Autosomal Recessive Neurodegenerative Disorder with Trichorrhexis Invaginata and Ectodermal Dysplasia K y m b e r l y A. G y u r e , MD**, T h a d d e u s W. K u r c z y n s k i , M D , P h D * , W i l l i a m G u n n i n g , PhD*, and Beatrice N. F r e n c h , M S N *
Two siblings are reported with an autosomal recessive syndrome characterized by hair and skin abnormalities, hypoplastic nails, generalized hypotonia, absent reflexes, and progressive neurologic deterioration. Although this disorder shares clinical features with an ectodermal dysplasia syndrome with neurodegenerative changes, no specific neuropathologic findings were present. Instead, trichorrhexis invaginata was found in some hair shafts. Hair analysis may be helpful in classifying clinically confusing neurologic conditions. Gyure KA, Kurczynski TW, Gunning W, French BN. Autosomal recessive neurodegenerative disorder with trichorrhexis invaginata and ectodermal dysplasia. Pediatr Neurol 1992;8:469-72.
Introduction Hair-shaft abnormalities occur in many well-described metabolic disorders and genetic syndromes [1]. Some of these hair anomalies also are observed in patients with neurologic disorders in which there is no known metabolic abnormality [2-4]. We report 2 siblings with hair and/or skin abnormalities, hypoplastic nails, generalized hypotonia, hypoactive/absent reflexes, and progressive neurologic deterioration. This disorder manifests features of both an ectodermal dysplasia and a neurodegenerative disease. Scanning electron microscopy revealed trichorrhexis invaginata, or bamboo hair, a microscopically distinctive
From the Departments of *Pediatrics and ¢Pathology; Medical College of Ohio; Toledo, Ohio; tDepartment of Pathology; Cleveland Clinic Foundation; Cleveland, Ohio.
hair-shaft defect that has been described almost exclusively in association with ichthyosiform dermatoses [1,5-7]. Case Reports Patient 1. This patient was born at 36 weeks gestation to a 39-yearold G4, P3 (1 first trimester spontaneous abortion) mother after a pregnancy complicated by breech presentation. The father was 36 years of age. There was no parental consanguinity and both parents were in good health. The patient was the first child of her mother's second marriage. The mother had 2 children from a previous marriage, a 14year-old boy in good health with no congenital anomalies and an 11year-old boy with a 6-year history of seizures following a viral illness. The mother also had 2 brothers who were born with hiatal hernias. The father has 2 healthy children from a previous marriage (ages 11 and 9 years). His 69-year-old mother is in a mental institution and he has a 16-year-old niece who has been diagnosed with Sturge-Weber syndrome. The patient was delivered vaginally and the Apgar score was 6 at 1 min and 9 at 5 min. Birth weight was 2.81 kg (25th percentile), length 45.8 cm (10th percentile), and head circumference (OFC) 33.5 cm (25th percentile). Multiple anomalies were observed at birth, including hypoplastic nails and bilateral simian creases. The skin, especially that of the scalp, was dry and rough with poorly developed dermal ridges. There was also generalized hypotonia with a lack of extension at the hips and a weak Moro reflex. The deep tendon reflexes were hypoactive. Chromosomal analysis revealed a normal female karyotype (46,XX). Cranial computed tomography (CT) and electroencephalography (EEG) were normal. The neonatal course was complicated by apneic episodes which were secondary to laryngomalacia. At age 3 months, the patient was hospitalized for bronchiolitis and evaluation of apneic episodes which occurred upon awakening. Her parents reported that she did not appear to respond to visual stimuli. Weight was 4.60 kg (10th percentile), length 58.5 cm (50th percentile), and OFC 39.0 cm (50th percentile). Physical examination revealed sparse, fine hair and hypoplastic nails, high-arched palate, umbilical hernia, bilateral inguinal hernias, and generalized hypotonia. A sleep EEG was normal. Sleep pneumogram was believed to be borderline with one episode of prolonged apnea. Brainstem auditory evoked responses revealed a marked distortion of the waveforms. Visual evoked potentials demonstrated no response on the right side. At age 10 months, the patient again was hospitalized because of 2 months of increasing respiratory difficulty. Her mother reported that she was unable to lift her head or suck on her bottle. Weight was 5.96 kg (< 5th percentile). Physical findings were similar to those observed at age 3 months except for marked upper airway congestion. Bronchoscopy demonstrated that the epiglottis was displaced posteriorly over the airway, obstructing inspiration. Gag and cough reflexes were absent. A gastrostomy tube was placed. CT demonstrated possible early cortical atrophy. EEG revealed diffuse slowing and lateralized sharp-wave activity consistent with a diffuse encephalopathy with features of a seizure disorder; she was treated with phenobarbital. Electromyography and nerve conduction study disclosed mild conduction slowing in the medial and peroneal nerves. Biopsy of the right quadriceps muscle demonstrated some variation in myofiber diameters with scattered, rounded, hypertrophic fibers manifesting some sarcoplasmic pallor. These changes were believed to be nonspecific. A right sural nerve biopsy was normal. Leukocyte arylsulfatase A and galactocerebrosidase activities were normal, as were plasma and urine amino acid profiles. At 12 months of age, the mother reported that the patient was no longer able to suck, did not smile, and did not move her legs. Weight
Communications should be addressed to: Dr. Kurczynski; Department of Pediatrics; Medical College of Ohio; P.O. Box 10008; Toledo, OH 43699-0008. Received March 19, 1992; June 1, 1992.
