Successful naltrexone-bupropion treatment after several treatment failures in a patient with severe monogenic obesity.

We describe the therapeutic journey of a 33-year-old patient with early-onset obesity (BMI 56.7 kg/m2) and hyperphagia due to a likely pathogenic heterozygous melanocortin-4 receptor (MC4R) gene variant. She was unsuccessfully treated with several intensive lifestyle interventions, gastric bypass surgery (-40 kg weight loss, followed by +39.8 kg weight regain), liraglutide 3 mg (-3.8% weight loss with sustained hyperphagia), and metformin treatment. However, naltrexone-bupropion treatment led to -48.9 kg (-26.7%) weight loss, of which -39.9 kg (-38.3%) was fat mass, in 17 months of treatment. Importantly, she reported improved hyperphagia and quality of life. We describe the potential beneficial effects of naltrexone-bupropion on weight, hyperphagia, and quality of life in a patient with genetic obesity. This extensive journey shows that various anti-obesity agents can be initiated, subsequently terminated when ineffective and substituted with other anti-obesity agents to identify the most efficient anti-obesity treatment.

Tongue Lip Adhesion in the Treatment of Robin Sequence: Respiratory, Feeding, and Surgical Outcomes.

OBJECTIVE: Objective evaluation of the efficacy of tongue lip adhesion (TLA) in the management of Robin sequence (RS). STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary referral hospital. PATIENTS, PARTICIPANTS: The craniofacial database of Amsterdam UMC, Vrije Universiteit Amsterdam was searched to identify infants with RS who underwent tong lip adhesion (TLA). Forty-one RS infants who underwent TLA from 1993 to 2016 were identified. INTERVENTIONS: TLA. MAIN OUTCOME MEASURE: The outcome measures were pre- and postoperative polysomnography results, nutritional status, weight gain, age at operation, hospital stay length, extubation time after TLA, and complications. RESULTS: Forty-one RS patients were included who had TLA at an average age of 26.6 days. In 16 cases a pre- and postoperative polysomnography was performed. In 13 of these cases (81.3%) improvement was observed, in 2 (12.5%) the results were inconclusive, and in 1 (6.3%) no improvement was seen. Patients were extubated after a mean of 2.2 days.The mean hospital stay was 40.2 days. Reintervention was needed in 7 patients because of a wound dehiscence. The mean age of TLA release was 9.7 months. At discharge, 9 (22%) children still needed total nutritional support for persistent feeding difficulties. The average growth from birth to adhesion release was 4.6 kg. CONCLUSION: This cohort demonstrates that TLA is a successful procedure in children with RS in terms of respiratory, feeding, and growth outcome. Only minor complications were seen in our cohort.

Further delineation of Malan syndrome.

Malan syndrome is an overgrowth disorder described in a limited number of individuals. We aim to delineate the entity by studying a large group of affected individuals. We gathered data on 45 affected individuals with a molecularly confirmed diagnosis through an international collaboration and compared data to the 35 previously reported individuals. Results indicate that height is > 2 SDS in infancy and childhood but in only half of affected adults. Cardinal facial characteristics include long, triangular face, macrocephaly, prominent forehead, everted lower lip, and prominent chin. Intellectual disability is universally present, behaviorally anxiety is characteristic. Malan syndrome is caused by deletions or point mutations of NFIX clustered mostly in exon 2. There is no genotype-phenotype correlation except for an increased risk for epilepsy with 19p13.2 microdeletions. Variants arose de novo, except in one family in which mother was mosaic. Variants causing Malan and Marshall-Smith syndrome can be discerned by differences in the site of stop codon formation. We conclude that Malan syndrome has a well recognizable phenotype that usually can be discerned easily from Marshall-Smith syndrome but rarely there is some overlap. Differentiation from Sotos and Weaver syndrome can be made by clinical evaluation only.

De novo mutations in the SET nuclear proto-oncogene, encoding a component of the inhibitor of histone acetyltransferases (INHAT) complex in patients with nonsyndromic intellectual disability.

The role of disturbed chromatin remodeling in the pathogenesis of intellectual disability (ID) is well established and illustrated by de novo mutations found in a plethora of genes encoding for proteins of the epigenetic regulatory machinery. We describe mutations in the "SET nuclear proto-oncogene" (SET), encoding a component of the "inhibitor of histone acetyltransferases" (INHAT) complex, involved in transcriptional silencing. Using whole exome sequencing, four patients were identified with de novo mutations in the SET gene. Additionally, an affected mother and child were detected who carried a frameshift variant in SET. Four patients were found in literature. The de novo mutations in patients affected all four known SET mRNA transcripts. LoF mutations in SET are exceedingly rare in the normal population and, if present, affect only one transcript. The pivotal role of SET in neurogenesis is evident from in vitro and animal models. SET interacts with numerous proteins involved in histone modification, including proteins encoded by known autosomal dominant ID genes, that is, EP300, CREBBP, SETBP1, KMT2A, RAC1, and CTCF. Our study identifies SET as a new component of epigenetic regulatory modules underlying human cognitive disorders, and as a first member of the Nucleosome Assembly Protein (NAP) family implicated in ID.

