key: cord-0913996-vp5358rr authors: Butler, MerlinG.; Palmer, CatherineG. title: PARENTAL ORIGIN OF CHROMOSOME 15 DELETION IN PRADER-WILLI SYNDROME date: 1983-06-04 journal: The Lancet DOI: 10.1016/s0140-6736(83)92745-9 sha: f3eefad19d628cbe1fc0d65a6322a60d6cc5a3ab doc_id: 913996 cord_uid: vp5358rr nan used to alter intestinal permeability in the laboratory animal is 250 mmol/1 whereas the quantity of5ICr-EDTA used in our tests is less than 1 pmol. The physological inertness of 5ICr-EDTA has been well documented 10 as a consequence of its widespread use as a premeability marker and its routine use to measure glomerular filtration rate. The fact that we found a deficit even in patients who were histologically normal can be explained most simply by the greater precision and sensitivity of radioactivity measurements compared with chromatography of sugars; it does not seem necessary to seek a more elaborate explanation. The convenience and practicability of a test depends on individual circumstances. We find no special difficulty in obtaining a 24 h urine collection, and a test which requires only a few minutes in the laboratory is welcomed by hard-pressed technical staff. The importance of the finding of a persistent selective defect in permeability by the small intestine of gluten-sensitive patients with histologically normal mucosa is that, while explaining many features of this enigmatic disorder, it offers clear research leads, a situation lacking of late in coeliac disease. SIR,-The letter from Dr Unsworth and colleagues (April 16, p 874) prompts us to report our data on gliadin and reticulin antibodies in the diagnosis of childhood coeliac disease (CCD). IgA and IgG gliadin antibodies were detected by immunofluorescence (IFL-AGA1) and micro-ELISA (ELISA-AGA2) while IgA and IgG reticulin-RI antibodies (RI -ARA) were sought by immunofluorescence.3 Sera from 50 children with CCD aged 2-10 years at different stages of the disease, and diagnosed according to defined criteria,4 were studied. As controls, sera from 166 patients with intestinal and non-intestinal conditions associated with immunological abnormalities were tested. 30 sera from healthy age-matched children were also studied. Results are reported in the Both IFL-AGA and ELISA-AGA were more sensitive than Rj-ARA (p<001). However, Rj-ARA were strictly confined to CCD, as was IFL-AGA, while ELISA-AGA were occasionally found in control patients. IFL-AGA and ELISA-AGA showed a very similar sensitivity, while IFL-AGA were slightly more specific than ELISA-AGA. Unlike Unsworth et al we could not find IFL-AGA in groups other than CCD. The low prevalences of IFL-AGA and ELISA-AGA and RI -AGA found by us in the gluten-free diet CCD subgroup are probably due to the fact that our patients were tested after a longer period (1 year instead of 3 months). Both sensitivity and specificity of IgA and IgG antibodies were identical for IFL-AGA, while IgG ELISA-AGA were more sensitive than IgA ELISA-AGA (p<0.01) but less specific. On the whole, IFL-AGA and ELISA-AGA gave similar results in the diagnosis of CCD. The choice of test will depend on the facilities available in each laboratory. pain may be a common presenting symptom of carcinoma of the colon. We believe this to be especially true in elderly patients. We and colleagues (D. L. Crosby and M. S. Pathy) have evaluated the presenting symptoms of 288 patients over the age of 65 years admitted with colorectal carcinoma to the acute geriatric or surgical ward at the University Hospital of Wales. Of the patients admitted to the geriatric ward with colonic carcinoma 39 -8% complained of abdominal pain, whilst of those admitted to the surgical ward 60% complained of abdominal pain. Of patients with rectal carcinoma 25% of those admitted to the geriatric ward and 28% of those admitted to the surgical ward had abdominal pain. Abdominal pain seems to be more common in colonic than in rectal carcinoma, but 1 in 4 of those who had rectal carcinoma complained of this symptom. Those patients admitted to the geriatric ward also appeared to present with more vague symptoms (eg, vomiting, anorexia, and general malaise). The classic triad of altered bowel habit, rectal bleeding, and tenesmus in rectal carcinoma was present in only 50% of the surgical patients. Tenesmus in particular was an uncommon symptom, being complained of by only 1 patient admitted to the geriatric department. It is thus important to consider the diagnosis of colorectal carcinoma in elderly patients who present with ill-defined symptoms rather than rely on the classical presentation of these conditions. The code for heteromorphisms described by AgNOR is: L=large, M=medium, S=small, -= inactive. GTG stained slides were scored for satellite stalk and short arm length (I= long, m= medium, s = short, -= absent stalk, p+=long, p = normal, p -= absent p arm). QFQ stained slides were