Gyure et al: Trichorrhexis Invaginata 469
Figure 1. Electron micrograph of a hair sample from Patient 2 revealing trichorrhexis m vaginata. was 5.84 kg (< 5th percentile), length 66.0 cm (< 5th percentile), and OFC 43.0 cm (< 5th percentile). On physical examination, the patient was lethargic. Her scalp hair was short and she had a generalized decrease in subcutaneous tissue. She also had no nails on the third through the fifth fingers bilaterally. The neurologic examination revealed generalized hypotonia with marked head lag. Deep tendon reflexes were absent. The patient exhibited no tracking responses and had a delayed response to pain. Over the next few months the patient continued to deteriorate neurologically and to have respiratory difficulty believed to be secondary to decreasing neural control of the tongue and epiglottis. After having several apneic episodes requiting oxygen resuscitation, the patient died at 16 months of age. Unfortunately, the autopsy examination was limited to the brain and spinal cord. The cerebrum was symmetric with a normal gyral and sulcal pattern. The cerebellum, brainstem, and spinal cord appeared normal grossly. Light microscopic examination of sections of the cerebrum and cerebellum revealed diffuse perineuronal vacuolation with diffuse degenerative changes in the neurons. There was no morphologic evidence of a specific metabolic disorder. Patient 2. This patient was born at 38 weeks gestation and was a sibling of Patient 1 (mother: age 43 years; father: 40 years). The pregnancy was again complicated by breech presentation. Two years before this pregnancy, a healthy infant girl was born to the same parents. She has no congenital anomalies. The patient was delivered vaginally. The Apgar scores were 8 at l min and 9 at 5 min. Birth weight was 3.55 kg (75th percentile), length 50.5 cm (50th percentile), and OFC 35.0 cm (50th percentile). His skin was leathery with scaling on the scalp and back; his nails were hypoplastic. Other abnormalities included a lack of eyebrows and minimal eyelashes, a high-arched palate, increased neck folds, and generalized hypotonia. The neonatal course was complicated by episodes of apnea which were terminated by mild stimulation. CT revealed no gross pathology. EEG demonstrated changes consistent with a seizure disorder. The patient was treated with phenobarbital. Bronchoscopy disclosed an intermittent upper airway obstruction from supraglottic structures. At age 8 months, the patient was evaluated for a seizure disorder. His mother reported that she had discontinued his phenobarbital shortly after discharge because of side effects. She described his seizures as twisting movements of his trunk that occurred upon falling asleep or
470
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waking from sleep. She also reported that he did not respond to visual stimulation, could not turn over, and had no ability to reach for objects. OFC was 45.0 cm t50th percentile). On physical examination, the patient was awake but demonstrated little responsiveness with generalized hypotonia and absent deep tendon reflexes. EEG demonstrated bursts of bilateral spike-and-wave discharges. At age 12 months, the patient was evaluated because of the inability to respond to visual stimuli. On examination, he did not follow light or exhibit a startle response. Bilateral corneal opacities were discovered. Magnetic resonance imaging (MRI) revealed prominent sulci and subarachnoid spaces bilaterally. Plasma and urine amino acid profiles were normal as well as plasma pyruvic and lactic acid levels. Plasma longchain fatty acids were slightly elevated. At age 15 months, corneal surgery was performed. At age 16 months, the patient had no head control and was unable to sit unsupported. Weight was 8.20 kg t< 5th percentile), length 78.0 cm (10th to 25th percentile), and OFC 46.2 cm (5th to 10th percentile). New physical findings included high-arched feet with hammertoes, no following of light, and spontaneous nystagmus with a fast component in the direction of lateral gaze. Skin biopsy was obtained from the right thigh. Light and electron micro~opic sections disclosed no morphotogic evidence of either a hidrotic or anhidrotic ectodermal dysplasia. Cultured skin fibroblast analysis revealed normal peroxisomaI plasmalogen