflammation. RESULTS: This study found an increase in delta height standard deviation score (SDS) for the whole group of 1.1 SDS after 2 years of rhGH treatment. Baseline metabolic profiles showed no cardiometabolic abnormalities in these children. Although 4 out of 18 children were obese, there were no signs of the metabolic syndrome. During rhGH treatment, serum low-density lipoprotein cholesterol concentrations decreased significantly (2.16-1.91 mmol/L, p = 0.04). Apolipoprotein B100 concentrations also showed a reduction after 24 months of treatment, but the other lipid and (apo)lipoprotein parameters did not change. While other endothelial function markers were stable, only vascular cell-adhesion molecule-1 concentrations increased (1,084-1,161 pg/mL, p < 0.01) during rhGH therapy. Furthermore, BMI and waist circumference improved during treatment. There were no signs of hypertension. CONCLUSIONS: At baseline and during rhGH therapy, there were no signs of the metabolic syndrome. This is the first study demonstrating that rhGH treatment in KS children is a safe and effective therapy and that it positively influences linear height without exerting adverse effects on a wide array of cardiovascular risk markers.

Duplication of the Pituitary Gland (DPG)-Plus Syndrome Associated With Midline Anomalies and Precocious Puberty: A Case Report and Review of the Literature.

Duplication of the pituitary gland (DPG)-plus syndrome is a very rare developmental disorder with few cases described in the literature and characterized by multiple midline and central nervous system malformations. The hypothalamus and hypophysis involvement may be clinically associated with endocrine abnormalities. A 5.9-year-old female child was admitted to our Clinic for premature thelarche and acceleration of growth. DPG-plus syndrome with paired infundibula and pituitary glands was diagnosed after birth, when she appeared small for gestational age and she presented with lingual hypoplasia, cleft palate, right choanal stenosis, nasopharyngeal teratoma, and facial dysmorphisms. Neuroimaging revealed a duplication of the infundibula, the pituitary gland, and the dens of the epistropheus despite surgical removal of a rhino-pharyngeal mass performed at the age of two months. An array-CGH revealed a 2p12 deletion. At our evaluation, bone age assessment resulted advanced and initial pubertal activation was confirmed by Gonadotropin-Releasing Hormone stimulation test. Hormonal suppression treatment was started with satisfactory results. This case shows that DPG-plus syndrome must be considered in presence of midline and craniofacial malformations and endocrinological evaluations should be performed for the prompt and appropriate management of pubertal anomalies.

A retrospective analysis of growth hormone therapy in children with Schaaf-Yang syndrome.

Short stature is a common phenotype in children with Schaaf-Yang syndrome (SYS). Prader-Willi syndrome (PWS) and SYS share several phenotypic features including short stature, muscular hypotonia and developmental delay/intellectual disability. Evidence exists that similar to PWS, growth hormone (GH) deficiency may also be a feature of SYS. Recombinant human GH (rhGH) therapy has been approved for PWS, but the effects of rhGH therapy in individuals with SYS have not yet been documented. This retrospective, questionnaire-based study analyzes the prevalence of rhGH therapy in children with SYS, the effects of rhGH therapy on anthropometric measures, and parental perception of the treatment. Twenty-six individuals with SYS were sent a clinical questionnaire and a request for growth charts. We found a significant increase in height z-score (p* = 0.04) as well as a significant decrease in body mass index 6 months after rhGH therapy initiation (p* = 0.04). Furthermore, height z-scores of the treated group (mean z-score = -1.00) were significantly higher than those of the untreated group (mean z-score = -3.36, p = 0.01) at time of enrollment. All parents reported an increase in muscle strength and endurance, and several families noted beneficial effects such as improved cognition and motor development.

Clinical and neuroimaging findings in 33 patients with MCAP syndrome: A survey to evaluate relevant endpoints for future clinical trials.

Megalencephaly-CApillary malformation-Polymicrogyria (MCAP) syndrome results from somatic mosaic gain-of-function variants in PIK3CA. Main features are macrocephaly, somatic overgrowth, cutaneous vascular malformations, connective tissue dysplasia, neurodevelopmental delay, and brain anomalies. The objectives of this study were to describe the clinical and radiological features of MCAP, to suggest relevant clinical endpoints applicable in future trials of targeted drug therapy. Based on a French collaboration, we collected clinical features of 33 patients (21 females, 12 males, median age of 9.9 years) with MCAP carrying mosaic PIK3CA pathogenic variants. MRI images were reviewed for 21 patients. The main clinical features reported were macrocephaly at birth (20/31), postnatal macrocephaly (31/32), body/facial asymmetry (21/33), cutaneous capillary malformations (naevus flammeus 28/33, cutis marmorata 17/33). Intellectual disability was present in 15 patients. Among the MRI images reviewed, the neuroimaging findings were megalencephaly (20/21), thickening of corpus callosum (16/21), Chiari malformation (12/21), ventriculomegaly/hydrocephaly (10/21), cerebral asymmetry (6/21) and polymicrogyria (2/21). This study confirms the main known clinical features that defines MCAP syndrome. Taking into account the phenotypic heterogeneity in MCAP patients, in the context of emerging clinical trials, we suggest that patients should be evaluated based on the main neurocognitive expression on each patient.

