- Email: [email protected]
Kabuki makeup syndrome (Niikawa-Kuroki syndrome) in Europe
Volume 105 Number 5
Schmidt-Sommerfeld E, Penn D, Wolf H: Carnitine deficiency in premature infants receiving total parenteral nutrition: Effect of L-carnitine supplementation. J PEDIATR 102:931, 1983.
Rep To the Editor." We agree that it is not yet clear whether carnitine must be considered an essential nutrient in a "defined group of infants at risk for carnitine deficiency." However, the aim of our study was to investigate whether carnitine supplementation, during lipid infusion performed in the course of routine total parenteral nutrition (TPN), could increase the oxidation of fatty acids administered at the time of TPN. The results, showing a significant increase (P < 0.001) in short-chain and long-chain acylcarnifine plasma values, suggest that carnitine-depleted tissues have been sufficiently restored in the group of infants given L-carnitine infusions, Nevertheless, the fact that simultaneous glucose infusion, which is normally performed in the course of TPN, depresses fatty acid oxidation makes studies of carnitine supplementation during TPN probably unsuitable to clarify the necessit!r of carnitine supplementation in infants not receiving carnitine along with nutrition. For this reason we have determined the urinary level of dicarboxylic acids (which are increased in dietarydependent carnitine deficiency~) in groups of infants receiving TPN. Preliminary data show that these values are within the normal range even in the group not receiving carnitine supplementation. In addition, we have undertaken a study in preterm and full-term infants fed, for various medical implications, formulas not containing carnitine. The preliminary results of this study show that the group without L-earnitine supplementation has higher free fatty acid and triglyceride plasma levels. Thus our results up to the present support the concept that carnitine administration during the first months of life improves lipid metabolism, even if no important lipid metabolic imbalance has been demonstrated in infants nourished without exogenous carnitine. Alberto Orzali, M.D. Firrnino F. Rubaltelli, M.D. Neona~fd Intensive Care Unit Department o f Pediatrics University o f Padova Padova, Italy
E d i t o r i a l correspondence
849
administered intravenously in neonates receiving mechanical venti ~ation. Although they report only transient cardiovascular effects (heart rate changes) and no immediate effect on blood pressure, as we had found previously) the hypoventilation seen in 10 of their patients is more worrying. Hypoventilation is not an uncommon compilation; Bourgeois et a12 reported an acute syndrome after pancuronium administration. In our own series,3 13 of 17 infants required increased ventilator pressures after intravenous pancuronium administration (100 ~Lg/kg) to maintain adequate blood gases, as assessed by arterial sampling immediately before and within 30 minutes of the injection. However, in that series there were no other serious side effects, and the increased ventilator pressure necessary to treat the hypoventilation was not associated with an increase in air leaks. Even very preterm infants are capable of vigorous respiratory effort while receiving artificial ventilation, and although all such spontaneous respiratory interaction may not be beneficial,4 between each positive pressure inflation spontaneous breathing makes a considerable contribution to the tidal exchange. This is abolished by paralysis, and this may be the cause of the hypoventilation after pancuronium administration. The administration of pancuronium has been associated with a reduction in the incidence of pneumothoraces in infants "fighting the ventilator," and this must surely justify its continued use in carefully selected patients? However, "acute hypoventilation syndrome" occurs so frequently as to restrict the use of this drug to adequately staffed neonatal intensive care units. Anne Greenough, M.A., D.C.H., M.R.C.P. University o f Cambridge Clinical School Cambridge CB2 2QQ, England REFERENCES
1.
2.
3.
4.
Runkle B, Bancalari E: Acute cardiopulmonary effects of pancuronium bromide in mechanically ventilated newborn infants. J P~DIATR 104:614, 1984. Bourgeois J, Beithier JC, Cottancin G, Milan J J, Bethenod M: Dangers de la curarisation au cours de la ventilation artificielle ehez le nouveau-ne. Pediatric 37:101, 1982. Greenough A, Wood S, Morley C J, Davis JA: Pancuronium prevents pneumothoraces in ventilated premature babies who actively expire against positive pressure inflation. Lancet 1-1, 1984. Greenough A, Morley C J, Davis JA: The interaction of spontaneous respiration with artificial ventilation in preterm babies. J PF~TR 103:769. 198"~.
REFERENCE
1.