synthesis enzymes and normal total very long-chain fatty acids, At age 20 months, the mother reported that he had made limited developmental progress with occasional smiling and vocalizing, but no speech development. Weight was 8.40 kg (< 5th percentile), length 81.0 cm (10th percentile), and OFC 46,0 cm (< 5th percentile); The examination was unchanged from that at age 15 months except for flattening of the tight occipital area. Hair samples were obtained for scanning electron microscopy which revealed trichorrhexis invaginata approximately 1.0 mm from each hair bulb (Fig 1). At age 27 months, his mother reported that the patient still was unable to respond to visual stimuli or to use speech, but was able to roll from back to front and smile. He continued to have 45 s episodes of apnea with apparent loss of consciousness. Weight was 10,0 kg (< 5th percentile), length 83.0 cm (< 5th percentile), and OFC 48,0 cm (< 5th percentile). The physical examination was unchanged except for some yellowish discoloration of the eyebrows and constant scratching of the trunk. Electron microscopy of additional hair samples did not reveal any specific abnormalities.
Discussion These 2 patients had many abnormalities in common, including sparse, abnormal hair, hypoplastic nails, higharched palate, high-arched feet with hammertoes, generalized hypotonia, decreased or absent reflexes, and impaired vision. Both were delivered vaginally after a breech presentation and had neonatal courses complicated by apneic episodes. Both patients exhibited marked developmental delays and abnormal growth patterns and both experienced a decline in neurologic function. Finally, abnormal EEGs were obtained from both patients and brain imaging studies disclosed evidence of cortical atrophy in both. It is clear that these 2 patients had the same progressive neurologic disorder. Because their parents are unaffected and because both a male and a female were affected, the most likely pattern of inheritance is autosomal recessive. Initially, each patient was believed to have a typical ectodermal dysplasia syndrome; however, the normal skin biopsy obtained from Patient 2 makes this categorization unlikely. A peroxisomal disorder was also considered; however, cultured skin fibroblast analysis of Patient 2 revealed normal peroxisomal plasmalogen synthesis enzymes and normal total very long-chain fatty acids. Other important diagnostic considerations included neurodegenerative disorders, such as infantile neuroaxonal dystrophy (IND) and Pelizaeus-Merzbacher disease (PMD). IND is an autosomal-recessive neurodegenerative disease. The typical clinical symptoms include initial slowing of developmental progress with later loss of acquired motor and intellectual milestones, early visual impairment, marked hypotonia, weakness, pyramidal tract signs, lower motor neuron involvement, and progressive deterioration with dementia leading to death before age l0 years [7,9]. These symptoms usually begin between 6 months and 2 years of age; however, Hunter et al. reported 2 brothers who were affected at birth [9]. Their patients were similar to ours in that both sets of patients presented with neonatal dysmorphic features, including high-arched palate, bilateral inguinal hernias, papery fingernails, hypotonia, and sparse hair; both sets of patients failed to make any significant developmental progress. However, the typical neuropathologic finding associated with IND, neuroaxonal spheroids or dystrophic axons [8-11], was not observed in either the sural nerve biopsy sections or the autopsy sections of our first patient. Another neurodegenerative condition that needs to be considered is the connatal type of PMD. Common clinical findings in this disorder include early nystagmus; marked developmental delay with regression in some patients; progressive pyramidal, cerebellar, and extrapyramidal signs; and stridor [12]. Patient 2 exhibited nystagmus on lateral gaze; both patients had marked developmental delays, as well as respiratory difficulty and stridor. The inheritance pattern of PMD is believed to be X-linked in most patients, but an autosomal recessive form has been described [13]. PMD is characterized by patchy demyelination or hypomyelination of the central nervous system with sparing of
