Manuka honey activates the aryl hydrocarbon receptor: Implications for skin inflammation.

Manuka honey (MH) is a complex nutritional material with antimicrobial, antioxidant and anti-inflammatory activity. We have previously shown that MH down regulates IL-4-induced CCL26 expression in immortalized keratinocytes. As MH contains potential ligands of the Aryl Hydrocarbon Receptor (AHR), a key regulator of skin homeostasis, we hypothesize that this effect is mediated via AHR activation. Here, we treated HaCaT cell lines, either stable transfected with an empty vector (EV-HaCaT) or in which AHR had been stable silenced (AHR-silenced HaCaT); or primary normal human epithelial keratinocytes (NHEK) with 2% MH for 24 h. This induced a 15.4-fold upregulation of CYP1A1 in EV-HaCaTs, which was significantly reduced in AHR-silenced cells. Pre-treatment with the AHR antagonist CH223191 completely abrogated this effect. Similar findings were observed in NHEK. In vivo treatment of the Cyp1a1Cre x R26ReYFP reporter mice strain's skin with pure MH significantly induced CYP1A1 expression compared with Vaseline. Treatment of HaCaT with 2% MH significantly decreased baseline CYP1 enzymatic activity at 3 and 6 h but increased it after 12 h, suggesting that MH may activate the AHR both through direct and indirect means. Importantly, MH downregulation of IL-4-induced CCL26 mRNA and protein was abrogated in AHR-silenced HaCaTs and by pre-treatment with CH223191. Finally, MH significantly upregulated FLG expression in NHEK in an AHR-dependent manner. In conclusion, MH activates AHR, both in vitro and in vivo, thereby providing a mechanism of its IL4-induced CCL26 downregulation and upregulation of FLG expression. These results have potential clinical implications for atopic diseases and beyond.

Case report: Durable response to ruxolitinib in a child with TREX1-related disorder.

Background: JAK inhibitors are useful in treating interferonopathies, presumably because they downregulate the JAK/STAT signaling. There are limited studies about the safety and effectiveness of using JAK inhibitors in children with TREX1-related disorders. Case presentation: We report an 8-year-old female who presented at five years of age with features suggestive of hemophagocytic lymphohistiocytosis (HLH)-like disorder. The infectious disease workup was negative. Neurological assessment was normal. A brain CT scan was performed because of headache. It showed a faint subcortical calcification at right frontal lobe and almost symmetrical calcification within the basal ganglia. Brain MRI showed bilateral symmetrical globus pallidus, high T1 signal intensities, and a few scattered nonspecific FLAIR hyperintensities in subcortical and deep white matter. IVIG as an immune modulating agent was administered initially which led to the resolution of fever, improvement of blood count parameters, inflammatory markers, and normalization of liver enzymes. The child remained afebrile with no significant events for several months, then had disease flare up. The patient was started on pulse methylprednisolone 30 mg/kg for three days, then continued on 2 mg/kg. Whole exome sequencing revealed a novel heterozygous missense TREX1 mutation NM_016381.3:c.223G > A p.(Glu75Lys). The child was started on ruxolitinib, 5 mg orally twice daily. The child has prolonged, durable remission after initiating ruxolitinib with no adverse effects. Steroids were tapered off and the patient is no longer on IVIG. The patient is still on ruxolitinib for more than two years. Conclusion: This case highlights the potential role of ruxolitinib in the treatment of TREX1-related disorders. A longer follow-up period is required to evaluate the long-term outcome.

Assessment of attitudes towards the use of preimplantation genetic diagnosis in a single center in Riyadh, Saudi Arabia.

In this cross-sectional study, we assessed the attitudes of the general public in Saudi Arabia regarding both medical and non-medical applications of pre-implantation genetic diagnosis (PGD). The study was conducted in King Abdullah Specialist Children's Hospital (KASCH) in Riyadh with a sample size of 377. Demographic information was collected, and attitudes towards applications of PGD were assessed using a pre-validated self-administered questionnaire. Out of the total sample size, 230 (61%) were males, 258 (68%) were married, 235 (63%) had one child or more, and 255 (68%) were older than 30 years of age representing the majority of participants. Only 87 (23%) of participants reported prior experience with PGD. Personally, knowing someone who had a prior experience with PGD was associated with higher attitude scores (more favorable attitudes towards PGD) (p-value = 0.04). The findings of this study indicate that our sample of Saudi individuals generally had a positive attitude towards the use of PGD.