High-sensitivity sequencing reveals multi-organ somatic mosaicism causing DICER1 syndrome.

BACKGROUND: Somatic mosaicism is being increasingly recognised as an important cause of non-Mendelian presentations of hereditary syndromes. A previous whole-exome sequencing study using DNA derived from peripheral blood identified mosaic mutations in DICER1 in two children with overgrowth and developmental delay as well as more typical phenotypes of germline DICER1 mutation. However, very-low-frequency mosaicism is difficult to detect, and thus, causal mutations can go unnoticed. Highly sensitive, cost-effective approaches are needed to molecularly diagnose these persons. We studied four children with multiple primary tumours known to be associated with the DICER1 syndrome, but in whom germline DICER1 mutations were not detected by conventional mutation detection techniques. METHODS AND RESULTS: We observed the same missense mutation within the DICER1 RNase IIIb domain in multiple tumours from different sites in each patient, raising suspicion of somatic mosaicism. We implemented three different targeted-capture technologies, including the novel HaloPlex(HS) (Agilent Technologies), followed by deep sequencing, and confirmed that the identified mutations are mosaic in origin in three patients, detectable in 0.24-31% of sequencing reads in constitutional DNA. The mosaic origin of patient 4's mutation remains to be unequivocally established. We also discovered likely pathogenic second somatic mutations or loss of heterozygosity (LOH) in tumours from all four patients. CONCLUSIONS: Mosaic DICER1 mutations are an important cause of the DICER1 syndrome in patients with severe phenotypes and often appear to be accompanied by second somatic truncating mutations or LOH in the associated tumours. Furthermore, the molecular barcode-containing HaloPlex(HS) provides the sensitivity required for detection of such low-level mosaic mutations and could have general applicability.

Etiology and pathogenesis of robin sequence in a large Dutch cohort.

Robin sequence (RS) can be defined as the combination of micrognathia and upper airway obstruction/glossoptosis causing neonatal respiratory problems, with or without a cleft palate and either isolated or non-isolated. Pathogenesis varies widely. We hypothesize that optimal treatment depends on pathogenesis and therefore patients should be stratified according to diagnosis. Here, we evaluate diagnoses and (presumed) pathogeneses in an RS cohort. Medical records of all RS patients presenting between 1995-2013 in three academic hospitals were evaluated. Four clinical geneticists re-evaluated all information, including initial diagnosis. Diagnoses were either confirmed, considered uncertain, or rejected. If uncertain or rejected, patients were re-evaluated. Subsequent results were re-discussed and a final conclusion was drawn. We included 191 RS patients. After re-evaluation and changing initial diagnoses in 48 of the 191 patients (25.1%), 37.7% of the cohort had isolated RS, 8.9% a chromosome anomaly, 29.3% a Mendelian disorder, and 24.1% no detectable cause. Twenty-two different Mendelian disorders were diagnosed, of which Stickler syndrome was most frequent. Stratification of diagnoses according to (presumed) pathogenic mechanism in 73 non-isolated patients with reliable diagnoses showed 43.9% to have a connective tissue dysplasia, 5.5% a neuromuscular disorder, 47.9% a multisystem disorder, and 2.7% an unknown mechanism. We diagnosed more non-isolated RS patients compared to other studies. Re-evaluation changed initial diagnosis in a quarter of patients. We suggest standardized re-evaluation of all RS patients. Despite the relatively high diagnostic yield pathogenesis could be determined in only 59.7% (71/119), due to limited insight in pathogenesis in diagnosed entities. Further studies into pathogenesis of entities causing RS are indicated.

A study of the clinical and radiological features in a cohort of 93 patients with a COL2A1 mutation causing spondyloepiphyseal dysplasia congenita or a related phenotype.

Type 2 collagen disorders encompass a diverse group of skeletal dysplasias that are commonly associated with orthopedic, ocular, and hearing problems. However, the frequency of many clinical features has never been determined. We retrospectively investigated the clinical, radiological, and genotypic data in a group of 93 patients with molecularly confirmed SEDC or a related disorder. The majority of the patients (80/93) had short stature, with radiological features of SEDC (n = 64), others having SEMD (n = 5), Kniest dysplasia (n = 7), spondyloperipheral dysplasia (n = 2), or Torrance-like dysplasia (n = 2). The remaining 13 patients had normal stature with mild SED, Stickler-like syndrome or multiple epiphyseal dysplasia. Over 50% of the patients had undergone orthopedic surgery, usually for scoliosis, femoral osteotomy or hip replacement. Odontoid hypoplasia was present in 56% (95% CI 38-74) and a correlation between odontoid hypoplasia and short stature was observed. Atlanto-axial instability, was observed in 5 of the 18 patients (28%, 95% CI 10-54) in whom flexion-extension films of the cervical spine were available; however, it was rarely accompanied by myelopathy. Myopia was found in 45% (95% CI 35-56), and retinal detachment had occurred in 12% (95% CI 6-21; median age 14 years; youngest age 3.5 years). Thirty-two patients complained of hearing loss (37%, 95% CI 27-48) of whom 17 required hearing aids. The ophthalmological features and possibly also hearing loss are often relatively frequent and severe in patients with splicing mutations. Based on clinical findings, age at onset and genotype-phenotype correlations in this cohort, we propose guidelines for the management and follow-up in this group of disorders.

Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype.

RAS signaling plays a key role in controlling appropriate cell responses to extracellular stimuli and participates in early and late developmental processes. Although enhanced flow through this pathway has been established as a major contributor to oncogenesis, recent discoveries have revealed that aberrant RAS activation causes a group of clinically related developmental disorders characterized by facial dysmorphism, a wide spectrum of cardiac disease, reduced growth, variable cognitive deficits, ectodermal and musculoskeletal anomalies, and increased risk for certain malignancies. Here, we report that heterozygous germline mutations in CBL, a tumor-suppressor gene that is mutated in myeloid malignancies and encodes a multivalent adaptor protein with E3 ubiquitin ligase activity, can underlie a phenotype with clinical features fitting or partially overlapping Noonan syndrome (NS), the most common condition of this disease family. Independent CBL mutations were identified in two sporadic cases and two families from among 365 unrelated subjects who had NS or suggestive features and were negative for mutations in previously identified disease genes. Phenotypic heterogeneity and variable expressivity were documented. Mutations were missense changes altering evolutionarily conserved residues located in the RING finger domain or the linker connecting this domain to the N-terminal tyrosine kinase binding domain, a known mutational hot spot in myeloid malignancies. Mutations were shown to affect CBL-mediated receptor ubiquitylation and dysregulate signal flow through RAS. These findings document that germline mutations in CBL alter development to cause a clinically variable condition that resembles NS and that possibly predisposes to malignancies.

R561C missense mutation in the SMARCAL1 gene associated with mild Schimke immuno-osseous dysplasia.

Autosomal-recessive Schimke immuno-osseous dysplasia (SIOD) characterized by spondyloepiphyseal dysplasia, focal-segmental glomerulosclerosis (FSGS), T-cell immunodeficiency and facial dysmorphism is caused by defects in the SMARCAL1 gene. The gene product is involved in the transcriptional regulation of other genes. A 12-year-old boy of consanginous Turkish descent developed disproportionate short stature from spondyloepiphyseal dysplasia at the age of 6 and nephrotic syndrome at the age of 10 years. Renal biopsy revealed FSGS, the kidney function was normal, T-lymphocytes were diminished without infectious complications, and he has had no cerebral ischemia. Analysis of the patient's SMARCAL1 gene revealed a novel homozygous C1798T transition leading to a R561C substitution. The parents and two healthy sisters were found to be heterozygous. A younger brother, who is also homozygous for the mutation, is clinically asymptomatic and has no proteinuria at the age of 18 months. Still, his CD4 cells are diminished. For SMARCAL1 mutations a clear genotype-phenotype correlation has been reported: severe SIOD with in utero or early-childhood onset leading to end-stage renal disease within a few years is caused by nonsense, frame shift or splice mutations. Many patients die from infections and cerebrovascular insults during childhood. Mild SIOD manifests later and progresses more slowly without infectious or cerebral vascular complications--the underlying defect being missense mutations in all three patients reported so far. The novel R561C missense mutation in our patient with mild SIOD is additional evidence for the genotype-phenotype correlation reported for SMARCAL1 mutations.

A homozygous MSH6 mutation in a child with café-au-lait spots, oligodendroglioma and rectal cancer.

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant condition due to heterozygous germline mutations in DNA mismatch repair genes, in particular MLH1, MSH2 and MSH6. Recently, a syndrome was recognized in which children develop haematological malignancies, solid tumours and signs of neurofibromatosis type 1 due to bi-allelic MMR gene mutations in MLH1, MSH2 and PMS2. Here we describe the child of healthy consanguineous parents who had café-au-lait spots, oligodendroglioma, and rectal cancer. The patient was homozygous for the MSH6 mutation c.3386_3388delGTG in exon 5 which has a predicted pathogenic effect. Germline NF1 gene mutation testing was negative. The rectal tumour showed microsatellite instability and absence of MSH6 staining, whereas the brain tumour was MSI stable and showed normal immunohistochemical expression of MSH6. Apparently, not only MLH1, MSH2 and PMS2, but also MSH6 is involved in the syndrome of childhood cancer and signs of neurofibromatosis type 1.