the peripheral nervous system; therefore, MRI scans are often helpful in confh'ming the diagnosis [12]. Both of our patients had evidence of peripheral nervous system disease; MRI in Patient 2 failed to reveal any evidence of demyelination or hypomyelination. Finally, the finding of trichorrhexis invaginata on electron microscopy of the hair in Patient 2 deserves mention. Hair-shaft abnormalities occur as a feature of several neurologic diseases, including Menkes disease, argininosuccinic aciduria, biotin deficiency, and Pollitt syndrome [2]. The clinical and laboratory findings exclude any of the known metabolic disorders. Pollitt syndrome has a number of similarities to our patients' disorder, but the hair shaft abnormalities include trichorrhexis nodosa, not invaginata, and it does not appear to be a progressive disease [3,4]. Trichorrhexis invaginata (bamboo hair) is a microscopically distinctive hair-shaft defect that has been described almost exclusively in association with ichthyosiform dermatoses as a part of Nethertons syndrome [1,5-7]. Other abnormalities occurring in Nethertons syndrome include atopy, urticaria, angioedema caused by eating nuts, mental retardation, delayed growth and development, recurrent infections, and aminoaciduria [6]. Trichorrhexis invaginata can also occur sporadically [14]. It is believed to result from a partial disturbance of the conversion of sulfhydryl groups into disulfide bonds in cortical keratin structures during keratinization [15]. The hair of Patient 1 was never examined microscopically, although it was observed to be sparse and fine on several examinations. Unfortunately, trichorrhexis invaginata was not found in a second hair sample from Patient 2, possibly because of the probability that the hairs were taken from different sites on each of the two occasions and because of the fact that the first time the hair was sampled it was plucked; the second time most of the hairs were cut. Although our patients did have some skin abnormalities, it is clear that they did not have either ichthyosis linearis circumflexa or lamellar ichthyosis; therefore, they did not have Nethertons syndrome [16]. The significance of the finding of trichorrhexis invaginata in our patient remains unknown. Our patients have a (presumably) autosomal recessive syndrome characterized by hair and/or skin abnormalities, hypoplastic nails, generalized hypotonia, hypoactive or absent deep tendon reflexes, and progressive neurologic deterioration. This disorder contains the clinical features of an ectodermal dysplasia syndrome and a neurodegenerative disorder (such as IND or PMD); however, pathologic evidence is lacking. Trichorrhexis invaginata was observed in hair samples of one of our patients, but it is of unknown clinical significance. This finding does suggest, however, that analysis of the hair of patients with neurologic conditions may be helpful in classifying the disorder. References
[1] B i r n b a u m PS, Baden HE Heritable disorders of hair. Dermatol Clin 1987;5:137-53.
Gyure et al: Trichorrhexis Invaginata 471
[2] Coulter DL, Beals TE Allen ILl. Neurotrichosis: Hair-shaft abnormalities associated with neurological diseases. Dev Med Child Neurol 1982;24:634-44. [3] Pollitt ILl, Jenner FA, Davies M. Sibs with mental and physical retardation and trichorrhexis nodosa with abnormal amino acid composition of the hair. Arch Dis Child 1968;43:211-6. [4] King MD, Gummer CL, Stephenson JBE Trichothiodystrophy Neurotrichocutaneous syndrome of Pollitt: A report of two unrelated cases. J Med Genet 1984;21:286-9. [5] M u r p h y GM, Griffiths WA, Grice K. Nethertons syndrome. J R Soc Med 1989;82:683-4. [6] Greene SL, Muller SA. Netherton's syndrome: Report of a c a ~ and review of the literature. J Am Acad Dermatol 1985;13:329-37. [7] Price VH. Structural anomalies of the hair shaft. In: Orfano CE, Happle R, eds. Hair and hair diseases. New York: Springer-Vedag, 1989;363-422. [8] R a m a e k e r s VT, Lake BD, Harding B, et al. Diagnostic difficulties in infantile neuroaxonal dystrophy: A clinicopathologic study of eight cases. Neuropediatrics 1987;18:170-5. [9] Hunter AGW, Jimenez CL, Carpenter BE MacDonald I. Neuroaxonal dystrophy presenting with neonatal dysmorphic features, early onset of peripheral gangrene, and a rapidly lethal course. Am J Med Genet 1987;28:171-80.