Obesity and Kidney Transplant Candidates: An Outcome Analysis Based on Body Mass Index.

Background Obesity is a well-established risk factor for a decline in renal function and post-operative complications. Also, obese patients suffer worse outcomes such as higher rates of wound complications, longer hospital stays, and delayed graft function (DGF) when compared to nonobese patients. The correlation between having a high BMI and the postoperative outcomes of kidney transplantation has not been investigated yet in Saudi Arabia. There is scarce evidence that patients with obesity who have undergone kidney transplantation are devoid of any complications before, during, or after their procedure. Methodology A retrospective cross-sectional study was conducted using charts of nearly 142 patients in King Abdullah Specialist Children's Hospital in Riyadh, who had kidney transplant surgery in the organ transplantation department. All Obese patients with BMI >29.9 who underwent Kidney Transplant Surgery in King Abdulaziz Medical City from 2015 to 2022 were used. Details of hospital admissions were retrieved. Results A total of 142 patients fulfilling the inclusion criteria were included. There was a significant difference between patients regarding pre-surgical history where all cases (100%; 2) with class three obesity were hypertensive and on dialysis versus (77.8%; 21) and (70.4%; 19) of class two obesity and (86.7%; 98) and (78.8%; 89) of class one obesity cases, respectively (P = 0.041). Regarding medical history, hypertension was reported among 121 (85%), followed by dialysis (77%; 110), diabetes mellitus (DM) (52%; 74), dyslipidemia (24%; 35), endocrine diseases (15%; 22), and cardiovascular diseases (16%; 23). Considering post-transplant complications, 14.1% (20) of the study cases had DM (16.8% of obese class one, 3.7% of obese class two, and none of obese class three; P = 0.996) and urinary tract infection (UTI) among 7% (10) of the cases (6.2% of obese class one, 11.1% of obese class two, and none of obese class three; P = 0.996). All these differences according to patients' BMI were statistically insignificant. Conclusion Obese patients are more likely to experience difficult intraoperative management along with a complicated postoperative course due to numerous concomitant comorbidities. Post-transplant DM (PTDM) was the most prominent post-transplant complication followed by UTI. A remarkable reduction in serum creatinine and blood urea nitrogen (BUN) has been observed at the time of discharge and after six months compared to pre-transplant measurements.

Immune dysregulation caused by homozygous mutations in CBLB.

CBL-B is an E3 ubiquitin ligase that ubiquitinates proteins downstream of immune receptors to downregulate positive signaling cascades. Distinct homozygous mutations in CBLB were identified in 3 unrelated children with early-onset autoimmunity, one of whom also had chronic urticaria. Patient T cells exhibited hyperproliferation in response to anti-CD3 cross-linking. One of the mutations, p.R496X, abolished CBL-B expression, and a second mutation, p.C464W, resulted in preserved CBL-B expression. The third mutation, p.H285L in the SH2 domain of CBL-B, was expressed at half the normal level in the patient's cells. Mice homozygous for the CBL-B p.H257L mutation, which corresponds to the patient's p.H285L mutation, had T and B cell hyperproliferation in response to antigen receptor cross-linking. CblbH257L mice had increased percentages of T regulatory cells (Tregs) that had normal in vitro suppressive function. However, T effector cells from the patient with the p.H285L mutation and CblbH257L mice were resistant to suppression by WT Tregs. Bone marrow-derived mast cells from CblbH257L mice were hyperactivated after FcεRI cross-linking, and CblbH257L mice demonstrated exaggerated IgE-mediated passive anaphylaxis. This study establishes CBL-B deficiency as a cause of immune dysregulation.

The burden of asthma among children and adolescents in Saudi Arabia: A national cross-sectional survey.

