Pili torti in association with citrullinemia

Pili torti in association with citrullinemia

Volume I2 Number 1, Part 2 January, 1985 16. 17. 18. 19. 20. 21. 22. in the Prader-Wiili syndrome: Light and electron microscopic study. J Neu...

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Number 1, Part 2 January, 1985

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20. 21.


in the Prader-Wiili syndrome: Light and electron microscopic study. J Neurol Sei 9:49-61, 1969. Afifi AK, Bergman RA: Steroid myopathy: A study of evolution of the muscle lesion in rabbits. Johns Hopkins Med J 124:66-87, 1969. Afifi AK, Zellweger H, McCormick WF, Mergner W: Congenital muscular dystrophy: Light and electron microscopic observations. J Neurol Neurosurg Psychiatry 32:273-280, 1969. Luft R, Ikkos D, Palmieri G, Ernster L, Afzelius B: A case of severe hypermetabolism of nonthyroid origin with a defect in the maintenance of mitochondrial respiratory control: A correlated clinical, biochemical and morphologic study. J Clin Invest 41:1776-1804, 1962. Afifi AK, Ibrahim MZM, Bergman RA, Abu Haydar N, Mire J, Bahuth N, Kaylani M: Morphologic features of hypermetabolic mitochondrial disease: A light microscopic, histochemical and electron microscopic study. J Neurol Sci 15:271-290, 1972. Spear I J: Lipodystrophia progressiva. Arch Intern Med 21:39-47, 1918. Neville HE: Ultrastructural changes in diseases of human skeletal muscle, in Vinken PJ, Bmyn GW, editors: Handbook of clinical neurology, vol. 40. Amsterdam, 1979, North-Holland Publishing Co., pp. 63-123. Mendell JR: Experimental myopathies: A review of experimental models and their relationship to human neuromuscular diseases, #1 Vinken PJ, Bruyn GW, editors:

Partial (localized) lipodystrophy






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Handbook of clinical neurology, vol. 40. Amsterdam, 1979. North-Holland Publishing Co., pp. 133-182. Engel WK, Bishop DW, Cunningham, GG: Tubular aggregates in type II muscle fibers: Ultrastructural and histochemical correlation. J Ultrastruct Res 31:507-525, 1970. MeJtzer HY, Kunch RW, Click J, Yang V: Incidence of Z band streaming and myofibrillar disruption in skeletal muscle from healthy young people. Neurology 26:853857, 1976. Mukuno K: Electron microscopic studies on human extraocular muscle under pathologic conditions. I. Rod formation in normal and diseased muscles (polymyositis and ocular myasthenia). Jpn J Ophthalmol 13:35-51, 1969. Zaynoun ST, Aftimes BG, Tenekjian KK, Bahuth N, Kurban AK: Extensive pityriasis alba: A histological, histochemical, and ultrastructural study. Br J Dermatol 108:83-90, 1983. Schuler G, Honigsmann H, Jaschke E, Wolfe K: Selective accumulation of lipid within melanocytes during photochemotherapy (PUVA) of psoriasis. Br J Dermatol 107:173-182, 1982. Silver DN, Becket LE, Welwig EB: Epidermal melanocytes in eruptive xanthomas. Arch Dermatol 107:84% 852, 1973. Piscatelli RL, Vieweg WVR, Havel RJ: Partial lipodystrophy: Metabolic studies in three patients. Ann Intern Med 73:963-970, 1970.

Pili torti in association with citrullinemia Harish P. Patel, M.D., and Mark E. Unis, M.D. Baltimore, MD A 21/2-year-old white girl with citrullinemia accompanied by neurologic symptoms presented with 2- to 3-week loss of scalp hair. Examination o f the scalp revealed 90% of the hairs to be broken off, leaving a stubble of hairs less than 1 mm in length. Microscopically, plucked hairs demonstrated flattening, twisting through 180 degrees on its own axis, and breakage at the point of twisting. A diagnosis of pill torti was established. Pili torti is a rare disorder that may be seen with some genetic syndromes. Its association with citrullinemia has not been reported previously. (J AM ACAD DERMATOL 12:203-206, 1985.)

From the Department of Dermatology, The Johns Hopkins University. Reprint requests to: Harish P. Patel, M.D.. Department of Dermatology, The Johns Hopkins University, 600 N. Wolfe St., Baltimore, MD 21005/301-955-2993.

Pili torti is a structural defect in w h i c h the hair shaft is twisted on its a x i s . l T h e a f f e c t e d hairs are flattened, and the shaft is twisted t h r o u g h 180 degrees at a few or m a n y points a l o n g its length.