Slonim AE, Borum PR, Tanaka K, Stanley CA, Kassetberg AG, Greene HL, Burr IM: Dietary-dependent carnitine deficiency as a cause of nonketotic hypoglycemia in an infant. J PED)ATR 99:551, 1981.
Pancuronium administration and immediate hypoventilation To the Editor: Runkle and BancalarP reinforce previous experiencez-3 of the need for extreme caution and observation when pancuronium is
Kabuki makeup s)'lzdrome (Niikawa-Kuroki syndrome) in Europe To the Editor." In 1981 Kuroki et aU and Niikawa et al. 2 described a new f syndrome, the Kabuki m~akeup syndrome, with characteristic findings of facial dysmorphia, mental retardation, and postnatal dwarfism. Soon afterward, eight more Japanese patients were described. The only patient mentioned outside of Japan was a
850
E d i t o r i a l correspondence
7-year-old South American girl? In 1981 we observed another patient with this new clinical entity. The patient, a boy, was born prematurely after 36 weeks gestation. Hydramnios was observed at birth. Apgar scores were 6 at both 1 and 5 minutes. Both parents are healthy Italians. His two sisters, 8 and 11 years old, are healthy. Examination revealed a mongoloid slant, broad nasal root, dysplastic ears, relatively short fingers and toes, hypoplastic genitalia~ and slight hypotonia of th e muscles. Disorders in central coordination and tonus as well as of mental and physical development were subsequently f6und. Dentition was la~te, starting in the twelfth month. Clinical investigation at the age of 2 years showed dwarfism and microcephalia. Weight was at the 25th percentile9 Bilateral epicanthus, flat nasal root, wide and flat nasal septum and flat nasal tip, large ma!formed ears, incisors widely spaced, and short plump fingers were observed. The viscera showed no abnormalities. Chromosomal analysis showed a normal karyotype. Roentgenographic examinations of the hand, thorax, spinal column, and skull and CT scan of the head demonstrated normal findings except for partial-bilateral relaxation of the diaphragm. EEG and ECG examifiations showed no peculiarities. Neither intrauterine infections nor metabolic disorders of any type were observed. The dermatoglyphics of the fingertips showed six whorls, three ulnar loops, and one arch. We could not identify any dermatoglyphic findings on the palm. which Niikawa et al? had reported, such as absence of triradius c and d. fusion of triradius b and c. and fusion of triradius c and d. The hypothenar area had a radial open-arched pattern on both sides (Dr. C. Steffens. Institute of Anthropology and Human Genetics. University of Heidelberg). Our patient has the main symptoms of the Kabuki makeup syndrome described by Niikawa and Kuroki except the skeletal abnormalities, which are not obligatory. !n addition, the dermatoglyphic anomalies of the palm are considered important m this syndrome. Our patient shows no such typical anomalies', his patterns are very common in our population. Nevertheless. Niikawa (personal communication. 1982~ agreed with us that our patient can be classified as another patient With Kabuki makeup syndrome. O. H. Braun. M.D. E. Schmid. M.D. Department o f Pediatrics Municipal Hospital D-7530 Pforzheim. West Germany REFERENCES
1.
2.
3.
Kuroki Y, Suzuki Y, Chy 0 H, Hata A, Matsui 1: A new malformation syndrome of long patpebrai fissures, large ears, depressed nasal tip, and skeletal anomalies associated with postnatal dwarfism and mental retardation. J PEDIaTR 99:570~ !981. Niikawa N, Matsuura N. Fuknshima Y. Ohsawa T. Kajii T: Kabuki make-up syndrome: A syndrome of mental retardation, unusual facies, large and protruding ears and postnatal growth deficiency. J PEOIA'rR 99:565, 1981. Koutras A,'Fisher s t : Niikawa-Kuroki syndrome: A new malformation 9 of postnata 1 dwarfism, mental
The Journal o f Pediatrics November 1984
4.
retardation, unusual face, and protruding ears. J PEDIATR 101:417, 1982. Niikawa N, Kuroki Y, Kajii T: The dermatoglyphie patter n of the Kabuki make-up syndrome. Clin Genet 21:315, 1982.