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[10] K h n u r a S. Terminal axon pathology in infantile neumaxonal dystrophy. Pediatr Neurol 1991 ;7:116-20. [11] Sehlinder D, Bishop DF, Wolfe I)E, et al. Neuro~x~mal d y s trophy due to lysosomal alpha-N-acetylgalactosaminid~sc deficiency. N Engl J Med 1989;320:1735-40. [12] Scheffer IE, Baraister M, Wilson J, Harding B. Kendall B. Brett EM. Pelizaeus-Merzbacher disease: Classiczd ~, connatal? Neuropediatrics 1991 ;22:71-8. [13] Beglelter ML, Harris DJ. Autosomal recessive form o| connatal Pelizaeus-Merzbacher disease. Am J Med Genet 1989;33:311-3. [14] Whiting DA. Structural abnormalities of the hair shaft. J Am Acad Dermatol 1987; 16:1-25. [15] lto M, lto K, Hashimoto K. Pathogenesis in trichorrhexis invaginata (bamboo hair). J Invest Dermatol 1984;83:1-6. [16] Hurwitz S, Kirsch N, McGuire J. Re-evaluation of ichthyosis and hair shaft abnormalities. Arch Dermatol 1971 ;103:266-71.
Two siblings are reported with an autosomal recessive syndrome characterized by hair and skin abnormalities, hypoplastic nails, generalized hypotonia, absent reflexes, and progressive neurologic deterioration. Although this disorder shares clinical features with an ectodermal dysplasia syndrome with neurodegenerative changes, no specific neuropathologic findings were present. Instead, trichorrhexis invaginata was found in some hair shafts. Hair analysis may be helpful in classifying clinically confusing neurologic conditions. Gyure KA, Kurczynski TW, Gunning W, French BN. Autosomal recessive neurodegenerative disorder with trichorrhexis invaginata and ectodermal dysplasia. Pediatr Neurol 1992;8:469-72.
Introduction Hair-shaft abnormalities occur in many well-described metabolic disorders and genetic syndromes [1]. Some of these hair anomalies also are observed in patients with neurologic disorders in which there is no known metabolic abnormality [2-4]. We report 2 siblings with hair and/or skin abnormalities, hypoplastic nails, generalized hypotonia, hypoactive/absent reflexes, and progressive neurologic deterioration. This disorder manifests features of both an ectodermal dysplasia and a neurodegenerative disease. Scanning electron microscopy revealed trichorrhexis invaginata, or bamboo hair, a microscopically distinctive
From the Departments of *Pediatrics and ¢Pathology; Medical College of Ohio; Toledo, Ohio; tDepartment of Pathology; Cleveland Clinic Foundation; Cleveland, Ohio.
hair-shaft defect that has been described almost exclusively in association with ichthyosiform dermatoses [1,5-7]. Case Reports Patient 1. This patient was born at 36 weeks gestation to a 39-yearold G4, P3 (1 first trimester spontaneous abortion) mother after a pregnancy complicated by breech presentation. The father was 36 years of age. There was no parental consanguinity and both parents were in good health. The patient was the first child of her mother's second marriage. The mother had 2 children from a previous marriage, a 14year-old boy in good health with no congenital anomalies and an 11year-old boy with a 6-year history of seizures following a viral illness. The mother also had 2 brothers who were born with hiatal hernias. The father has 2 healthy children from a previous marriage (ages 11 and 9 years). His 69-year-old mother is in a mental institution and he has a 16-year-old niece who has been diagnosed with Sturge-Weber syndrome. The patient was delivered vaginally and the Apgar score was 6 at 1 min and 9 at 5 min. Birth weight was 2.81 kg (25th percentile), length 45.8 cm (10th percentile), and head circumference (OFC) 33.5 cm (25th percentile). Multiple anomalies were observed at birth, including hypoplastic nails and bilateral simian creases. The skin, especially that of the scalp, was dry and rough with poorly developed dermal ridges. There was also generalized hypotonia with a lack of extension at the hips and a weak Moro reflex. The deep tendon reflexes were hypoactive. Chromosomal analysis revealed a normal female karyotype (46,XX). Cranial computed tomography (CT) and electroencephalography (EEG) were normal. The neonatal course was complicated by apneic episodes which were secondary to laryngomalacia. At age 3 months, the patient was hospitalized for bronchiolitis and evaluation of apneic episodes which occurred upon awakening. Her parents reported that she did not appear to respond to visual stimuli. Weight was 4.60 kg (10th percentile), length 58.5 cm (50th percentile), and OFC 39.0 cm (50th percentile). Physical examination revealed sparse, fine hair and hypoplastic nails, high-arched palate, umbilical hernia, bilateral inguinal hernias, and generalized hypotonia. A sleep EEG was normal. Sleep pneumogram was believed to be borderline with one episode of prolonged apnea. Brainstem auditory evoked responses revealed a marked distortion of the waveforms. Visual evoked potentials demonstrated no response on the right side. At age 10 months, the patient again was hospitalized because of 2 months of increasing respiratory difficulty. Her mother reported that she was unable to lift her head or suck on her bottle. Weight was 5.96 kg (< 5th percentile). Physical findings were similar to those observed at age 3 months except for marked upper airway congestion. Bronchoscopy demonstrated that the epiglottis was displaced posteriorly over the airway, obstructing inspiration. Gag and cough reflexes were absent. A gastrostomy tube was placed. CT demonstrated possible early cortical atrophy. EEG revealed diffuse slowing and lateralized sharp-wave activity consistent with a diffuse encephalopathy with features of a seizure disorder; she was treated with phenobarbital. Electromyography and nerve conduction study disclosed mild conduction slowing in the medial and peroneal nerves. Biopsy of the right quadriceps muscle demonstrated some variation in myofiber diameters with scattered, rounded, hypertrophic fibers manifesting some sarcoplasmic pallor. These changes were believed to be nonspecific. A right sural nerve biopsy was normal. Leukocyte arylsulfatase A and galactocerebrosidase activities were normal, as were plasma and urine amino acid profiles. At 12 months of age, the mother reported that the patient was no longer able to suck, did not smile, and did not move her legs. Weight
Communications should be addressed to: Dr. Kurczynski; Department of Pediatrics; Medical College of Ohio; P.O. Box 10008; Toledo, OH 43699-0008. Received March 19, 1992; June 1, 1992.
Gyure et al: Trichorrhexis Invaginata 469
Figure 1. Electron micrograph of a hair sample from Patient 2 revealing trichorrhexis m vaginata. was 5.84 kg (< 5th percentile), length 66.0 cm (< 5th percentile), and OFC 43.0 cm (< 5th percentile). On physical examination, the patient was lethargic. Her scalp hair was short and she had a generalized decrease in subcutaneous tissue. She also had no nails on the third through the fifth fingers bilaterally. The neurologic examination revealed generalized hypotonia with marked head lag. Deep tendon reflexes were absent. The patient exhibited no tracking responses and had a delayed response to pain. Over the next few months the patient continued to deteriorate neurologically and to have respiratory difficulty believed to be secondary to decreasing neural control of the tongue and epiglottis. After having several apneic episodes requiting oxygen resuscitation, the patient died at 16 months of age. Unfortunately, the autopsy examination was limited to the brain and spinal cord. The cerebrum was symmetric with a normal gyral and sulcal pattern. The cerebellum, brainstem, and spinal cord appeared normal grossly. Light microscopic examination of sections of the cerebrum and cerebellum revealed diffuse perineuronal vacuolation with diffuse degenerative changes in the neurons. There was no morphologic evidence of a specific metabolic disorder. Patient 2. This patient was born at 38 weeks gestation and was a sibling of Patient 1 (mother: age 43 years; father: 40 years). The pregnancy was again complicated by breech presentation. Two years before this pregnancy, a healthy infant girl was born to the same parents. She has no congenital anomalies. The patient was delivered vaginally. The Apgar scores were 8 at l min and 9 at 5 min. Birth weight was 3.55 kg (75th percentile), length 50.5 cm (50th percentile), and OFC 35.0 cm (50th percentile). His skin was leathery with scaling on the scalp and back; his nails were hypoplastic. Other abnormalities included a lack of eyebrows and minimal eyelashes, a high-arched palate, increased neck folds, and generalized hypotonia. The neonatal course was complicated by episodes of apnea which were terminated by mild stimulation. CT revealed no gross pathology. EEG demonstrated changes consistent with a seizure disorder. The patient was treated with phenobarbital. Bronchoscopy disclosed an intermittent upper airway obstruction from supraglottic structures. At age 8 months, the patient was evaluated for a seizure disorder. His mother reported that she had discontinued his phenobarbital shortly after discharge because of side effects. She described his seizures as twisting movements of his trunk that occurred upon falling asleep or
470
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waking from sleep. She also reported that he did not respond to visual stimulation, could not turn over, and had no ability to reach for objects. OFC was 45.0 cm t50th percentile). On physical examination, the patient was awake but demonstrated little responsiveness with generalized hypotonia and absent deep tendon reflexes. EEG demonstrated bursts of bilateral spike-and-wave discharges. At age 12 months, the patient was evaluated because of the inability to respond to visual stimuli. On examination, he did not follow light or exhibit a startle response. Bilateral corneal opacities were discovered. Magnetic resonance imaging (MRI) revealed prominent sulci and subarachnoid spaces bilaterally. Plasma and urine amino acid profiles were normal as well as plasma pyruvic and lactic acid levels. Plasma longchain fatty acids were slightly elevated. At age 15 months, corneal surgery was performed. At age 16 months, the patient had no head control and was unable to sit unsupported. Weight was 8.20 kg t< 5th percentile), length 78.0 cm (10th to 25th percentile), and OFC 46.2 cm (5th to 10th percentile). New physical findings included high-arched feet with hammertoes, no following of light, and spontaneous nystagmus with a fast component in the direction of lateral gaze. Skin biopsy was obtained from the right thigh. Light and electron micro~opic sections disclosed no morphotogic evidence of either a hidrotic or anhidrotic ectodermal dysplasia. Cultured skin fibroblast analysis revealed normal peroxisomaI plasmalogen synthesis enzymes and normal total very long-chain fatty acids, At age 20 months, the mother reported that he had made limited developmental progress with occasional smiling and vocalizing, but no speech development. Weight was 8.40 kg (< 5th percentile), length 81.0 cm (10th percentile), and OFC 46,0 cm (< 5th percentile); The examination was unchanged from that at age 15 months except for flattening of the tight occipital area. Hair samples were obtained for scanning electron microscopy which revealed trichorrhexis invaginata approximately 1.0 mm from each hair bulb (Fig 1). At age 27 months, his mother reported that the patient still was unable to respond to visual stimuli or to use speech, but was able to roll from back to front and smile. He continued to have 45 s episodes of apnea with apparent loss of consciousness. Weight was 10,0 kg (< 5th percentile), length 83.0 cm (< 5th percentile), and OFC 48,0 cm (< 5th percentile). The physical examination was unchanged except for some yellowish discoloration of the eyebrows and constant scratching of the trunk. Electron microscopy of additional hair samples did not reveal any specific abnormalities.
