PHACE syndrome: Infantile hemangiomas associated with multiple congenital anomalies: Clues to the cause

Infantile hemangiomas (IH) are the most common vascular tumor of infancy with an estimated 80,000 annual diagnoses in the United States. The genetic mechanisms underlying IH and the related multi-organ birth defect syndromes, PHACE (an acronym for P osterior fossa brain malformations, segmental facial H emangiomas, A rterial anomalies, C ardiac defects, E ye anomalies, and sternal clefting or supraumbilical raphe) and LUMBAR (an acronym for L ower body hemangiomas, U rogenital anomalies, M yelopathy, B one deformities, A norectal malformations/ A rterial anomalies, R enal anomalies) remain unsolved. With advances in next generation sequencing (NGS), genomic alterations have been identified in a wide range of vascular anomaly syndromes. We hypothesize that PHACE is a genetic disorder, caused by somatic mutations, likely in cancer genetic pathways. Identification of the genetic etiology will lead to improved diagnosis in PHACE syndrome and development of targeted therapies for IH and related congenital anomalies.     

A review of DICER1: structure,function and contribution to disease

DICER1 is an important housekeeping gene that encodes a multi-domain enzyme that functions in small RNA processing. The enzymatic products function in several pathways including RNA interference, DNA damage repair and antiviral response. At the protein level, endoribonuclease DICER also plays a role in many human illnesses, and much research is being done to clarify the full spectrum of its functions and relation to neoplastic and non-neoplastic disease. Both somatic and germline mutations in DICER1 have been identified, and germline mutations have been associated with at least two named syndromes: DICER1 syndrome and GLOW syndrome. The ubiquitous nature of this enzyme makes it an attractive target for future study and therapeutic potential, but much remains to be learned.     

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.     

Excretion of the mono- and divalent ions in relation to flow rate in bartter's and pseudo bartter's syndromes in parotid saliva. comparative studies to the syndrome of conn

Summary In three patients, one with Bartter's syndrome and two with pseudo-Bartter's syndrome, the excretion pattern of mono- and divalent ions of the parotid saliva was studied as a function of flow rate. The results were compared with those observed in normal adults and in two patients with Conn's syndrome.In both Bartter's and pseudo-Bartter's syndromes, salivary K⁺ secretion was more than two times higher if compared with the corresponding flow rates. Other symptoms of the complex alterations of electrolyte transport in Bartter's and pseudo-Bartter's syndromes were the increased salivary excretion of calcium, magnesium, bicarbonate and inorganic phosphorus. Na⁺ reabsorption was slightly decreased in the patient with true Bartter's syndrome, and moderately increased in pseudo-Bartter's syndrome.The typical feature in the two patients with Conn's syndrome showed to be an excessive increase of salivary sodium reabsorption. The total amount of sodium actively reabsorbed by the duct system (J*_ac), exceeded the normal range by about a factor of 2–3. Simultaneously, and in contrast to Bartter's syndrome, the flow-dependent concentrations of bicarbonate were markedly and those of magnesium slightly lower. The concentrations of potassium and inorganic phosphorus were moderately elevated, whereas those of calcium were markedly increased.Quantitative as well as qualitative differences in the salivary electrolyte patterns in these diseases provide strong arguments against an exclusive role of aldosterone in the pathogenesis of the electrolyte disturbances in Bartter's and pseudo-Bartter's syndrome.Experiments on human parotid glands clearly demonstrate that alterations of transepithelial electrolyte transport in this disease are not only confined to the different segments of the renal tubulus, but seem to be a symptom of a generalized disturbance of electrolyte transport.Supported by the Deutschen Forschungsgemeinschaft.     

ADULT-syndrome: An autosomal-dominant disorder with pigment anomalies,ectrodactyly, nail dysplasia,and hypodontia

We describe a family with at least seven living persons who are affected by an hitherto undescribed autosomal-dominant syndrome with variable expression, bearing close resemblance to the EEC syndrome and related disorders. The main manifestations are hypodontia and/or early loss of permanent teeth, ectrodactyly, obstruction of lacrimal ducts, onychodysplasia, and excessive freckling. We propose the acronym ADULT (acro-der-mato-ungual-lacrimal-tooth)-syndrome for this condition. © 1993 Wiley-Liss, Inc.     

XXY male with X-linked dominant chondrodysplasia punctata (Happle syndrome)

Happle syndrome is an X-linked dominant disorder with presumed lethality in hemizy-gous males; familial occurrence is rare. We describe a family with Happle syndrome affecting individuals in 3 generations. A man in this family is the first known male patient with Happle syndrome. He is severely affected; this may be due to his 47, XXY kary-Otype. © 1995 Wiley-Liss, Inc.     