Patel and Unis

Fig. 1. Alopecia with sparing of frontal hairs. Eyebrows appear normal. Involvement of sites other than the scalp has been reported in more severe cases. The eyebrows may be sparse and twisted.Z Pili torti may appear as the only abnormality, and most such cases are due to an autosomal recessive gene.a,4 It occurs in female more frequently than in male patients, and the majority are blond. B y the age of 2 or 3 years, and occasionally later, the haii: is replaced by brittle hair with a strikingly spangled appearance 1 Affected hairs may break off easily. Normal hair may replace most of the pili torti during later years of childhood. However, some patients remain severely affected throughout life.

CASE REPORT A 289 white girl with citrullinemia (argininosuccinate synthetase deficiency) diagnosed in the early neonatal period was seen in consultation at The Johns Hopkins Hospital for evaluation of a 2- to 3-week history of an unusual alopecia. The patient was a 2,580-gm product of a full-term

Journal of the American Academy of Dermatology

pregnancy and uncomplicated delivery, with an Apgar score of 10 at 5 minutes. On the first day of life she was noted to be lethargic with poor feeding. A sepsis workup gave negative results. On day 6, she had a respiratory arrest with hypothermia and hypotension; subsequently a serum ammonia level was obtained and was found to be 1,200 M (normal, less than 35). Her condition was initially managed with exchange transfusions, peritoneal dialysis, and sodium benzoate and arginine infusions. Dietary management since that time has included a protein-restricted diet with the essential amino acids arginine and omithine, vitamin supplementation, and sodium benzoate administration. The patient displays profoundly delayed developmental milestones, severe mental retardation, mixed cerebral palsy, and growth parameters below the third percentile for age. Other problems include microcephaly,strabismus, possible gastroesophageal reflux, and increased infections, especially recurrent otitis media. Recently her mother noted hair loss while combing or brushing, with extensive resultant alopecia over a 2- to 3-week period. The patient has a 13-year old brother with no hair abnormality. Another sibling, a female, died at 9 days of age because of "atypical sepsis." Both her parents have normal hair. Examination disclosed a height of 84 cm, weight of 8.9 kg, and head circumference of 39.5 cm (all less than the third percentile). Temperature was 36.6 ~ C, pulse was 120 beats/min, respirations were 32/rain, and blood pressure was 100/60 mm Hg. In general, the patient was an active young child who was dysmorphic but in no distress. Examination of the head and neck was remarkable for microcephaly, discolored teeth, poor light reflex, and decreased mobility of the left tympanic membrane. Approximately 90% of the scalp hairs were broken off, leaving a stubble of hairs less than 1 mm in length. There was sparing of the frontal hairs, and eyebrows were normal (Fig. 1), Easy breakage of frontal hairs on plucking was noted. Examination of the lungs, heart, abdomen, genitalia, and extremities resulted in no remarkable findings. Neurologic examination revealed hyperreflexia, bilateral Babinski's signs, choreoathetoid movements on intention, persistent primitive reflexes, and poor gross motor function and equilibrium. Laboratory values included hematocrit, 38.3 vol%; white blood cell count, 8,600/mm ~, with 34 polymorphonuclear leukocytes, 5 bands, 52 lymphocytes, 5 monocytes, 2 basophils, and 1 eosinophil; and platelet count, 217,000. Serum chemistry studies revealed sodium, 146 mEq/liter (135-148); potassium, 3.8 mEq/

Volume 12 Number 1, Part 2 January, 1985

Pill torti with citrullinemia


Fig. 2. Hair of scalp showing characteristic twisting (pili torti). liter (3.5-5.0); chloride, 108 mEq/liter (96-109); blood urea nitrogen, 16 mg/dl (12-25); creatinine, 0.5 mg/dl (0.4-1.5); glucose, 92 mg/dl (60-105); uric acid, 1.1 mg/dl (4.2-8.8); albumin, 3.3 gm/dl (3.2-5.3); total bilirubin, 0.4 mg/dl (0.3-1.2); direct bilimbin, 0.1 mg/dl (0.1-0.4); aspartate aminotransferase, 52 IU/ liter (0-41); alanine aminotransferase, 61 IU/liter (033); alkaline phosphatase, 325 IU/liter (95-218); lactate dehydrogenase, 234 IU/liter (0-223); and ammonia, 162 M/liter (11-35). Extensive evaluation of plasma amino acid levels was performed, and normal levels were found for aspartic acid, threonine, serine, asparagine, glutamic acid, proline, glycine, alanine, valine, cystine, methionine, isoleucine, leucine, tyrosine, phenylalanine, tryptophan, ornithine, lysine, glutamine, and histidine. Citrulline was markedly elevated at 5,149 p.mol/liter (10-34). Arginine was decreased at 9/zmol/liter (15-115); however, two other determinations were within normal limits. Microscopic examination of plucked hairs revealed 180-degree twisting around the long axis to the hair shaft of numerous flattened hairs (Fig. 2). A scalp biopsy was refused by the patient's mother, but the clinical appearance of the scalp itself was normal. Four months post hospitalization, the patient continues to have hair breakage and hair loss, despite normalization of plasma arginine.