Background: Asthma disease is one of the most common chronic diseases of childhood. Studies assessing asthma prevalence in Saudi Arabia have been variable and not recently updated. Objectives: We sought to assess asthma prevalence, severity, and related risk factors among children and adolescents in Saudi Arabia. Methods: A national, cross-sectional design was used following the Global Asthma Network phase I design. A total of 3817 children aged 6 to 7 years and 4138 adolescents aged 13 to 14 years were recruited from 137 primary and 140 intermediate schools across 20 regions by using a multistage stratified cluster sampling technique. Standardized written questionnaires were answered by the adolescents and by the parents or guardians of the children. The adolescents also answered a video-based questionnaire. Results: Overall, the prevalences of current wheeze were 10.4% and 13.3% and the prevalences of asthma ever were 13.8% and 15.7%, % in children and adolescents, respectively. Of all the children and adolescents, 5.2% and 5.6% had symptoms of severe asthma, respectively. Among those who reported asthma, 86.0% of the children and 74.8% of the adolescents had their asthma confirmed by a doctor, and 53.0% and 32.4%, respectively, were provided with a written plan to control their asthma. The main risk factors associated with current wheeze included antibiotic use in the first year of life, a history of being diagnosed with pneumonia in children, paracetamol use, and having a cat at home during the past 12 months in adolescents. Conclusions: The prevalence of asthma in children and adolescents in Saudi Arabia is within the average international range and is at a plateau phase.

The Saudi Initiative for Asthma - 2021 Update: Guidelines for the diagnosis and management of asthma in adults and children.

The Saudi Initiative for Asthma 2021 (SINA-2021) is the fifth version of asthma guidelines for the diagnosis and management of asthma for adults and children, which is developed by the SINA group, a subsidiary of the Saudi Thoracic Society. The main objective of the SINA is to have guidelines that are up to date, simple to understand, and easy to use by healthcare workers dealing with asthma patients. To facilitate achieving the goals of asthma management, the SINA panel approach is mainly based on the assessment of symptom control and risk for both adults and children. The approach to asthma management is aligned for age groups: adults, adolescents, children aged 5-12 years, and children aged less than 5 years. SINA guidelines have focused more on personalized approaches reflecting better understanding of disease heterogeneity with the integration of recommendations related to biologic agents, evidence-based updates on treatment, and the role of immunotherapy in management. Medication appendix has also been updated with the addition of recent evidence, new indications for existing medication, and new medications. The guidelines are constructed based on the available evidence, local literature, and the current situation at national and regional levels. There is also an emphasis on patient-doctor partnership in the management that also includes a self-management plan.

Persistent Hypokalemia post SARS-coV-2 infection, is it a life-long complication? Case report.

INTRODUCTION AND IMPORTANCE: SARS-CoV-2 is a novel infection that has affected millions of people around the world. Complications of the infection may affect multiple systems including cardiovascular, neurological, gastrointestinal, urinary, and pulmonary systems. Hypokalemia, which is a life-threatening condition that may lead to arrhythmia and possibly death, has been noticed in more than half of the COVID-19 patients. Further understanding of the disease process and its complications is necessary to guide in preventing the complications from happening in the first place and finding treatment for patients with an already established complications. CASE PRESENTATION: A 34-year old male from Philippines who lives in Saudi Arabia - Riyadh and works as health care provider with no previous history of any medical illness. Presented by himself to the emergency department (ED) with dry cough, shortness of breath, fever, malaise, and fatigability for five days. On examination (RR 25), (T 38.6 °C) and (O2 89% Room air), on auscultation there was a decrease on air entry bilaterally with scattered crepitations, no wheezing or stridor. Covid-19 swab was positive, (Day 1) potassium 2.91 (mmol/L) magnesium (mmol/L) with normal baseline before getting infected. CLINICAL DISCUSSION: Patient while in the hospital was on daily potassium oral and IV replacement with IV magnesium replacement. Investigation showed 24Hr urine potassium 47.3 (mmol/L), 24Hr urine magnesium 5.52 (mmol/L), 24Hr urine Creatinine 9.25 (mmol/L), (TTKG) Transtubular Potassium Gradient 18 and (VBG) PH:7.38, Pco2:44 (mmHg) Po2:55 (mmHg) HCO3:25 (mEq/L). Patient has an increased renal potassium loss with normal VBG on separate days and normal Blood pressure that excludes diseases with associated acidemia or alkalemia. Our patient didn't want to go for any invasive diagnostic procedures and favored to wait for spontaneous recovery. CONCLUSION: We followed up the potassium level of our patient for more than 5 months since he was diagnosed with COVID-19 to find out that he is still having hypokalemia, as well as, hypomagnesemia. Long term complications of COVID-19 infection such as hypokalemia and hypomagnesemia need to be observed and followed up closely to avoid life-threatening arrythmias and seizures. The attention of the scientific community to possible long term or permanent complications is needed to help find preventive measures and treatment for patients with complications.

Responsiveness of sphingosine phosphate lyase insufficiency syndrome to vitamin B6 cofactor supplementation.

