Heterozygous loss-of-function variants significantly expand the phenotypes associated with loss of GDF11.

PURPOSE: Growth differentiation factor 11 (GDF11) is a key signaling protein required for proper development of many organ systems. Only one prior study has associated an inherited GDF11 variant with a dominant human disease in a family with variable craniofacial and vertebral abnormalities. Here, we expand the phenotypic spectrum associated with GDF11 variants and document the nature of the variants. METHODS: We present a cohort of six probands with de novo and inherited nonsense/frameshift (4/6 patients) and missense (2/6) variants in GDF11. We generated gdf11 mutant zebrafish to model loss of gdf11 phenotypes and used an overexpression screen in Drosophila to test variant functionality. RESULTS: Patients with variants in GDF11 presented with craniofacial (5/6), vertebral (5/6), neurological (6/6), visual (4/6), cardiac (3/6), auditory (3/6), and connective tissue abnormalities (3/6). gdf11 mutant zebrafish show craniofacial abnormalities and body segmentation defects that match some patient phenotypes. Expression of the patients' variants in the fly showed that one nonsense variant in GDF11 is a severe loss-of-function (LOF) allele whereas the missense variants in our cohort are partial LOF variants. CONCLUSION: GDF11 is needed for human development, particularly neuronal development, and LOF GDF11 alleles can affect the development of numerous organs and tissues.

A common HLA haplotype in leukaemic families in Trinidad - abstract

In a previous study, 6 of 10 patients with acute lymphoblastic ;leukaemia (ALL) were found to have the HLA-B40 antigen, 4 of these 6 patients carrying both the HLA-A2 and B40 antigens. Three of these 4 patients have since died. In the present study, family studies were performed in order to determine whether the HLA-A2 and B40 antigens constituted a haplotype in these individuals. Of the 4 families, 3 were available for HLA typing. Results show that HLA-A2/B40 did constitute a haplotype in all three families. Furthermore, the haplotype in all cases was found to be of maternal origin. Whether this haplotype is associated with an immune response gene which conveys susceptibility of the disease cannot be determined from this small study. Further typing of leukaemic children and their families (including DR antigens) should be pursued. These findings may be found to have prognostic implications for treatment, since patients with the HLA-A2/B40 and A2/B12 haplotypes have been shown to have improved long-term survival with transfer factor immunotherapy in other populations (AU)

Lindane toxicity in an infant

A four-month-old infant with severe impetigo who had prolonged daily applications of lindane presented with two seizure episodes. His blood lindane level was 1.27 ppm. Caution should be exercised when using lindane in infants and children. Proper instruction and close supervision are essential (AU)

Paediatric acquired immunodeficiency syndrome (PAIDS) in Trinidad and Tobago

The first twenty-one cases of Paediatric Acquired Immunodeficiency Syndrome (PAIDS) in Trinidad and Tobago were studied. An overwhelming majority of patients were of African descent. Most of the children presented within the first year of life, the average time between presentation and death was one and a half months, and the majority presented with either diarrhoea or pneumonia or failure to thrive, common conditions in the West Indies. Fever lasting longer than two weeks as well as hepatomegaly were clues which led to a definite diagnosis (AU)

Immunophenotypic and HLA studies in childhood acute lymphoblastic leukemia in Trinidad, West Indies

Between October 1983 and May 1986, 17 cases of childhood acute lymphoblastic leukemia (ALL) were admitted to the General Hospital, Port of Spain, Trinidad. Fifteen of those cases were under 10 years of age, seven of whom presented with joint or bone pains. Boys outnumbered girls by almost 5:1 and the ethnic distribution showed a preponderance of patients of East Indian origin. At last follow-up (May 1989), the survival rate of the 15 under-ten-year-old patients was 71 percent. Immunophenotype studies on nine of the 17 patients revealed six carrying T cell markers and three carrying markers suggestive of a pre-B phenotype. HLA tissue typing on ten patients showed an enhanced frequency of the HLA-B40 antigen when compared with controls (p less than 0.05). This antigen was present in six of the patients typed and four carried the HLA-A2 and B40 antigens together, two of whom also carried the CW3 antigen and the other two carried untypable C antigens. Three of the four carrying HLA-A2 and B40 have died. Two of the three pre-B cases also carried the HLA-A2 and B40 antigens. HLA studies on three of the four families showed that HLA-A2 and B40 were on the same chromosome, i.e., a haplotype inherited from the mother in each case. None of the cases carried the HLA-B5 antigen although this antigen had a frequency of 37.8 percent in the control group (p less than 0.05 percent). None of the controls with the HLA-B40 antigen carried the CW3 antigen. Further evidence of a disease association must await typing of the D locus antigens but current evidence would suggest an association between HLA-B40 and childhood ALL in Trinidad. (AU)