Brothers with novel compound heterozygous mutations in COL27A1 causing dental and genital abnormalities

COL27A1 encodes a collagen type XXVII alpha 1 chain. It is the product of this gene that provides the structural support of connective tissue and is reported to be the causative gene of Steel syndrome (OMIM #615155). The primary symptoms of patients with this defect are consistent with systemic bone disease; however, recent reports note findings of intellectual disability and hearing loss. In this study, we identified novel COL27A1 compound heterozygous variants in two brothers with rhizomelia and congenital hip dislocation as well as dental and genital abnormalities that have not yet been reported in Steel syndrome. This variant, of maternal origin, caused an amino acid substitution of arginine for glycine, c.2026G>C or p.G676R, in the collagen helix domain, which is assumed to damage the structure of the helix. The paternally transmitted variant, c.2367G>A, is located at the 3′ end of exon 12, and cDNA analysis revealed a splicing alteration. These novel, compound heterozygous COL27A1 variants might indicate an association of the gene with tooth and genital abnormalities.     

Catch them if you are aware: PTEN postzygotic mosaicism in clinically suspicious patients with PTEN Hamartoma Tumour Syndrome and literature review

PTEN germline variants cause PTEN Hamartoma Tumour Syndrome (PHTS). Of individuals fulfilling diagnostic criteria, 41–88% test negative for PTEN germline variants, while mosaicism could be an explanation. Here we describe two individuals with PTEN mosaicism. First, a 21-year-old female presented with macrocephaly and a venous malformation. Next generation sequencing analysis on her venous malformation identified the mosaic pathogenic PTEN variant c.493-2A>G (23%). This variant was initially missed in blood due to low frequency (<1%), but detected in buccal swab (21%). Second, a 13-year-old male presented with macrocephaly, language developmental delay, behavioral problems, and an acral hyperkeratotic papule. Targeted PTEN analysis identified the mosaic pathogenic variant c.284C>T (11%) in blood, which was confirmed via buccal swab. These two cases suggest that PTEN mosaicism might be more common than currently reported. PTEN mosaicism awareness is important to enable diagnosis, which facilitates timely inclusion in cancer surveillance programs improving prognosis and life expectancy.     

Marfan and cri du chat syndromes in an 18-month-old child: evidence of phenotype interaction

We report on an 18-month-old girl who has both the cri du chat and Marfan syndromes. She was born at term to a 29-year-old woman with the clinical diagnosis of Marfan syndrome. An evaluation for developmental delay at 2 months of age showed a karyotype of 46,XX,del(5)(15.1), consistent with cri du chat syndrome. At age 18 months she was tall (90 cm, >95th centile), with an decreased upper segment:lower segment ratio (1.0), and microcephalic (OFC 42.5 cm, <5th centile). Facial features were typical of cri du chat syndrome. The palm, middle finger and foot lengths were at or above the 95th centile for age. She was hypotonic, and her developmental level was approximately 8–10 months. Echocardiography showed redundant mitral valve tissue, mild mitral insufficiency, dilated aortic sinuses, and a small muscular VSD. We would have anticipated that a patient with an autosomal deletion who also had Marfan syndrome would have had growth failure. However, in this patient the skeletal features of Marfan syndrome (increased body length, decreased upper segment:lower segment ratio, and increased palm, finger, and foot length) predominate.     

Mild macrocytosis in Williams-Beuren syndrome

ObjectiveTo evaluate the occurrence and estimate the frequency of macrocytosis in Williams-Beuren syndrome (WBS).Study designComplete blood count (CBC) data from 179 subjects with WBS aged 1-69 were collected, with common parameters assessed for trends. Z-transformed mean corpuscular volume (MCV) was compared with each laboratory's reference range as well as with control data from the National Health and Nutrition Examination Survey (NHANES) 2013-2014 data archives.ResultsJust over a third (35%) subjects had at least one recorded incidence of macrocytosis. In comparisons of CBC parameters with an expected population mean, MCV and MCH were greater than, while Hct and RDW were lower than, expected values. The distribution of erythrocyte MCV is shifted to the right in WBS compared to controls, as was the mean value. Despite this, anemia was absent, except in a single medically complex WBS subject. Though there was a paucity of data available of variables that could potentially cause an elevated MCV, no obvious etiology could be elucidated.ConclusionsMild macrocytosis without anemia affects a moderate subset of WBS patients, leading to a rightward shift in the MCV distribution curve. Providers encountering isolated mild macrocytosis in WBS can consider observation over further workup.     

Incidence of major chromosomal abnormalities in a referred population for suspected chromosomal aberrations: a report of 357 cases

The present report describes the cytogenetic findings in 357 cases referred for suspected chromosomal abnormalities because of abnormal clinical features. Chromosomal anomalies were found in 97 (27.2 %) of the cases studied. A significantly high rate of chromosomal abnormalities was found in a population with clinical abnormalities in comparison to an unselected population (0.48–0.55 %).     