Identification of an individual with a SYGNAP1 pathogenic mutation in India.

Exome sequencing is a prominent tool to identify novel and deleterious mutations which could be non-sense, frameshift, and canonical splice-site mutations in a specific gene. De novo mutations in SYNGAP1, which codes for synaptic RAS-GTPase activating the protein, causes Intellectual disability (ID) and Autism Spectrum Disorder (ASD). SYNGAP1 related ASD/ID is one of the rare diseases that are detrimental to the healthy neuronal developmental and disrupts the global development of a child. We report the first SYNGAP1 heterozygous patient from Indian cohort. We report a case of a child of 2-year old with global developmental delay, microcephaly subtle dysmorphism, absence seizures, disrupted sleep, delay in learning a language, and eating problems. Upon further validation, the child has a few traits of ASD. Here, based on focused exome sequencing, we report a de novo heterozygous mutation in SYNGAP1 exon 11 with c. 1861 C > T (p.arg621ter). Currently, the child is on Atorvastatin, a RAS inhibitor, already available in the market for the treatment of hypercholesterolemia and has shown considerable improvement in global behaviour and cognitive development. The long-term follow up of the child's development would contribute to the already existing knowledge of the developmental trajectory in individuals with SYNGAP1 heterozygous mutation. In this report, we discuss the finding of a novel mutation in one of the genes, SYNGAP1, implicated in ASD/ID. Besides, we discuss the current treatment prescribed to the patient and the progress of global developmental of the child.

"Electrifying dysmorphology": Potassium channelopathies causing dysmorphic syndromes.

Potassium channels are a heterogeneous group of membrane-bound proteins, whose functions support a diverse range of biological processes. Genetic disorders arising from mutations in potassium channels are classically recognized by symptoms arising from acute channel dysfunction, such as periodic paralysis, ataxia, seizures, or cardiac conduction abnormalities, often in a patient with otherwise normal examination findings. In this chapter, we review a distinct subgroup of rare potassium channelopathies whose presentations are instead suggestive of a developmental disorder, with features including intellectual disability, craniofacial dysmorphism or other physical anomalies. Known conditions within this subgroup are: Andersen-Tawil syndrome, Birk-Barel syndrome, Cantú syndrome, Keppen-Lubinsky syndrome, Temple-Baraitser syndrome, Zimmerman-Laband syndrome and a very similar disorder called Bauer-Tartaglia or FHEIG syndrome. Ion channelopathies are unlikely to be routinely considered in the differential diagnosis of children presenting with developmental concerns, and so detailed description and photographs of the clinical phenotype are provided to aid recognition. For several of these disorders, functional characterization of the genetic mutations responsible has led to identification of candidate therapies, including drugs already commonly used for other indications, which adds further impetus to their prompt recognition. Together, these cases illustrate the potential for mechanistic insights gained from genetic diagnosis to drive translational work toward targeted, disease-modifying therapies for rare disorders.

Gomez-López-Hernández syndrome: A case report with clinical and molecular evaluation and literature review.

Gomez-López-Hernández syndrome (GLHS) is characterized by rhombencephalosynapsis (RES), alopecia, trigeminal anesthesia and a distinctive phenotype, including brachyturricephaly. It has been suggested that GLHS should be considered as part of the spectrum of RES-associated conditions that include alopecia, trigeminal anesthesia, and craniofacial anomalies, rather than a distinct entity. To the best of our knowledge, 57 patients with GLHS have been described. Despite its first description in 1979, the etiology of this syndrome remains unknown. Here, we describe, to our knowledge, the first case of a patient with GLHS who was molecularly evaluated and had been prenatally exposed to misoprostol. We also reviewed the clinical and morphological features of the patients described to date to better delineate the phenotype and focus on any evidence for adverse pregnancy outcomes or exposure, including teratogens.

A Case Report of Pycnodysostosis Associated with Multiple Pituitary Hormone Deficiencies and Response to Treatment

Pycnodysostosis is a rare autosomal recessive osteosclerotic bone disorder associated with short stature and multiple bony abnormalities. Growth hormone (GH) deficiency may contribute to short stature in about 50% of patients. Available literature has rarely reported other pituitary hormone deficiencies in pyknodysostosis. Though the management remains conservative, recombinant human GH (rhGH) has been tried in selected patients. Here we present a case of pycnodysostosis which was evaluated for associated co-morbidities and found to have multiple pituitary hormone deficiencies. A 7-year-old girl was referred to our centre for evaluation of short stature. On examination, she had frontal and occipital bossing, limited mouth opening, hyperdontia with multiple carries, short and stubby digits and short stature. Investigation revealed dense sclerotic bones with frontal and occipital bossing, non-fusion of sutures with obtuse mandibular angle, non-pneumatised sinuses, small 'J' shaped sella turcica, acro-osteolysis of digits and absent medullary cavities. Cathepsin-K gene mutation analysis confirmed the diagnosis of pycnodysostosis. She was screened for associated co-morbidities and was found to have concomitant GH deficiency. Treatment with rhGH brought about an increase of 1 standard deviation score in height over 2 years and also unmasked central hypothyroidism at three months necessitating thyroxine replacement.

Phospho-valproic acid (MDC-1112) reduces pancreatic cancer growth in patient-derived tumor xenografts and KPC mice: enhanced efficacy when combined with gemcitabine.

New chemotherapeutic agents are needed for pancreatic cancer (PC). We have previously shown that phospho-valproic acid (MDC-1112) is effective in cell-line xenografts of PC. Here, we explored whether MDC-1112 is effective in additional clinically relevant animal models of PC and whether MDC-1112 enhances the anticancer effect of clinically used chemotherapeutic agents. MDC-1112 alone strongly reduced patient-derived pancreatic tumor xenograft growth, and extended survival of LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre (KPC) mice. In both models, MDC-1112 inhibited STAT3 activation and its downstream signals, including Bcl-xL and cyclin D1. In human PC cell lines, P-V enhanced the growth inhibitory effect of gemcitabine (GEM), Abraxane and 5-FU, but not that of irinotecan. Normal human pancreatic epithelial cells were more resistant to the cytotoxic effects of MDC-1112/GEM combination. Furthermore, MDC-1112 enhanced GEM's effect on colony formation, apoptosis, cell migration, and cell invasion. In vivo, MDC-1112 and GEM, given alone, reduced patient-derived pancreatic tumor xenograft growth by 58% and 87%, respectively; whereas MDC-1112/GEM combination reduced tumor growth by 94%, inducing tumor stasis. In conclusion, MDC-1112 should be further explored as a potential agent to be used in combination with GEM for treating PC.

Growth and Clinical Characteristics of Children with Floating-Harbor Syndrome: Analysis of Current Original Data and a Review of the Literature.

BACKGROUND: Floating-Harbor syndrome (FHS) is a rare condition characterized by dysmorphic facial features, short stature, and expressive language delay. OBJECTIVE: The aim of this study was to describe a cohort of patients with FHS and review the literature about the response to recombinant human growth hormone (rhGH) therapy. METHODS: Anthropometric and laboratory data from 7 patients with FHS were described. The molecular diagnosis was established by multigene analysis. Moreover, we reviewed the literature concerning patients with FHS treated with rhGH. RESULTS: All 7 patients were born small for gestational age. At first evaluation, 6 patients had a height standard deviation score (SDS) ≤-2 and 1 had short stature in relation to their target height. Bone age was usually delayed, which rapidly advanced during puberty. Nonspecific skeletal abnormalities were frequently noticed, and normal to elevated plasma IGF-I levels were observed in all except 1 patient with growth hormone deficiency. Information about 20 patients with FHS treated with rhGH was analyzed (4 from our cohort and 16 from the literature). The median height changes during the treatment period (approx. 2.9 years) were 1.1 SDS (range from -0.4 to 3.1). Nontreated patients had an adult height SDS of -4.1 ± 1.2 (n = 10) versus -2.6 ± 0.8 SDS (n = 7, p 0.012) for treated patients. CONCLUSION: We observed a laboratory profile compatible with IGF-1 insensitivity in some patients with FHS. Nevertheless, our study suggests that children with FHS may be considered as candidates for rhGH therapy. Further studies are necessary to establish the real benefit and safety of rhGH therapy in these patients.

CHILD syndrome: successful treatment of skin lesions with topical lovastatin and cholesterol lotion.

CHILD syndrome (Congenital Hemidysplasia, Ichthyosiform erythroderma, Limb Defects) is a rare X-linked dominant disease. The authors report a 2-month-old patient presenting with typical features of CHILD syndrome that was treated with a topical solution containing cholesterol and lovastatin, with complete clearance of her CHILD nevus. The changes in skin lipid metabolism that explain the CHILD ichthyosiform nevus and their correction through topical application of cholesterol and lovastatin are discussed.

Preoperative administration of propranolol reduced the surgical risks of PHACES syndrome in a 14-month-old girl.

PHACES syndrome is an uncommon neurocutaneous disorder first identified in 1996. Patients with PHACES syndrome often require surgical treatment for their anomalies, including intracranial vasculopathy, coarctation/interruption of the aorta, intracardiac defects, glaucoma/cataract and sternal defects. Risk factors associated with the symptoms of intraoperative/perioperative management include ischaemic stroke due to the cerebral vasculopathy, airway obstruction due to the subglottic/tracheal haemangiomas and massive bleeding due to the large haemangiomas. Recently, propranolol is considered as first-line therapy for patients with infantile haemangiomas (IHs). However, until now, there have been no reported cases of PHACES syndrome treated by propranolol to reduce the surgical risks associated with IH. In this report, we describe a case of a 14-month-old Japanese girl with PHACES syndrome treated by propranolol for IH before surgical closure of the ventricular septum defect. Oral administration of propranolol was effective in decreasing the size of IH, leading to the uneventful perioperative course.