Pre-admission treatment in childhood diarrhoeal diseases, Port-of-Spain General Hospital

The case records of 1295 children admitted to the Gastroenteritis Unit, Port-of-Spain General Hospital were reviewed. Data on age, mode of referral, pre-admission treatment, in hospital management and outcome were analysed. Of the 192 cases referred, 169 were referred by general practitioners, 18 by health centres and 3 by paediatricians. The bulk of admissions (1165) were however, self-referrals. 82 (46 percent) of the cases referred by general practitioners had documented evidence of pre-admission treatment. Only 7 (8.5 percent) received the recommended treatment with rehydration salts. The rest (91.5 percent) were treated with antidiarrheals, antibiotics or antiemetics. Lack of effectiveness of drug therapy, use of ORF (oral rehydration fluid) and health education are emphasized. (AU)

Fanconi's aplastic anaemia in two sisters in Trinidad and Tobago

This report describes two cases of Fanconi's anaemia in Trinidadian sisters of East Indian origin. The cases have been confirmed by chromosomal analysis which showed increased breaks and ring forms. Anorexia was a persistent finding in both cases. One of the sisters also had a poor growth hormone response. (AU)

Childhood asthma education project - abstract

An educational programme, consisting of a booklet explained by a nurse in four sessions and the showing of a videotaped dramatization of the same informaton, was administered to 16 parents of asthmatic children. Fifteen comparable parents were followed and used as a control group. This preliminary report shows that the parents of both groups had similar levels of knowledge of asthma at the initial test. On retesting at the six-month follow-up, the parents in both groups did significantly better than on the initial test. However, the experimental group's improvement was statistically better than that of the controls (p=0.003). More important are the changes in attitude and behaviour implied by the higher rate of casualty visits, and the higher rate of attacks identified in cases as compared with controls. The fall in admissions among cases, while controls had a steady rate of admissions in both the year of the study and in the preceeding year, has positive economic implications that are especially exciting in a developing country such as ours (AU)

Eikenella corrodens brain abscess in a child with congenital heart disease

We report the isolation of Eikenella corrodens from a brain abscess in a child with cyanotic congenital heart disease in Trinidad (AU)

Paediatric medical services in Tobago (1980-1986) - abstract

This study examined the pattern of admissions to and deaths and transfers from the children's ward of the County Hospital, Tobago, between 1980 and 1986. Data on admissions, births and premature births, deaths and newborn deaths were obtained from the Hospital's annual reports. The medcial records of children who died and of those who were transferred to the Port-of-Spain General Hospital were reviewed. Each year there were from 900 to 1075 births with 12 to 31 (mean 19) newborn deaths. There were from 843 to 1060 children admitted with 3 to 14 (mean 7) deaths. Six deaths were due to "surgical" causes and 34 were 'medical'. One third of total ward deaths were from lower respiratory tract infection. This is high when compared with national (13.8 percent) and Port-of-Spain General Hospital (23.2 percent) rates. Four of five children with acute gastroenteritis and dehydration died more than twenty-four hours after admission. Two sicklers with fever received no antibiotics for twenty-four hours. A child with cloudy cerebrospinal fluid received 80 mg/kg/d of ampicillin for the first day of treatment. There were 64 transfers: 40 were neonates, of which 23 had severe neonatal jaundice. The rate of transfer is increasing yearly. These observations suggest that there should be a paediatrician resident in Tobago (AU)

Immunological surface marker and histocompatibility antigens in childhood acute Lymphoblastic leukaemia in Trinidad - abstract

Between October, 1983 and May, 1986, seventeen cases of childhood acute lymphoblastic leukaemia (ALL) were diagnosed on clinical grounds, supported by the findings of blast cells in the blood film or the bone marrow aspirate. All the patients had more than 25 percent blast cells in the bone marrow. Patients were described as belonging to a particular ethnic group when all four grandparents belonged to that group. Typing for lymphocyte surface markers was done at the time of the initial diagnosis. Fifteen of seventeen cases were under 10 years of age. Boys outnumbered girls by almost 5:1 Ten of the seventeen patients were of East Indian origin; five were of mixed ethnicity, with three of these having at least one grandparent of East Indian origin. Seven of the patients under ten years of age presented with bone and/or joint pains. Nine of the seventeen ALL patients were successfully phenotyped for immunological surface markers. Six of these carried T-cell markers. Four of the six T-cell clones were thymocytes (three stage III and one stage I). Three patients were common ALL antigen-positive (CALLA+) but these also had markers suggestive of a pre-B phenotype (OK-, OKB2+, CALLA+ and OKT-10+). HLA tissue typing of ten of the patients showed an enhanced frequency of th HLA B-40 antigen when compared with controls (p<.0001). This antigen was present in 60 percent of the patients typed, 40 percent of whom carried the HLA A2/B40 halotype. None of the cases carried the HLA B-5 antigen although this antigen had a frequency of 19 percent in the control group (p<0.05). The antigen A-11 showed a decreased frequency (10 percent percent in patients compared with controls (13.3 percent), while B-15 showed an increased frequency (15.0 percent) compared with the control group (4.0 percent), but these differences were not statistically significant. Childhood leukaemia in Trinidad is primarily a disease of East Indian children. Bone or joint pain seems to be a common presenting feature and the common ALL antigen type of leukaemia is less common than T-cell leukaemia, Current evidence would suggest a linkage diequilibrium between HLA B-40 and childhood ALL in Trinidad (AU)