Analysis of prevalence and degree of macrocephaly in patients with germline PTEN mutations and of brain weight in Pten knock-in murine model

PTEN Hamartoma Tumour Syndrome (PHTS) includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), and other conditions resulting from germline mutation of the PTEN tumour suppressor gene. Although macrocephaly, presumably due to megencephaly, is found in both CS and BRRS, the prevalence and degree have not been formally assessed in PHTS. We evaluated head size in a prospective nested series of 181 patients found to have pathogenic germline PTEN mutations. Clinical data including occipital-frontal circumference (OFC) measurement were requested for all participants. Macrocephaly was present in 94% of 161 evaluable PHTS individuals. In patients ≤ 18 years, mean OFC was +4.89 standard deviations (SD) above the population mean with no difference between genders (P = 0.7). Among patients >18 years, average OFC was 60.0 cm in females and 62.8 cm in males (P < 0.0001). To systematically determine whether macrocephaly was due to megencephaly, we examined Pten(M3M4) missense mutant mice generated and maintained on mixed backgrounds. Mice were killed at various ages, brains were dissected out and weighed. Average brain weight for Pten(M3M4) homozygous mice (N = 15) was 1.02 g compared with 0.57 g for heterozygous mice (N = 29) and 0.49 g for wild-type littermates (N = 24) (P < 0.0001). Macrocephaly, secondary to megencephaly, is an important component of PHTS and more prevalent than previously appreciated. Patients with PHTS have increased risks for breast and thyroid cancers, and early diagnosis is key to initiating timely screening to reduce patient morbidity and mortality. Clinicians should consider germline PTEN testing at an early point in the diagnostic work-up for patients with extreme macrocephaly.     

Mild Beckwith-Wiedemann and severe long-QT syndrome due to deletion of the imprinting center 2 on chromosome 11p

We report on a young woman admitted to our Cardiology Unit because of an episode of cardiac arrest related to a long-QT syndrome (LQTS). This manifestation was part of a broader phenotype, which was recognized as a mild form of Beckwith-Wiedemann syndrome (BWS). Molecular analysis confirmed the diagnosis of BWS owing to a maternally inherited deletion of the centromeric imprinting center, or ICR2, an extremely rare genetic mechanism in BWS. The deletion interval (198 kb) also included exons 11–16 of the KCNQ1 gene, known to be responsible for LQTS at locus LQT1. No concomitant mutations were found in any other of the known LQT genes. The proposita''s mother carries the same deletion in her paternal chromosome and shows manifestations of the Silver-Russell syndrome (SRS). This report describes the smallest BWS-causing ICR2 deletion and provides the first evidence that a paternal deletion of ICR2 leads to a SRS-like phenotype. In addition, our observation strongly suggests that in cases of LQTS due to mutation of the KCNQ1 gene (LQT1), an accurate clinical genetic evaluation should be done in order to program the most appropriate genetic tests.     

Peripheral erythrophagocytosis in two reptiles

Two cases of peripheral erythrophagocytosis in reptiles are presented. The first case was from an anorectic and depressed adult bearded dragon (Pogona vitticeps) that had a massively elevated white blood cell count (158×10⁹/l) due to an increase in circulating azurophils with approximately 12% of these cells exhibiting erythrophagia. The second case was from an adult Children’s python (Liasis childreni) with a protracted history of anorexia after an episode of respiratory tract disease. Blood from the snake demonstrated a moderate basophilia (2.3×10⁹/l) and a normal azurophil count (4.1×10⁹/l) but with approximately 66% of the azurophils containing phagocytosed erythrocytes. While the cause of the erythrophagocytosis could not be definitively identified in these cases, a leukemoid-type monocyte population in the bearded dragon resulted in a differential of myeloproliferative disease, while the Children’s python exhibited cytological features suggestive of acquired haemophagocytic syndrome.     

Pain in individuals with RASopathies: Prevalence and clinical characterization in a sample of 80 affected patients

Pain in individuals with RASopathies is a neglected topic in literature. In this article, we assessed prevalence and profile of pain in a sample of 80 individuals affected by RASopathies. The study sample included individuals with Noonan syndrome (N = 42), Costello syndrome (N = 17), and cardio‐facio‐cutaneous syndrome (N = 21). A set of standardized questionnaires and scales were administered (VAS/numeric scale, r‐FLACC, Wang‐Baker scale, NPSI, BPI, NCCPC‐R) to detect and characterize acute and chronic pain and to study the influence of pain on quality of life (PEDs‐QL, SF‐36) and sleeping patterns (SDSC); revision of past medical history and multisystemic evaluation was provided. Available clinical data were correlated to the presence of pain. High prevalence of acute (44%) and chronic (61%) pain was documented in the examined sample. Due to age and intellectual disability, acute pain was localized in 18/35 individuals and chronic pain in 33/49. Muscle‐skeletal and abdominal pain was more frequently reported. The intensity of acute and chronic pain interfered with daily activities in 1/3 of the sample. Pain negatively impacted on QoL and sleeping patterns. This work documents that pain is highly prevalent in RASopathies. Future studies including subjective and objective measures of pain are required to discriminate a somatosensory abnormality from an abnormal elaboration of painful stimuli at a central level.     