Response to ADH in nephrogenic diabetes insipidus type 2 To the Editor.9 There is controversy as to whether we can distinguish two types of nephrogenic diabetes insip[dus (NDI) by the response of urinary cyclic adenosine~monophosphate (cAMP) excretion after the administration of: antidiuretic hormone (ADH), because it has been reported that aimost no urinary cAMP response occurs even in !~atients with ADH-deficient diabetes insipidus after ADH administration. 1 If Ohzeki et al.~ are correct, theirs is the'first report to demonstrate an exaggerated cAMP response (609% arid 1984% increases) after ADH administration in patients with so-called NDI type 2. We think the basal urinary cAMP in their patient 2 was extremely'low (only 1 / 5 0 of our mean value; normal urinary c A M P in our laboratory using the same kit was 2.5 to 7.8 umol/g m creatinine) and that the Peak urinary cAMP value after DDAVP (1-desamino-8-D-argin!ne vasopi"essin) in the same patient was relatively low. Basal urinary cAMP excretion is the sum of 9 cAMP (normal 20 to 35 pmol/ml), which is excreted ~nto the urine, and nephrogenic cAMP (normal 2 to 5 nmol/dl glomerular filtrate), which is considered to be a reliable indicator of parathyi'oid function (not ADH). Therefore it is relatively stable. We agree that the peak urinary cAMP excretion (49 #tool/gin creatinine) in patient 1 is very high. Second, we cannot understand why the duration of the cAMP response was so short (30 to 90 minutes) in their patients, because the plasma concentration of DDAVP lasts at least 2 hours. Third, urinary CAMP excretion after water deprivation should be high in NDI type 2 because endogenous ADH is high in NDI and stimulates urinary cAMP excretion in ND1 type 2. In pseud0hypoparathyroidism type 23 (another receptor disease considered to be an abnorma!ity beyond.adenylate cyclase), basal urinary cAMP has been reported to be high. Thus we think that urinary cAMP excretion (preferably with plasma cAMP) before and after water deprivation should b6 shown. These considerations are important to elucidate the pathogenesis of the disease. Toshiyuki Yasuda, M.D. Hironori Nakaiima, M.D. Department o f Pediatrics Chiba University School o f Medicine I-8-1 Inohana, Chiba-shi. Chiba 280. Japan
REFERENCES
1. 2.
Yoshida S: Syndrome of vasopressin unresponsiveness. Metab Dis 14:1163, 1977 (i n Japanese.) Ohzeki T, Igarashi T, Okamoto A: Familial cases of congenital nephrogenic diabetes insipidus type If': Remarkable increment of ~urinary cAMP in response to antidiuretic hormone. J PEOIATR 104:593, 1984.
Schmidt-Sommerfeld E, Penn D, Wolf H: Carnitine deficiency in premature infants receiving total parenteral nutrition: Effect of L-carnitine supplementation. J PEDIATR 102:931, 1983.
Rep To the Editor." We agree that it is not yet clear whether carnitine must be considered an essential nutrient in a "defined group of infants at risk for carnitine deficiency." However, the aim of our study was to investigate whether carnitine supplementation, during lipid infusion performed in the course of routine total parenteral nutrition (TPN), could increase the oxidation of fatty acids administered at the time of TPN. The results, showing a significant increase (P < 0.001) in short-chain and long-chain acylcarnifine plasma values, suggest that carnitine-depleted tissues have been sufficiently restored in the group of infants given L-carnitine infusions, Nevertheless, the fact that simultaneous glucose infusion, which is normally performed in the course of TPN, depresses fatty acid oxidation makes studies of carnitine supplementation during TPN probably unsuitable to clarify the necessit!r of carnitine supplementation in infants not receiving carnitine along with nutrition. For this reason we have determined the urinary level of dicarboxylic acids (which are increased in dietarydependent carnitine deficiency~) in groups of infants receiving TPN. Preliminary data show that these values are within the normal range even in the group not receiving carnitine supplementation. In addition, we have undertaken a study in preterm and full-term infants fed, for various medical implications, formulas not containing carnitine. The preliminary results of this study show that the group without L-earnitine supplementation has higher free fatty acid and triglyceride plasma levels. Thus our results up to the present support the concept that carnitine administration during the first months of life improves lipid metabolism, even if no important lipid metabolic imbalance has been demonstrated in infants nourished without exogenous carnitine. Alberto Orzali, M.D. Firrnino F. Rubaltelli, M.D. Neona~fd Intensive Care Unit Department o f Pediatrics University o f Padova Padova, Italy
E d i t o r i a l correspondence
849
administered intravenously in neonates receiving mechanical venti ~ation. Although they report only transient cardiovascular effects (heart rate changes) and no immediate effect on blood pressure, as we had found previously) the hypoventilation seen in 10 of their patients is more worrying. Hypoventilation is not an uncommon compilation; Bourgeois et a12 reported an acute syndrome after pancuronium administration. In our own series,3 13 of 17 infants required increased ventilator pressures after intravenous pancuronium administration (100 ~Lg/kg) to maintain adequate blood gases, as assessed by arterial sampling immediately before and within 30 minutes of the injection. However, in that series there were no other serious side effects, and the increased ventilator pressure necessary to treat the hypoventilation was not associated with an increase in air leaks. Even very preterm infants are capable of vigorous respiratory effort while receiving artificial ventilation, and although all such spontaneous respiratory interaction may not be beneficial,4 between each positive pressure inflation spontaneous breathing makes a considerable contribution to the tidal exchange. This is abolished by paralysis, and this may be the cause of the hypoventilation after pancuronium administration. The administration of pancuronium has been associated with a reduction in the incidence of pneumothoraces in infants "fighting the ventilator," and this must surely justify its continued use in carefully selected patients? However, "acute hypoventilation syndrome" occurs so frequently as to restrict the use of this drug to adequately staffed neonatal intensive care units. Anne Greenough, M.A., D.C.H., M.R.C.P. University o f Cambridge Clinical School Cambridge CB2 2QQ, England REFERENCES
1.