Paediatric acquired immune deficiency syndrome: report of the first case from Trinidad

A case of Acquired Immune Deficiency Syndrome (AIDS) in an infant at the age of 5 months is reported from Trinidad. The father who was bisexual died from AIDS before the birth of the child. The mother is HTLV-III antibody-positive and is healthy at present. This is the first report of paediatric AIDS (PAIDS) from Trinidad (AU)

Childhood urinary tract infection - abstract

This is the first published report on the bacteriology and sensitivity pattern in urinary tract infections in the region. One hundred of four hundred and eighty-four urine specimens from children less than ten years of age at the General Hospital, Port-of-Spain, grew 10 (5) colonies of a single organism. Forty-four per cent of these organisms were E. Coli, 21 percent Klebsiella and 16 percent Enterobacter. There was a high percentage of isolates sensitive to Furadantin (94 percent, Cephaloridine (89 percent). Nalidixic acid (82 percent) and Gentamycin (81 percent). There were only 42 percent of isolates sensitive to Ampicillin/Amoxycillin. It was concluded that Ampicillin/Amoxycillin are no longer first-line drugs, nor are they appropriate "best guess" drugs in children with urinary tract infection at our hospital (AU)

The significance of serum IgE levels in Trinidad and Tobago - abstract

In Trinidad, normal non-atopic children, mean age 2.5 years, had serum IgE's of 133 Ku/l whereas in the northern hemisphere the corresponding value for 9-month to 3-year-old children is 33 Ku/1 and the adult mean is 100 Ku/1. However, childhood asthmatics with helminthic infestation had a mean serum IgE of 1,432 Ku/l. On the other hand, childhood asthmatics whose stools were negative for helminths had significantly (840 Ku/l) less serum IgE, confirming the additive effect of helminths upon the type I hypersensitivity response in children. Those children who were diagnosed as having atopic dermatitis had the highest mean serum IgE concentrations (1,892 Ku/l). Blood Donors had a mean serum IgE of 231 Ku/l. It is concluded that serum IgE is of significant importance in identifying the atopic state, even in countries with endemic helminthic infestation. However, local normal and abnormal ranges need to be established before the results can be correctly interpreted (AU)

Allergies in Trinidad and Tobago - abstract

Observations for over eighteen months with the establishment of an Allergy Clinic at the Port-of-Spain General Hospital are being presented. Skin testing for immediate Type I hypersensitivity by the Gell and Coombs classification was done on all patients with a history of allergy. The skin testing results showed that 63 percent of the patients were positive to Dermatophagoides pteronys-sinus; 55 percent positive to D. fariniae; 48 percent to house dust; 31 percent to a mixture of 4 moulds and 32 percent to a mixture of feathers. Therefore house dust mites and house dust were the major offending allergens. This confirms the observation in the temperate region that asthma is related to allergy and to house dust mites. During the course of this clinic, it was observed that in the majority of the patients with allergies, illnesses seemed to occur at the time of the year coinciding with that of the highest humidity. Consequently, a retrospective study of asthma with hospital data on admission was reviewed over a five-year period, 1975-1979. The mean monthly admission rate was 66 (range 46 to 98) with a rate of 57 (range 46 to 69) from January to September and 90 (range 86 to 98) from October to December. This seems to correlate with humidity which is low January to May (mean 79.4 percent) and high in July to December (mean 85.3 percent). The lag between the rise in humidity and the rise in admissions in October could suggest that the relationship is not a direct cause-effect one. The radioimmunoassay method was used for quatitating the serum IgE in a selected group of patients. Mean for the first 26 patients was 485 iu/ml and in only 7 of the first 26 patients done for IgE was less than 300 iu/ml the suggested upper limit. These are high values compared with non-allergic Swedish children whose mean is 66 iu/ml. and healthy Ethiopian children free of parasites whose mean was 325 iu/ml using a similar technique (AU)