H‐ferritin and proinflammatory cytokines are increased in the bone marrow of patients affected by macrophage activation syndrome

Macrophage activation syndrome (MAS) is hyperinflammatory life‐threatening syndrome, associated typically with high levels of serum ferritin. This is an iron storage protein including heavy (H) and light (L) subunits, categorized on their molecular weight. The H‐/L subunits ratio may be different in tissues, depending on the specific tissue and pathophysiological status. In this study, we analysed the bone marrow (BM) biopsies of adult MAS patients to assess the presence of: (i) H‐ferritin and L‐ferritin; (ii) CD68⁺/H‐ferritin⁺ and CD68⁺/L‐ferritin⁺; and (iii) interleukin (IL)‐1β, tumour necrosis factor (TNF) and interferon (IFN)‐γ. We also explored possible correlations of these results with clinical data. H‐ferritin, IL‐1β, TNF and IFN‐γ were increased significantly in MAS. Furthermore, an increased number of CD68⁺/H‐ferritin⁺ cells and an infiltrate of cells co‐expressing H‐ferritin and IL‐12, suggesting an infiltrate of M1 macrophages, were observed. H‐ferritin levels and CD68⁺/H‐ferritin⁺ cells were correlated with haematological involvement of the disease, serum ferritin and C‐reactive protein. L‐ferritin and CD68⁺/L‐ferritin⁺ cells did not correlate with these parameters. In conclusion, during MAS, H‐ferritin, CD68⁺/H‐ferritin⁺ cells and proinflammatory cytokines were increased significantly in the BM inflammatory infiltrate, pointing out a possible vicious pathogenic loop. To date, H‐ferritin and CD68⁺/H‐ferritin⁺ were associated significantly with haematological involvement of the disease, suggesting biomarkers assessing severity of clinical picture.     

Further evidence for the location of the blepharophimosis syndrome (BPES) at 3q22.3-q23

Fryns JP, Strømme P, van den Berghe H. Further evidence for the location of the blepharophimosis syndrome (BPES) at 3q22.3-q23.
Clin Genet 1993: 44: 149–151. © Munksgaard, 1993
We report a 6-year-old, mentally retarded boy with typical clinical signs and symptoms of the blepharophimosis syndrome ( b lepharophimosis, p tosis, e picanthus inversus s yndrome (BPES)), born to normal parents. Chromosome studies revealed an interstitial deletion in the long arm of chromosome 3: del(3)(q22.3—q23). This observation reinforces previous suggestions that the location of the BPES gene is at 3q2, i.e. 3q22.3-q23.     

Velo-facio-skeletal syndrome in a mother and daughter

We present a woman and her daughter with an apparently new short stature syndrome associated with facial and skeletal anomalies and hypernasality. Manifestations included hypertelorism with broad and high nasal bridge, epicanthal folds, narrow and high arched palate, mild mesomelic brachymelia, short broad hands, prominent finger pads, hyperextensibility of hand joints, small feet, nasal voice, and normal intelligence. The mother had short stubby thumbs and the daughter had posteriorly angulated ears and delayed bone age. The morphology of the nose and the hypernasality are reminiscent to those in the velo-cardio-facial syndrome. High resolution banding and fluorescent in situ hybridization studies showed no evidence of 22q11 deletions. Differentiation from Aarskog syndrome and Robinow syndrome is discussed. © 1995 Wiley-Liss, Inc.     

Historic and future development of high-frequency ventilation

High-frequency ventilation (HFV) has not one but several histories. Proceeding along largely independent pathways are techniques using frequencies of 1–5 Hz and techniques using 10–40 Hz, the former being introduced by Sjostrand in 1971, the latter by Lunkenheimer in 1972. It was nearly ten years before it was recognized that these techniques must radically alter our concepts of gas transport within the lung. There has also been an unfortunate series of clinical studies purporting to show that HFV is superior to conventional ventilation in patients with lung disease. There is no doubt that nearly all reports show that HFV controls PaCO₂ very easily, and that the mechanisms by which this is achieved is the primary topic of the symposium. What has not been proved is that HFV is better than conventional ventilation in increasing PaO₂. The mechanisms of oxygen exchange when the lung has extensive shunts are quite different from those for CO₂ exchange, and this problem has not been rigorously addressed.