scored for satellite intensity after Pans nomenclature (1=negative, 2 = pale, 3= medium, 4= intense, 5 = brilliant).' The deleted chromosome in each case is identified by an asterisk. chromosome 15 (breakpoints qll and ql3) in 21 patients and normal chromosomes in the remaining individuals. Clinical differences between the deletion and non-deletion chromosome groups have been identifIed.5,6 The mean ages at conception for 11 affected individuals in the deletion group were 30 years for the father and 27 years for the mother. The mean age of the PWS child at time of examination was 11 years. Parental studies to determine the origin of the chromosome deletion in eleven families utilised variants affecting the satellite region of chromosome 15.7 Short arm regions of acrocentric chromosomes are considered stable and a reasonable number of variants permits parental origin determination. These regions at or near the centromere are useful for linkage analysis because of their position and constitutive heterochromatin composition both of which preclude crossing over. The variants were identified at high resolution by sequential staining with G-banding and silver of the nucleolar organising region (NOR) or G and Q banding. In all eleven families, the chromosome 15 donated by the father was identified as the chromosome in which the deletion had occurred (table). Both sets of parents' chromosomes were normal; thus all chromosome deletions were de novo. The probability that the father would donate the chromosome resulting in the deletion in all cases in our sample by chance was less than 1 in 1000 (½)11. Why should the deletion affect only the chromosome donated by the father? The continued proliferation of male gametogenesis makes this stage more vulnerable to environmental insult than is female meiosis, which is arrested for a long period. If chromosome 15 is sensitive to a particular environmental agent, there may be a greater chance for chromosomal breakage to occur. One possible agent is human coronavirus. One or more loci for sensitivity to human coronavirus 229E have been identified on the long arm (qll-qter) of chromosome 15 by cell hybridisation.8 This finding of paternal origin of deletions in PWS suggests that other deletion syndromes -be investigated to establish whether paternal origin of de novo deletions is more widespread. insulin-dependent diabetes with no known precipitating factors the study of genetic and immunological factors is of considerable interest. We report the results of HLA typing and islet cell antibody status in a family in which two siblings are affected by the disorder. Both the mother and the father are unaffected. There was no evidence of consanguinity but grandparents on both sides of the family had the same surname. Of their three children two (A and C) now have diabetes mellitus, partial cranial diabetes insipidus, and optic atrophy. Sibling A presented at age 8 years with classical symptoms of diabetes mellitus. He is now well controlled with twice-daily 'Rapitard' insulin. Aged 10 he noted decreasing visual acuity and was found to have optic atrophy. Despite good blood glucose control he complained of persistent thirst and polyuria. Aged 15 he was found to have diabetes insipidus on water deprivation test (maximum urine osmolality 643 mosmol/kg, plasma osmolality rising from 295 to 302 mosmol/kg). An intranasal test dose of desmopressin produced a maximum urine osmolality of 790 mosmol/kg. Treatment with desmopressin 10 µg at night has resulted in complete resolution of thirst and polyuria. Now aged 16 he has early signs of pubertal development. Sibling C presented with decreased visual acuity at age 10 and was found to have early optic atrophy. 1 year later she complained of excessive morning thirst, polyuria, and nocturia. A water deprivation test demonstrated a maximum urine osmolality of 344 mosmol/kg. Urine concentrated normally with intranasal desmopressin and an evening dose of 5 µg resulted in complete resolution of her symptoms. Fasting blood sugar at this time was 4 6 6 mmol/l. 1 year later recurrence of thirst and polvuria developed. associated with hyperglycaemia (21 mmol/1) and ketonuria. She is now controlled with twice daily insulin. Sibling B (aged 15) has remained symptom-free with no ocular changes and normal glucose tolerance. Fluorescence studies for islet cell antibodies3 were negative in all family members. HLA typing is shown in the table. Ein Syndrom von Adipositas, Kleinwuch, Kryptorchismus and Oligophrenic nach Myatonieratigam Zustad in Neugeborenenalter Syndromes of hypotonia, hypomentia-hypogonadism—obesity (HHHO) or Prader-Willi syndrome Prader-Willi syndrome Deletions of chromosome 15 as a cause of the Prader-Willi syndrome Diabetes mellitus and optic atrophy amongst siblings Diabetes mellitus and optic atrophy Islet cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies