- Email: [email protected]
A NEW MALFORMATION SYNDROME?
840 isolates
were
identified by Dr. 1. G.
Murray
as
Torulopsi
glabrata. On Dec. 21 a full laparotomy was carried out, but, apart from the seroturbid fluid, showed no abnormality othe] than a small pancreatic pseudocyst. There was no evidence of fat necrosis. Since few superficial veins were by this time available foi administration of amphotericin B, and since there was some suggestion of diabetic nephropathy (previous history of lefl renal carbuncle in 1956), treatment was started with 5fluorocytosine (minimum inhibitory concentration for the yeast, 0-25 g. per ml.). The dose was of 9 g. daily (200 mg. per kg.) by mouth. Serum concentrations of 5-fluorocytosine were estimated on two occasions as 20 g. per ml. and 10 g. per ml. In addition, 100 mg. of amphotericin B was instilled into the bladder daily. Treatment was continued for ten days, and at the end of this time the patient was well enough to return home. Blood and urine cultures yielded no further growth of yeasts. No depression of the blood-count or impairment of liver-function tests was observed. Torulopsis glabrata is a common vaginal commensal which occasionally causes urinary-tract infection and rarely septicaemia in debilitated patients. Successful treatment with amphotericin B has been reported. 5-fluorocytosine, which can be administered orally, has been used with good results in Candida septicaemia and in cryptococcal meningitis 2,3; and it appears to have eradicated the blood infection with Torulopsis in the present case, though it is possible that clearing of the bladder infection, in which urinary 5-fluorocytosine was assisted by amphotericin B, contributed to this. Toxic effects4 were not observed during this short ("0111’<::1"
with mnc1f’1’tf’ h)f)nf-1<*vpt<:
Departments of Surgery and Bacteriology, Royal Infirmary, Bristol.
A. J. WEBB D. C. E. SPELLER K. G. BUCKLER.
A NEW MALFORMATION SYNDROME? a sibship of five males and three females, three boys and one girl were born with a syndrome which has apparently not been described before. Only two of the affected children and two of the normal sibs (one boy and one girl in each case) are still alive and have been examined. The clinical features (see accompanying figure) were as follows:
SIR,-In
(1) Extensive bone deficiencies in all limbs ; (2) scarcity of hair the whole body; (3) large, thin, protruding, and deformed pinnas (helix partly unrolled); (4) abnormal dentition (widely spaced teeth, most of them small and conical; permanence of some deciduous teeth and absence of some permanent ones); (5) hypoplastic nipples and areolas; (6) discrete simple goitre; (7) impaired mental performance; (8) sexual underdevelopment; (9) hypoplastic nails; (10) gynaecomastia (discrete); (11) growth retardation; (12) unilateral (right) incomplete hare-lip; (13) electroencephalographic abnormalities; (14) electrocardiographic abnormalities; (15) metabolic abnormalities. Signs 8-13 were only present in the boy. (The girl has over
or toes at all.) Only the girl had electrocardioabnormalities. Both had simple goitres, but this graphic may have been fortuitous. Mental impairment, which was found in both, may have been of cultural origin. It is thus doubtful whether these signs (8-14) are all components of the syndrome. It is postulated that this syndrome is due to the homozygosity of a rare autosomal-recessive gene. no
syndrome.
Metabolic Abnormalities
Paper chromatography of the urine of the two patients an excess (larger in the boy than in the girl) of tryptophan and/or tyrosine. This may be a characteristic of the syndrome. The patients, and their parents, refused revealed
to
aHow blood
to
be taken for further studies.
Dermatoglyphics Dermatoglyphic analysis two
of the upper extremities of the
patients revealed the following:
In the boy the left hand had only two metacarpals and two fingers. One of the fingers had a tented arch and the other a radial loop (RC7). The remainder of the palm showed unusual lines, without the normal flexion creases, and with only one digital triradius. Near the most distal bracelet crease there was a simple whorl with an atypical core. The distal part of the right limb was represented only by an elongated appendage (without fingers). On this there were two areas with atypical lines (some of them interrupted), surrounded by non-ridged skin. In the girl the terminal appendage on the left upper limb had no fingers, but showed palm-like interrupted lines. At the end of the appendage there was a pattern resembling a double whorl without triradii. On the right side there was a ball-like appendage with interrupted and dissociated ridges.