2.
3.
4.
Runkle B, Bancalari E: Acute cardiopulmonary effects of pancuronium bromide in mechanically ventilated newborn infants. J P~DIATR 104:614, 1984. Bourgeois J, Beithier JC, Cottancin G, Milan J J, Bethenod M: Dangers de la curarisation au cours de la ventilation artificielle ehez le nouveau-ne. Pediatric 37:101, 1982. Greenough A, Wood S, Morley C J, Davis JA: Pancuronium prevents pneumothoraces in ventilated premature babies who actively expire against positive pressure inflation. Lancet 1-1, 1984. Greenough A, Morley C J, Davis JA: The interaction of spontaneous respiration with artificial ventilation in preterm babies. J PF~TR 103:769. 198"~.
REFERENCE
1.
Slonim AE, Borum PR, Tanaka K, Stanley CA, Kassetberg AG, Greene HL, Burr IM: Dietary-dependent carnitine deficiency as a cause of nonketotic hypoglycemia in an infant. J PED)ATR 99:551, 1981.
Pancuronium administration and immediate hypoventilation To the Editor: Runkle and BancalarP reinforce previous experiencez-3 of the need for extreme caution and observation when pancuronium is
Kabuki makeup s)'lzdrome (Niikawa-Kuroki syndrome) in Europe To the Editor." In 1981 Kuroki et aU and Niikawa et al. 2 described a new f syndrome, the Kabuki m~akeup syndrome, with characteristic findings of facial dysmorphia, mental retardation, and postnatal dwarfism. Soon afterward, eight more Japanese patients were described. The only patient mentioned outside of Japan was a
850
E d i t o r i a l correspondence
7-year-old South American girl? In 1981 we observed another patient with this new clinical entity. The patient, a boy, was born prematurely after 36 weeks gestation. Hydramnios was observed at birth. Apgar scores were 6 at both 1 and 5 minutes. Both parents are healthy Italians. His two sisters, 8 and 11 years old, are healthy. Examination revealed a mongoloid slant, broad nasal root, dysplastic ears, relatively short fingers and toes, hypoplastic genitalia~ and slight hypotonia of th e muscles. Disorders in central coordination and tonus as well as of mental and physical development were subsequently f6und. Dentition was la~te, starting in the twelfth month. Clinical investigation at the age of 2 years showed dwarfism and microcephalia. Weight was at the 25th percentile9 Bilateral epicanthus, flat nasal root, wide and flat nasal septum and flat nasal tip, large ma!formed ears, incisors widely spaced, and short plump fingers were observed. The viscera showed no abnormalities. Chromosomal analysis showed a normal karyotype. Roentgenographic examinations of the hand, thorax, spinal column, and skull and CT scan of the head demonstrated normal findings except for partial-bilateral relaxation of the diaphragm. EEG and ECG examifiations showed no peculiarities. Neither intrauterine infections nor metabolic disorders of any type were observed. The dermatoglyphics of the fingertips showed six whorls, three ulnar loops, and one arch. We could not identify any dermatoglyphic findings on the palm. which Niikawa et al? had reported, such as absence of triradius c and d. fusion of triradius b and c. and fusion of triradius c and d. The hypothenar area had a radial open-arched pattern on both sides (Dr. C. Steffens. Institute of Anthropology and Human Genetics. University of Heidelberg). Our patient has the main symptoms of the Kabuki makeup syndrome described by Niikawa and Kuroki except the skeletal abnormalities, which are not obligatory. !n addition, the dermatoglyphic anomalies of the palm are considered important m this syndrome. Our patient shows no such typical anomalies', his patterns are very common in our population. Nevertheless. Niikawa (personal communication. 1982~ agreed with us that our patient can be classified as another patient With Kabuki makeup syndrome. O. H. Braun. M.D. E. Schmid. M.D. Department o f Pediatrics Municipal Hospital D-7530 Pforzheim. West Germany REFERENCES
1.