Ectodermal defects include keratosis pilaris, dental abnormalities, dystrophic nails, and corneal opacities. Pill torti may also occur as a manifestation of (1) Menkes' syndrome (a sex-linked recessive disorder with progressive psychomotor retardation, convulsions, instability of temperature, genera/ failure to thrive, widespread arterial degeneration, scorbutic bone changes, and low levels of serum copper and ceruloplasmin'%6), (2) Bj6rnstad's syndrome (an autosomal recessive disorder with sensorineural deafness*'7), (3) Crandali's syndrome (probably a sex-linked recessive disorder with hypogonadism and deafnessS), and (4) hidrotic ectodermal dysplasia (an autosomal dominant disorder with characteristic facies and dental defects'J). Citrullinemia is a rare genetic error of the urea cycle. There is a deficiency of argininosuccinate synthetase, resulting in an increase in blood ammonia, citrullinemia, and arginine deficiency.1~ Argininosuccinic aciduria (absence or deficiency of argininosuccinate lyase) is also a rare genetic error of the urea cycle. This may lead to accumulation of argininosuccinic acid in body fluids and arginine deficiency. An increase in blood am-

DISCUSSION Classic pill torti is part of a clinical syndrome that represents a form of ectodermal dysplasia.

*BjornstadR: Pill torti and sensory-neuralloss of hearing.Proceedings of the SeventhMeetingof the NorthernDermatologicalSociety, Copenhagen,May, 1965.


Journal of the American Academy of Dermatology

Patel and Unis

monia and citrullinemia m a y also result. '~ Half of the patients with argininosuccinic aciduria have abnormally fragile hair, with some showing trichorrhexis nodosa. One case of argininosuccinic aciduria and pill torti has been reported, t~ At present the exact biochemical factors responsible for hair abnormalities associated with urea cycle enzyme deficiency disorders are not known. Early speculations concerning the abnormality were related to a possible arginine deficiency in the hair. An improvement in the quality and quantity of the hair was reported to have occurred in one case after supplementation o f the diet with arginine. 12 However, arginine levels were not measured either before or after treatment. One case of argininosuccinic aciduria has been reported to show normal arginine levels but 50% of the normal value of cystine in the hair. 1:~In this case an improvement in the quality of hair was accompanied with an increase in cystine content to about 75% of the normal value. TMIn our patient the correction of plasma arginine deficiency has not ameliorated the hair loss, although we were unable to directly measure hair amino acid levels to help correlate this finding. It is not completely clear whether either of these amino acids have a cause-and-effect relationship in the hair abnormality, although it is tempting to speculate that disordered protein synthesis might be playing an important role.


1. Ronchese F: Twisted hairs (pill torti). Arch Dermatol Syphilol 26:98-109, 1932. 2. Mitchell-Heggs GB, May WR: Pill torti. Proc R Soc Meal 40:481, 1947. 3. Appel B, Messina SJ: Pill torti hereditaria. N Engl J Med 226:912-915, 1942. 4. Gates RR: Human genetics, vol. 1. New York, 1946, The Macmillan Co., p. 309. 5. Danks DM: Steely hair, mottled mice and copper metabolism. N Engl J Med 193:1147-1149, 1975. 6. Danks DM, Campbell PE, Stevens BJ, et al: Menkes' kinky hair syndrome: An inherited defect in copper absorption with widespread effects. Pediatrics 50:188-201, 1972. 7. Robinson GC, Johnston MM: Pill torti and sensory neural hearing loss. J Pediatr 70:621-623, 1967. 8. Crandall BF, Samec L, Sparkes RS, et al: A familial syndrome of deafness, alopecia and hypogondadism. J Pediatr 82:461-465, 1973. 9, Rook A, Dawber R: Diseases of the hair and scalp. Oxford, England, 1982, Blackwell Scientific Publications, Ltd., p. 188. 10. Walser M: Urea cycle disorders and other congenital hyperammonemic syndromes, in Stanbury JB, Wyngaarder JB, Frederickson DS, Goldstein JL, Brown MS, editors: The metabolic basis of inherited diseases. New York, 1983, McGraw-Hill Book Co., pp. 402-438. 11. Philips ME, Barrie H, Cream JJ: Argininosuccinic aciduria with pill torti. J R Soc Med 74:221-222, 1981. 12. Hartlage PL, Coryell ME, Hall K, et al: Argininosuccinic aciduria: Perinatal diagnosis and early management. J Pediatr 85:86-88, 1974. 13. Potter JL, Timmons GD, West R, et al: Argininosuccinic aciduria: The hair abnormality. Am J Dis Child 127:724-727, 1974. 14. Potter JL, Timmons GD, Silvidi AA: Argininosuccinic aciduria: The hair abnormality revisited. Am J Dis Child 134:1095-1096, 1980.