These data represent extensive dermatoglyphic disturbThe parents, however, had normal dermatoglyphics.
ances.
Chromosomes Chromosome analysis was performed on cultured leucocytes from the venous blood of three members of the family, using a slight modification of a widely used tech-
nique.1 All the cells selected for analysis were photographed for chromosome counting and karyotyping. Patau’s counting procedure was used when possible. The three individuals investigated had normal karyotypes.
fingers
English, M. P. Rev. med. vet. Myc. 1967, 6, 103. Tassel, D., Madoff, M. A. J. Am. med. Ass. 1968, 206, 830. Watkins, J. S., Campbell, M. J., Gardner-Medwin, D., Ingham, H. R., Murray, I. G. Br. med. J. 1969, iii, 29. 4. Grunberg, E., Prince, H. N., Utz, J. P. Proceedings of Fifth International Congress of Chemotherapy (edited by K. H. Spitzy and H. Haschek); vol. IV, p. 69. Vienna, 1967. 1. 2. 3.
Brother and sister with the malformation
Unfortunately technical difficulties made it impossible to more cells from the father, or the cells of the boy. The patients and their parents did not
examine affected allow us
to
take any
more
blood.
A full
description of this syndrome will appear in the American _7ournal of Human Genetics. This work was sponsored by the Fund for Overseas Research Grants and Education Inc., the Rockefeller Foundation, the National Research Council of Brazil, the Calouste Gulbenkian 1. Moorhead, P.
Hungerford,
S., Nowell, P. C., Mellman, W. J., Battips, D. M., Expl Cell Res. 1960, 20, 613.
D. A.
841 Foundation, and the research council of the Federal University wF PO’l"on!:l
Laboratory of Human Genetics and Department of Pædiatrics, Federal University of Parana, Curitiba, Pr., Brazil.
NEWTON FREIRE-MAIA IZRAIL CAT V. L. V. LOPES ELEIDI ALICE CHAUTARD F. A. MARCALLO I. J. CAVALLI R. F. PILOTTO MARIA CARMEN SCHETINO A. A. DER BEDROSSIAN.
vertebral-anomaly syndrome with the specific preaxial defect being variable. Division of Medical Genetics, and
Departments of Pediatrics, Medicine, and Surgery,
Washington University School of Medicine, St. Louis, Missouri.
1. 2.
Say, B., Gerald, P. S. Lancet, 1968, ii, 688. Fuhrmann, W. ibid. p. 918. 3. Fuhrmann, W., Rieger, A., Vogel, F. Arch.Kinderheilk. 1958, 158, 264. 4.
Tunte, W. Lancet, 1968, ii,
1081.
QUINTON
your leader
(March 21, p. 597) you erred in achieve complete vagal denervation of the stomach leaves gastric acid secretion unaffected. In truth, there is evidence that partial vagotomy will reduce acid output by the stomach in rats 1,2 and cats and dogs.3 Stening and Isenberg3 found that hemivagotomy would reduce the acid response to insulin hypoglycaemia by 35-50% in cats and dogs, and I see no reason why this effect should not also occur in man. Intentional section of only one vagal trunk has not been practised on human beings, as far as I am able to discover, and therefore there has been no opportunity to examine this finding in man. If partial vagotomy is partially successful in reducing acid output by the human stomach in response to food, it may be sufficient to cure peptic-ulcer disease in its milder forms. stating that failure
POLYDACTYLY/IMPERFORATE-ANUS/
BARBARA
JESSIE L. TERNBERG.
VAGOTOMY
SiR,-In
VERTEBRAL-ANOMALIES SYNDROME SIR,-In 1968, Say and Gerald1 described a syndrome of polydactyly, imperforate anus, and vertebral anomalies. In a survey of 186 patients with polydactyly, they found 10 patients with this syndrome, 8 of whom had preaxial polydactyly. In response to this report Fuhrmann2 noted his previous description3 of a boy with imperforate anus, preaxial polydactyly of the right hand, and possible congenital heart-disease, whose younger brother also had an imperforate anus. The mother had, preaxial polydactyly of the right hand. Tiinte4 reviewed a series of 103 patients with anal atresia, and found 3 with unilateral hypoplasia or aplasia of the thumb, and one with an abnormal thumb. He added 2 other cases with thumb abnormalities and imperforate anus. We wish to report a case with imperforate anus, and vertebral and renal anomalies who had a hypoplastic thumb on the left hand and preaxial polydactyly of the right foot. The patient was the product of a full-term, uncomplicated pregnancy. His mother was 37 years old and his father 49. They are not consanguineous. One previous miscarriage occurred. The mother had 2 healthy boys during a previous marriage. Physical examination at age 11 hours showed a hypoplastic left thumb. There was preaxial polydactyly of the right foot. A covered-anus type of imperforate anus and a perianal fistula were present. A ’ Hypaque’ fistulogram showed no urethral communication. X-rays showed the following: cleft vertebrx T3, 4, 5, and 7; hemivertebrae T10 and T12; and fusion of the left 7th, 8th, and 9th ribs, left 10th and llth ribs, right 6th and 7th, 9th and 10th, and llth and 12th ribs with associated rib deformities. There was thoracic-curve reversal with left thoracolumbar scoliosis. An intravenous urogram showed a slightly enlarged and hydronephrotic right kidney. There was no radiographic evidence of a left kidney. A large poorly emptying bladder was noted, but it has since functioned normally. Blood-lymphocyte karyotype analysis revealed a normal 46XY male pattern. An operation was performed to excise the fistula and to form an anus. The hypoplastic left thumb was tied off. This patient has an imperforate anus and vertebral anomalies associated with limb segmentation abnormalities. He exhibits both the preaxial polydactyly reported in the cases of Say and Gerald and of Fuhrmann, and the preaxial deletion anomalies of the cases of Tunte. Case 8 of Say and Gerald had left-sided tibial polydactyly with absent tibia and patella, deformed fibula, and hypoplastic left hemipelvis, also illustrating deletion and polydactyly in the same patient. These cases suggest that there are probably not two separate syndromes with deletion versus polydactyly, but rather that there may be a preaxial defect/imperforate anus/
ROBERT L. KAUFMAN
to
Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
R. M. PRESHAW.
A RAPID METHOD FOR NUCLEAR SEXING SIR,-The article on sex and gender (Feb. 21, p. 405), stresses the importance of early knowledge of an individual’s chromosomal, gonadal, and genital sex in relation to adequate evolution of social sex during education. This seems not only true for patients with ambiguous genitalia,
but also for individuals with Turner’s
or
Klinefelter’s
syndrome, who are usually not diagnosed before puberty. Especially in patients with the 45,XO chromosomal constitution, early diagnosis may have therapeutic implications.4 Many doctors, in our experience, are still neglecting the possibility of instant diagnosis of sex-chromosome disorders by the simple method of sex-chromatin analysis in nuclei from buccal-mucosa cells. This prompts us to describe briefly a technique for the preparation of buccal mucosa smears, which, in our opinion, is no more complicated than drawing a blood-sample and less time-consuming than a white-blood-cell count. Furthermore, it is less expensive. After removal of superficial mucus, suitable cells are obtained by scraping the buccal epithelium firmly with a sterile metal spatula (avoid bleeding). The material is well spread on a clean glass slide. Immediate fixation is achieved by spraying twice with a commercial hairspray from a distance of 20-40 cm. Airdrying takes 2-3 minutes. The dry slides may be shipped or stored. Otherwise they are stained by applying one drop of aceto-orcein and then covered.
Nuclei with an
localised at low magnification and examined oil-immersion objective (x 100). The hairspray fixing procedure means that the nuclei partially maintain their three-dimensional configuration, so they have to be examined at different optic levels. University Institute of Human Genetics, H. HOEHN are
Freiburg, Germany.
West
LINDA Z. GORMAN.
Shay, H. S., Komarov, S. A., Gruenstein, M. Archs Surg. 1949, 59, 210. 2. Rivilis, J., Yaffe, M., Preshaw, R. M. Proc. Soc. exp. Biol. Med. 1968, 127, 310. 3. Stening, G. F., Isenberg, J. I. Am. J. Physiol. 1969, 217, 962. 4. Tzagournis, M. J. Am. med. Ass. 1969, 210, 2373. 1.
were
identified by Dr. 1. G.