Sphingosine-1-phosphate (S1P) lyase is a vitamin B6-dependent enzyme that degrades sphingosine-1-phosphate in the final step of sphingolipid metabolism. In 2017, a new inherited disorder was described caused by mutations in SGPL1, which encodes sphingosine phosphate lyase (SPL). This condition is referred to as SPL insufficiency syndrome (SPLIS) or alternatively as nephrotic syndrome type 14 (NPHS14). Patients with SPLIS exhibit lymphopenia, nephrosis, adrenal insufficiency, and/or neurological defects. No targeted therapy for SPLIS has been reported. Vitamin B6 supplementation has therapeutic activity in some genetic diseases involving B6-dependent enzymes, a finding ascribed largely to the vitamin's chaperone function. We investigated whether B6 supplementation might have activity in SPLIS patients. We retrospectively monitored responses of disease biomarkers in patients supplemented with B6 and measured SPL activity and sphingolipids in B6-treated patient-derived fibroblasts. In two patients, disease biomarkers responded to B6 supplementation. S1P abundance and activity levels increased and sphingolipids decreased in response to B6. One responsive patient is homozygous for an SPL R222Q variant present in almost 30% of SPLIS patients. Molecular modeling suggests the variant distorts the dimer interface which could be overcome by cofactor supplementation. We demonstrate the first potential targeted therapy for SPLIS and suggest that 30% of SPLIS patients might respond to cofactor supplementation.

Multiple Family Members With Delayed Cord Separtion and Combined Immunodeficiency With Novel Mutation in IKBKB.

Background: Inhibitor of kappa kinase 2 (IKK2) deficiency is a recently described combined immunodeficiency. It undermines the nuclear factor-kappa B (NF-κB) activation pathway. Methods: The clinical and immunological data of four patients diagnosed with combined immunodeficiency (CID) from two related Saudi families were collected. Autozygosity mapping of all available members and whole exome sequencing of the index case were performed to define the genetic etiology. Results: The patients had early onset (2-4 months of age) severe infections caused by viruses, bacteria, mycobacteria, and fungi. They all had hypogammaglobulinemia and low absolute lymphocyte count. Their lymphocytes failed to respond to PHA mitogen stimulation. A novel homozygous non-sense mutation in the IKBKB gene, c.850C>T (p. Arg284*) was identified in the index patient and segregated with the disease in the rest of the family. He underwent hematopoietic stem cell transplantation (HSCT) from a fully matched sibling with no conditioning. The other three patients succumbed to their disease. Interestingly, all patients had delayed umbilical cord separation. Conclusion: IKK2 deficiency causes CID with high mortality. Immune reconstitution with HSCT should be considered as early as possible. Delayed umbilical cord separation in CID patients may be a clue to IKK2 deficiency.

JAK Inhibitor Therapy in a Child with Inherited USP18 Deficiency.

Deficiency of ubiquitin-specific peptidase 18 (USP18) is a severe type I interferonopathy. USP18 down-regulates type I interferon signaling by blocking the access of Janus-associated kinase 1 (JAK1) to the type I interferon receptor. The absence of USP18 results in unmitigated interferon-mediated inflammation and is lethal during the perinatal period. We describe a neonate who presented with hydrocephalus, necrotizing cellulitis, systemic inflammation, and respiratory failure. Exome sequencing identified a homozygous mutation at an essential splice site on USP18. The encoded protein was expressed but devoid of negative regulatory ability. Treatment with ruxolitinib was followed by a prompt and sustained recovery. (Funded by King Saud University and others.).

Corrigendum to "Colonic basidiobolomycosis presenting with intestinal obstruction and a normal eosinophil count" [IDCases 17 (2019) e00565].

[This corrects the article DOI: 10.1016/j.idcr.2019.e00565.].

Colonic basidiobolomycosis presenting with intestinal obstruction and a normal eosinophil count.

Gastrointestinal basidiobolomycosis (GIB), caused by Basidiobolus ranrum, is a rare fungal infection with a limited geographic distribution. The majority of the cases are reported from the warm areas of Arizona in USA, Saudi Arabia and Iran. We report a middle aged patient who was admitted to hospital with suspected metastatic colonic carcinoma. He presented with constipation, anorexia and weight loss. Computed tomography scan disclosed a mass involving the mid and distal sigmoid colon and hypodense lesion in hepatic segment IV. Excised tissue during a Hartmann's surgery showed an extensive eosinophil-rich transmural inflammation with mural necrotizing granulomas and several broad septated fungal hyphae. He was commenced on voriconazole following surgery. The diagnosis of basidiobolomycosis was established by histopathological examination. Since the diagnosis was not suspected preoperatively tissue culture for fungi was not collected. However molecular testing confirmed the diagnosis of GIB. Therapy involved a combination of surgical resection of the mass and prolonged voriconazole treatment. Increased awareness among physicians is needed for early diagnosis and treatment of GIB.

The Saudi Initiative for Asthma - 2019 Update: Guidelines for the diagnosis and management of asthma in adults and children.

This is the fourth version of the updated guidelines for the diagnosis and management of asthma, developed by the Saudi Initiative for Asthma (SINA) group, a subsidiary of the Saudi Thoracic Society. The main objective of the SINA is to have guidelines that are up to date, simple to understand, and easy to use by healthcare workers dealing with asthma patients. To facilitate achieving the goals of asthma management, the SINA panel approach is mainly based on the assessment of symptom control and risk for both adults and children. The approach to asthma management is now more aligned for different age groups. The guidelines have focused more on personalized approaches reflecting better understanding of disease heterogeneity with integration of recommendations related to biologic agents, evidence-based updates on treatment, and role of immunotherapy in management. The medication appendix has also been updated with the addition of recent evidence, new indications for existing medication, and new medications. The guidelines are constructed based on the available evidence, local literature, and current situation at national and regional levels. There is also an emphasis on patient-doctor partnership in the management that also includes a self-management plan.

Attitude of Saudi medical students towards complementary and alternative medicine.

BACKGROUND: Alternative medicine is defined as medical therapies that are not regarded as orthodox by the medical profession. The teaching of complementary and alternative medicine (CAM) in medical schools is becoming prevalent worldwide. Only a few studies have been done to assess medical students' attitude toward CAM and the need for CAM courses. MATERIALS AND METHODS: An observational, descriptive, cross-sectional study was conducted on medical students in two universities, King Saud (KSU) and Majmaah (MU) medical colleges, between February and April 2015. A survey was developed and validated by a pilot study. Data were gathered from both colleges by means of hard and soft copy surveys. Medical students of both genders from the 1st year to the 5th year from both universities were targeted in this study. Fifth-year students from Majmaah and students from the preparatory year were excluded from the study. KSU students comprised 1433, while MU students comprised only 180. The sample size was 384. Data were analyzed using SPSS software. RESULTS: The study included 399 medical students. Bloodletting is the most known modality (80.7%), while homeopathy is the least known with a percentage of 7.47%. The overall assessment of the attitude toward CAM was neutral, with a mean of 3.1. Students who had taken a CAM course previously were more satisfied with their knowledge than those who had not, showing a statistical significance of P = 0.0001. CONCLUSION: This study showed a lack of knowledge of CAM among medical students. There was an association between taking a CAM course and students' satisfaction with their knowledge. Most of the students agreed with the inclusion of CAM courses in the medical curriculum.

Hyperglycemia in Children Hospitalized with Acute Asthma.

Hyperglycemia is frequently observed in adults with acute asthma. We aimed to assess the frequency of hyperglycemia and its relation to outcomes in children admitted with acute asthma. In this retrospective study, we reviewed medical records of non-diabetic 166 children (66 girls) with the mean age of 5.4 ± 2.6 years (range of 2-12 years), who were hospitalized with acute asthma between January 2012 through December 2014. Data pertaining to demographics, vital signs, oxygen saturation, serum blood glucose level, electrolytes, blood gases, and admission were collected. Children with other chronic conditions were excluded. The findings were that hyperglycemia (blood glucose ≥ 11.1 mmol/l) was observed in 38.6% of children. The median baseline blood glucose (IQR) was 9.8 mmol/l (7.2-13.3 mmol/l). Blood glucose level was associated with the length of hospitalization, with a median extension of 1.8 days, but was inversely associated with the serum potassium and bicarbonate levels. There were no associations between baseline blood glucose and age, gender, baseline respiratory rate, oxygen saturation, or intensive care admission. Hyperglycemia resolved spontaneously in all affected children. We conclude that hyperglycemia is common in children hospitalized with acute asthma. Hyperglycemia could be considered as a marker of a longer hospital stay.

Admission predictability of children with acute asthma.