Discussion These 2 patients had many abnormalities in common, including sparse, abnormal hair, hypoplastic nails, higharched palate, high-arched feet with hammertoes, generalized hypotonia, decreased or absent reflexes, and impaired vision. Both were delivered vaginally after a breech presentation and had neonatal courses complicated by apneic episodes. Both patients exhibited marked developmental delays and abnormal growth patterns and both experienced a decline in neurologic function. Finally, abnormal EEGs were obtained from both patients and brain imaging studies disclosed evidence of cortical atrophy in both. It is clear that these 2 patients had the same progressive neurologic disorder. Because their parents are unaffected and because both a male and a female were affected, the most likely pattern of inheritance is autosomal recessive. Initially, each patient was believed to have a typical ectodermal dysplasia syndrome; however, the normal skin biopsy obtained from Patient 2 makes this categorization unlikely. A peroxisomal disorder was also considered; however, cultured skin fibroblast analysis of Patient 2 revealed normal peroxisomal plasmalogen synthesis enzymes and normal total very long-chain fatty acids. Other important diagnostic considerations included neurodegenerative disorders, such as infantile neuroaxonal dystrophy (IND) and Pelizaeus-Merzbacher disease (PMD). IND is an autosomal-recessive neurodegenerative disease. The typical clinical symptoms include initial slowing of developmental progress with later loss of acquired motor and intellectual milestones, early visual impairment, marked hypotonia, weakness, pyramidal tract signs, lower motor neuron involvement, and progressive deterioration with dementia leading to death before age l0 years [7,9]. These symptoms usually begin between 6 months and 2 years of age; however, Hunter et al. reported 2 brothers who were affected at birth [9]. Their patients were similar to ours in that both sets of patients presented with neonatal dysmorphic features, including high-arched palate, bilateral inguinal hernias, papery fingernails, hypotonia, and sparse hair; both sets of patients failed to make any significant developmental progress. However, the typical neuropathologic finding associated with IND, neuroaxonal spheroids or dystrophic axons [8-11], was not observed in either the sural nerve biopsy sections or the autopsy sections of our first patient. Another neurodegenerative condition that needs to be considered is the connatal type of PMD. Common clinical findings in this disorder include early nystagmus; marked developmental delay with regression in some patients; progressive pyramidal, cerebellar, and extrapyramidal signs; and stridor [12]. Patient 2 exhibited nystagmus on lateral gaze; both patients had marked developmental delays, as well as respiratory difficulty and stridor. The inheritance pattern of PMD is believed to be X-linked in most patients, but an autosomal recessive form has been described [13]. PMD is characterized by patchy demyelination or hypomyelination of the central nervous system with sparing of
the peripheral nervous system; therefore, MRI scans are often helpful in confh'ming the diagnosis [12]. Both of our patients had evidence of peripheral nervous system disease; MRI in Patient 2 failed to reveal any evidence of demyelination or hypomyelination. Finally, the finding of trichorrhexis invaginata on electron microscopy of the hair in Patient 2 deserves mention. Hair-shaft abnormalities occur as a feature of several neurologic diseases, including Menkes disease, argininosuccinic aciduria, biotin deficiency, and Pollitt syndrome [2]. The clinical and laboratory findings exclude any of the known metabolic disorders. Pollitt syndrome has a number of similarities to our patients' disorder, but the hair shaft abnormalities include trichorrhexis nodosa, not invaginata, and it does not appear to be a progressive disease [3,4]. Trichorrhexis invaginata (bamboo hair) is a microscopically distinctive hair-shaft defect that has been described almost exclusively in association with ichthyosiform dermatoses as a part of Nethertons syndrome [1,5-7]. Other abnormalities occurring in Nethertons syndrome include atopy, urticaria, angioedema caused by eating nuts, mental retardation, delayed growth and development, recurrent infections, and aminoaciduria [6]. Trichorrhexis invaginata can also occur sporadically [14]. It is believed to result from a partial disturbance of the conversion of sulfhydryl groups into disulfide bonds in cortical keratin structures during keratinization [15]. The hair of Patient 1 was never examined microscopically, although it was observed to be sparse and fine on several examinations. Unfortunately, trichorrhexis invaginata was not found in a second hair sample from Patient 2, possibly because of the probability that the hairs were taken from different sites on each of the two occasions and because of the fact that the first time the hair was sampled it was plucked; the second time most of the hairs were cut. Although our patients did have some skin abnormalities, it is clear that they did not have either ichthyosis linearis circumflexa or lamellar ichthyosis; therefore, they did not have Nethertons syndrome [16]. The significance of the finding of trichorrhexis invaginata in our patient remains unknown. Our patients have a (presumably) autosomal recessive syndrome characterized by hair and/or skin abnormalities, hypoplastic nails, generalized hypotonia, hypoactive or absent deep tendon reflexes, and progressive neurologic deterioration. This disorder contains the clinical features of an ectodermal dysplasia syndrome and a neurodegenerative disorder (such as IND or PMD); however, pathologic evidence is lacking. Trichorrhexis invaginata was observed in hair samples of one of our patients, but it is of unknown clinical significance. This finding does suggest, however, that analysis of the hair of patients with neurologic conditions may be helpful in classifying the disorder. References
[1] B i r n b a u m PS, Baden HE Heritable disorders of hair. Dermatol Clin 1987;5:137-53.
Gyure et al: Trichorrhexis Invaginata 471
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