Murray
as
Torulopsi
glabrata. On Dec. 21 a full laparotomy was carried out, but, apart from the seroturbid fluid, showed no abnormality othe] than a small pancreatic pseudocyst. There was no evidence of fat necrosis. Since few superficial veins were by this time available foi administration of amphotericin B, and since there was some suggestion of diabetic nephropathy (previous history of lefl renal carbuncle in 1956), treatment was started with 5fluorocytosine (minimum inhibitory concentration for the yeast, 0-25 g. per ml.). The dose was of 9 g. daily (200 mg. per kg.) by mouth. Serum concentrations of 5-fluorocytosine were estimated on two occasions as 20 g. per ml. and 10 g. per ml. In addition, 100 mg. of amphotericin B was instilled into the bladder daily. Treatment was continued for ten days, and at the end of this time the patient was well enough to return home. Blood and urine cultures yielded no further growth of yeasts. No depression of the blood-count or impairment of liver-function tests was observed. Torulopsis glabrata is a common vaginal commensal which occasionally causes urinary-tract infection and rarely septicaemia in debilitated patients. Successful treatment with amphotericin B has been reported. 5-fluorocytosine, which can be administered orally, has been used with good results in Candida septicaemia and in cryptococcal meningitis 2,3; and it appears to have eradicated the blood infection with Torulopsis in the present case, though it is possible that clearing of the bladder infection, in which urinary 5-fluorocytosine was assisted by amphotericin B, contributed to this. Toxic effects4 were not observed during this short ("0111’<::1"
with mnc1f’1’tf’ h)f)nf-1<*vpt<:
Departments of Surgery and Bacteriology, Royal Infirmary, Bristol.
A. J. WEBB D. C. E. SPELLER K. G. BUCKLER.
A NEW MALFORMATION SYNDROME? a sibship of five males and three females, three boys and one girl were born with a syndrome which has apparently not been described before. Only two of the affected children and two of the normal sibs (one boy and one girl in each case) are still alive and have been examined. The clinical features (see accompanying figure) were as follows:
SIR,-In
(1) Extensive bone deficiencies in all limbs ; (2) scarcity of hair the whole body; (3) large, thin, protruding, and deformed pinnas (helix partly unrolled); (4) abnormal dentition (widely spaced teeth, most of them small and conical; permanence of some deciduous teeth and absence of some permanent ones); (5) hypoplastic nipples and areolas; (6) discrete simple goitre; (7) impaired mental performance; (8) sexual underdevelopment; (9) hypoplastic nails; (10) gynaecomastia (discrete); (11) growth retardation; (12) unilateral (right) incomplete hare-lip; (13) electroencephalographic abnormalities; (14) electrocardiographic abnormalities; (15) metabolic abnormalities. Signs 8-13 were only present in the boy. (The girl has over
or toes at all.) Only the girl had electrocardioabnormalities. Both had simple goitres, but this graphic may have been fortuitous. Mental impairment, which was found in both, may have been of cultural origin. It is thus doubtful whether these signs (8-14) are all components of the syndrome. It is postulated that this syndrome is due to the homozygosity of a rare autosomal-recessive gene. no
syndrome.
Metabolic Abnormalities
Paper chromatography of the urine of the two patients an excess (larger in the boy than in the girl) of tryptophan and/or tyrosine. This may be a characteristic of the syndrome. The patients, and their parents, refused revealed
to
aHow blood
to
be taken for further studies.
Dermatoglyphics Dermatoglyphic analysis two
of the upper extremities of the
patients revealed the following:
In the boy the left hand had only two metacarpals and two fingers. One of the fingers had a tented arch and the other a radial loop (RC7). The remainder of the palm showed unusual lines, without the normal flexion creases, and with only one digital triradius. Near the most distal bracelet crease there was a simple whorl with an atypical core. The distal part of the right limb was represented only by an elongated appendage (without fingers). On this there were two areas with atypical lines (some of them interrupted), surrounded by non-ridged skin. In the girl the terminal appendage on the left upper limb had no fingers, but showed palm-like interrupted lines. At the end of the appendage there was a pattern resembling a double whorl without triradii. On the right side there was a ball-like appendage with interrupted and dissociated ridges.