OBJECTIVES: We aimed to evaluate the seasonal variations of acute asthma presentation in children and the utility of the pediatric asthma score (PAS) and its components in early admission prediction. METHODS: As part of a randomized controlled trial addressing the clinical efficacy of budesonide nebulization in the treatment of acute asthma in children, the PAS was measured at baseline, 1st, 2nd, 3rd, and 4th h from the start of medications. Decision of admission was taken at or beyond the 2nd h. RESULTS: Out of a total 906 emergency department (ED) visits with moderate-to-severe acute asthma, 157 children were admitted. June to September had the lowest number of visits. The admission-to-discharge ratio varied throughout the year. During the ED stay, between baseline and 3rd h, admission predictability of the total score improved progressively with a small difference between the 2nd and 3rd h. The total score remained the strongest predictor of admission at every time point compared to its individual components. The drop of PAS from baseline to the 2nd h was not a good predictor of admission. Oxygen saturation (OS) and respiratory rate (RR) had relatively higher predictability than other components. CONCLUSIONS: Decision of admission could be made to many children with moderate-to-severe acute asthma at the 2nd h of ED stay based on their total PAS. OS and RR should be part of any scoring system to evaluate acute asthma in children.

Honey is potentially effective in the treatment of atopic dermatitis: Clinical and mechanistic studies.

INTRODUCTION: As manuka honey (MH) exhibits immunoregulatory and anti-staphylococcal activities, we aimed to investigate if it could be effective in the treatment of atopic dermatitis (AD). METHODS: Adult volunteers with bilateral AD lesions were asked to apply MH on one site overnight for seven consecutive days and leave the contralateral site untreated as possible. Three Item Severity score was used to evaluate the response. Skin swabs were obtained from both sites before and after treatment to investigate the presence of staphylococci and enterotoxin production. In addition, the ability of MH and its methanolic and hexane extracts to down regulate IL4-induced CCL26 protein release from HaCaT cells was evaluated by enzyme linked immunosorbent assay. Also, the ability of MH to modulate calcium ionophore-induced mast cell degranulation was assessed by enzyme immunoassay. RESULTS: In 14 patients, AD lesions significantly improved post MH treatment versus pre-treatment as compared to control lesions. No significant changes in the skin staphylococci were observed after day 7, irrespective of honey treatment. Consistent with the clinical observation, MH significantly down regulated IL4-induced CCL26 release from HaCaT cells in a dose-dependent manner. This effect was partially lost, though remained significant, when methanolic and hexane extracts of MH were utilized. In addition, mast cell degranulation was significantly inhibited following treatment with MH. CONCLUSIONS: MH is potentially effective in the treatment of AD lesions based on both clinical and cellular studies through different mechanisms. This needs to be confirmed by randomized and controlled clinical trials.

Accelerating matchmaking of novel dysmorphology syndromes through clinical and genomic characterization of a large cohort.

PURPOSE: Dysmorphology syndromes are among the most common referrals to clinical genetics specialists. Inability to match the dysmorphology pattern to a known syndrome can pose a major diagnostic challenge. With an aim to accelerate the establishment of new syndromes and their genetic etiology, we describe our experience with multiplex consanguineous families that appeared to represent novel autosomal recessive dysmorphology syndromes at the time of evaluation. METHODS: Combined autozygome/exome analysis of multiplex consanguineous families with apparently novel dysmorphology syndromes. RESULTS: Consistent with the apparent novelty of the phenotypes, our analysis revealed a strong candidate variant in genes that were novel at the time of the analysis in the majority of cases, and 10 of these genes are published here for the first time as novel candidates (CDK9, NEK9, ZNF668, TTC28, MBL2, CADPS, CACNA1H, HYAL2, CTU2, and C3ORF17). A significant minority of the phenotypes (6/31, 19%), however, were caused by genes known to cause Mendelian phenotypes, thus expanding the phenotypic spectrum of the diseases linked to these genes. The conspicuous inheritance pattern and the highly specific phenotypes appear to have contributed to the high yield (90%) of plausible molecular diagnoses in our study cohort. CONCLUSION: Reporting detailed clinical and genomic analysis of a large series of apparently novel dysmorphology syndromes will likely lead to a trend to accelerate the establishment of novel syndromes and their underlying genes through open exchange of data for the benefit of patients, their families, health-care providers, and the research community.Genet Med 18 7, 686-695.