2.
3.
Kuroki Y, Suzuki Y, Chy 0 H, Hata A, Matsui 1: A new malformation syndrome of long patpebrai fissures, large ears, depressed nasal tip, and skeletal anomalies associated with postnatal dwarfism and mental retardation. J PEDIaTR 99:570~ !981. Niikawa N, Matsuura N. Fuknshima Y. Ohsawa T. Kajii T: Kabuki make-up syndrome: A syndrome of mental retardation, unusual facies, large and protruding ears and postnatal growth deficiency. J PEOIA'rR 99:565, 1981. Koutras A,'Fisher s t : Niikawa-Kuroki syndrome: A new malformation 9 of postnata 1 dwarfism, mental
The Journal o f Pediatrics November 1984
4.
retardation, unusual face, and protruding ears. J PEDIATR 101:417, 1982. Niikawa N, Kuroki Y, Kajii T: The dermatoglyphie patter n of the Kabuki make-up syndrome. Clin Genet 21:315, 1982.
Response to ADH in nephrogenic diabetes insipidus type 2 To the Editor.9 There is controversy as to whether we can distinguish two types of nephrogenic diabetes insip[dus (NDI) by the response of urinary cyclic adenosine~monophosphate (cAMP) excretion after the administration of: antidiuretic hormone (ADH), because it has been reported that aimost no urinary cAMP response occurs even in !~atients with ADH-deficient diabetes insipidus after ADH administration. 1 If Ohzeki et al.~ are correct, theirs is the'first report to demonstrate an exaggerated cAMP response (609% arid 1984% increases) after ADH administration in patients with so-called NDI type 2. We think the basal urinary cAMP in their patient 2 was extremely'low (only 1 / 5 0 of our mean value; normal urinary c A M P in our laboratory using the same kit was 2.5 to 7.8 umol/g m creatinine) and that the Peak urinary cAMP value after DDAVP (1-desamino-8-D-argin!ne vasopi"essin) in the same patient was relatively low. Basal urinary cAMP excretion is the sum of 9 cAMP (normal 20 to 35 pmol/ml), which is excreted ~nto the urine, and nephrogenic cAMP (normal 2 to 5 nmol/dl glomerular filtrate), which is considered to be a reliable indicator of parathyi'oid function (not ADH). Therefore it is relatively stable. We agree that the peak urinary cAMP excretion (49 #tool/gin creatinine) in patient 1 is very high. Second, we cannot understand why the duration of the cAMP response was so short (30 to 90 minutes) in their patients, because the plasma concentration of DDAVP lasts at least 2 hours. Third, urinary CAMP excretion after water deprivation should be high in NDI type 2 because endogenous ADH is high in NDI and stimulates urinary cAMP excretion in ND1 type 2. In pseud0hypoparathyroidism type 23 (another receptor disease considered to be an abnorma!ity beyond.adenylate cyclase), basal urinary cAMP has been reported to be high. Thus we think that urinary cAMP excretion (preferably with plasma cAMP) before and after water deprivation should b6 shown. These considerations are important to elucidate the pathogenesis of the disease. Toshiyuki Yasuda, M.D. Hironori Nakaiima, M.D. Department o f Pediatrics Chiba University School o f Medicine I-8-1 Inohana, Chiba-shi. Chiba 280. Japan
REFERENCES
1. 2.
Yoshida S: Syndrome of vasopressin unresponsiveness. Metab Dis 14:1163, 1977 (i n Japanese.) Ohzeki T, Igarashi T, Okamoto A: Familial cases of congenital nephrogenic diabetes insipidus type If': Remarkable increment of ~urinary cAMP in response to antidiuretic hormone. J PEOIATR 104:593, 1984.