These data represent extensive dermatoglyphic disturbThe parents, however, had normal dermatoglyphics.
ances.
Chromosomes Chromosome analysis was performed on cultured leucocytes from the venous blood of three members of the family, using a slight modification of a widely used tech-
nique.1 All the cells selected for analysis were photographed for chromosome counting and karyotyping. Patau’s counting procedure was used when possible. The three individuals investigated had normal karyotypes.
fingers
English, M. P. Rev. med. vet. Myc. 1967, 6, 103. Tassel, D., Madoff, M. A. J. Am. med. Ass. 1968, 206, 830. Watkins, J. S., Campbell, M. J., Gardner-Medwin, D., Ingham, H. R., Murray, I. G. Br. med. J. 1969, iii, 29. 4. Grunberg, E., Prince, H. N., Utz, J. P. Proceedings of Fifth International Congress of Chemotherapy (edited by K. H. Spitzy and H. Haschek); vol. IV, p. 69. Vienna, 1967. 1. 2. 3.
Brother and sister with the malformation
Unfortunately technical difficulties made it impossible to more cells from the father, or the cells of the boy. The patients and their parents did not
examine affected allow us
to
take any
more
blood.
A full
description of this syndrome will appear in the American _7ournal of Human Genetics. This work was sponsored by the Fund for Overseas Research Grants and Education Inc., the Rockefeller Foundation, the National Research Council of Brazil, the Calouste Gulbenkian 1. Moorhead, P.
Hungerford,
S., Nowell, P. C., Mellman, W. J., Battips, D. M., Expl Cell Res. 1960, 20, 613.
D. A.
841 Foundation, and the research council of the Federal University wF PO’l"on!:l
Laboratory of Human Genetics and Department of Pædiatrics, Federal University of Parana, Curitiba, Pr., Brazil.
NEWTON FREIRE-MAIA IZRAIL CAT V. L. V. LOPES ELEIDI ALICE CHAUTARD F. A. MARCALLO I. J. CAVALLI R. F. PILOTTO MARIA CARMEN SCHETINO A. A. DER BEDROSSIAN.
vertebral-anomaly syndrome with the specific preaxial defect being variable. Division of Medical Genetics, and
Departments of Pediatrics, Medicine, and Surgery,
Washington University School of Medicine, St. Louis, Missouri.
1. 2.
Say, B., Gerald, P. S. Lancet, 1968, ii, 688. Fuhrmann, W. ibid. p. 918. 3. Fuhrmann, W., Rieger, A., Vogel, F. Arch.Kinderheilk. 1958, 158, 264. 4.
Tunte, W. Lancet, 1968, ii,
1081.
QUINTON
your leader
(March 21, p. 597) you erred in achieve complete vagal denervation of the stomach leaves gastric acid secretion unaffected. In truth, there is evidence that partial vagotomy will reduce acid output by the stomach in rats 1,2 and cats and dogs.3 Stening and Isenberg3 found that hemivagotomy would reduce the acid response to insulin hypoglycaemia by 35-50% in cats and dogs, and I see no reason why this effect should not also occur in man. Intentional section of only one vagal trunk has not been practised on human beings, as far as I am able to discover, and therefore there has been no opportunity to examine this finding in man. If partial vagotomy is partially successful in reducing acid output by the human stomach in response to food, it may be sufficient to cure peptic-ulcer disease in its milder forms. stating that failure
POLYDACTYLY/IMPERFORATE-ANUS/
BARBARA
JESSIE L. TERNBERG.
VAGOTOMY
SiR,-In
VERTEBRAL-ANOMALIES SYNDROME SIR,-In 1968, Say and Gerald1 described a syndrome of polydactyly, imperforate anus, and vertebral anomalies. In a survey of 186 patients with polydactyly, they found 10 patients with this syndrome, 8 of whom had preaxial polydactyly. In response to this report Fuhrmann2 noted his previous description3 of a boy with imperforate anus, preaxial polydactyly of the right hand, and possible congenital heart-disease, whose younger brother also had an imperforate anus. The mother had, preaxial polydactyly of the right hand. Tiinte4 reviewed a series of 103 patients with anal atresia, and found 3 with unilateral hypoplasia or aplasia of the thumb, and one with an abnormal thumb. He added 2 other cases with thumb abnormalities and imperforate anus. We wish to report a case with imperforate anus, and vertebral and renal anomalies who had a hypoplastic thumb on the left hand and preaxial polydactyly of the right foot. The patient was the product of a full-term, uncomplicated pregnancy. His mother was 37 years old and his father 49. They are not consanguineous. One previous miscarriage occurred. The mother had 2 healthy boys during a previous marriage. Physical examination at age 11 hours showed a hypoplastic left thumb. There was preaxial polydactyly of the right foot. A covered-anus type of imperforate anus and a perianal fistula were present. A ’ Hypaque’ fistulogram showed no urethral communication. X-rays showed the following: cleft vertebrx T3, 4, 5, and 7; hemivertebrae T10 and T12; and fusion of the left 7th, 8th, and 9th ribs, left 10th and llth ribs, right 6th and 7th, 9th and 10th, and llth and 12th ribs with associated rib deformities. There was thoracic-curve reversal with left thoracolumbar scoliosis. An intravenous urogram showed a slightly enlarged and hydronephrotic right kidney. There was no radiographic evidence of a left kidney. A large poorly emptying bladder was noted, but it has since functioned normally. Blood-lymphocyte karyotype analysis revealed a normal 46XY male pattern. An operation was performed to excise the fistula and to form an anus. The hypoplastic left thumb was tied off. This patient has an imperforate anus and vertebral anomalies associated with limb segmentation abnormalities. He exhibits both the preaxial polydactyly reported in the cases of Say and Gerald and of Fuhrmann, and the preaxial deletion anomalies of the cases of Tunte. Case 8 of Say and Gerald had left-sided tibial polydactyly with absent tibia and patella, deformed fibula, and hypoplastic left hemipelvis, also illustrating deletion and polydactyly in the same patient. These cases suggest that there are probably not two separate syndromes with deletion versus polydactyly, but rather that there may be a preaxial defect/imperforate anus/
ROBERT L. KAUFMAN
to
Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
R. M. PRESHAW.
A RAPID METHOD FOR NUCLEAR SEXING SIR,-The article on sex and gender (Feb. 21, p. 405), stresses the importance of early knowledge of an individual’s chromosomal, gonadal, and genital sex in relation to adequate evolution of social sex during education. This seems not only true for patients with ambiguous genitalia,
but also for individuals with Turner’s
or
Klinefelter’s
syndrome, who are usually not diagnosed before puberty. Especially in patients with the 45,XO chromosomal constitution, early diagnosis may have therapeutic implications.4 Many doctors, in our experience, are still neglecting the possibility of instant diagnosis of sex-chromosome disorders by the simple method of sex-chromatin analysis in nuclei from buccal-mucosa cells. This prompts us to describe briefly a technique for the preparation of buccal mucosa smears, which, in our opinion, is no more complicated than drawing a blood-sample and less time-consuming than a white-blood-cell count. Furthermore, it is less expensive. After removal of superficial mucus, suitable cells are obtained by scraping the buccal epithelium firmly with a sterile metal spatula (avoid bleeding). The material is well spread on a clean glass slide. Immediate fixation is achieved by spraying twice with a commercial hairspray from a distance of 20-40 cm. Airdrying takes 2-3 minutes. The dry slides may be shipped or stored. Otherwise they are stained by applying one drop of aceto-orcein and then covered.
Nuclei with an
localised at low magnification and examined oil-immersion objective (x 100). The hairspray fixing procedure means that the nuclei partially maintain their three-dimensional configuration, so they have to be examined at different optic levels. University Institute of Human Genetics, H. HOEHN are
Freiburg, Germany.
West
LINDA Z. GORMAN.
Shay, H. S., Komarov, S. A., Gruenstein, M. Archs Surg. 1949, 59, 210. 2. Rivilis, J., Yaffe, M., Preshaw, R. M. Proc. Soc. exp. Biol. Med. 1968, 127, 310. 3. Stening, G. F., Isenberg, J. I. Am. J. Physiol. 1969, 217, 962. 4. Tzagournis, M. J. Am. med. Ass. 1969, 210, 2373. 1.