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Keywords:

  • cardio-facio-cutaneous;
  • cardiofacio cutaneous;
  • CFC;
  • onion bulb formations;
  • peripheral neuropathy;
  • islet cell hyperplasia;
  • thymic atrophy

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

Many phenotypic manifestations have been reported in cardiofaciocutaneous (CFC) syndrome, but none, to date, are pathognomonic or obligatory. Previous histopathological studies reported findings in skin and hair; no autopsy studies have been published. We report the clinical and autopsy findings of a 7-year-old boy with severe CFC syndrome and malnutrition of psychosocial origin. Manifestations of CFC, reported previously, included macrocephaly and macrosomia at birth; short stature; hypotonia; global developmental delays; dry, sparse thin curly hair; sparse eyebrows and eyelashes; dilated cerebral ventricles; high cranial vault; bitemporal constriction; supraorbital ridge hypoplasia; hypertelorism; ptosis; exophthalmos; depressed nasal bridge; anteverted nostrils; low-set, posteriorly-rotated, large, thick ears; decayed, dysplastic teeth; strabismus; hyperelastic skin; wrinkled palms; keratosis pilaris atrophicans faciei; ulerythema ophryogenes; hyperkeratosis; gastroesophageal reflux; and tracheobronchomalacia. Additional findings, not previously reported, include islet cell hyperplasia, lymphoid depletion, thymic atrophy and congenital hypertrophy of peripheral nerves with onion bulb formations. Although the islet cell hyperplasia, lymphoid depletion, and thymic atrophy are nonspecific findings that may be associated with either CFC or malnutrition, the onion bulb hypertrophy is specific for a demyelinating–remyelinating neuropathy. These findings implicate congenital peripheral neuropathy in the pathogenesis of the developmental delays, feeding difficulties, respiratory difficulties, ptosis and short stature in this case. Additional studies of other cases of CFC are needed. © 2005 Wiley-Liss, Inc.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

The cardiofaciocutaneous (CFC) syndrome, described in 1986 by Reynolds et al. [1986] and Baraitser and Patton [1986], comprises multiple congenital abnormalities, a characteristic facial appearance, facultative mental retardation, early failure to thrive, congenital heart defects, ectodermal anomalies and short stature [Kavamura et al., 2003]. Typical cases are sporadic and without parental consanguinity. The sex ratio is nearly equal. Age at diagnosis ranges from birth to 25 years; advanced paternal age (over 35 years) has been reported [Verloes et al., 1988; Sorge et al., 1989; Somer et al., 1992]. Although the cause is unknown, de novo mutation of an autosomal dominant gene seems the most likely mechanism.

Prior to 1986, cases of CFC syndrome were reported as variants of Noonan or Costello syndromes, the main differential diagnoses [Navaratnam, 1973; Cantú et al., 1982; Bottani et al., 1991; Fryer et al., 1991; Krajewska-Walasek et al., 1996]. Between 1986 and 2002, the diagnosis was based on clinical observations. In 2002, a more objective method of diagnosis was provided by the CFC index, which has great specificity and low sensitivity and selects good examples of the syndrome [Kavamura et al., 2002].

Recently the diagnosis of CFC syndrome was further refined by description of the severe phenotype, which includes polyhydramnios, hyperkeratotic skin lesions, sparse curly hair, cardiac defect, growth retardation, characteristic facial anomalies, mental retardation, macrocephaly, severe feeding problems requiring gastrostomy tube feedings, neurologic impairment or developmental delay (especially in motor and speech skills) and ocular abnormalities or dysfunction [Grebe and Clericuzio, 2000].

Histopathologic studies of CFC syndrome are very few. However, all have focused on skin and/or hair [Navaratnam, 1973; Verloes et al., 1988; Graham et al., 1989; Piérard et al., 1990; Somer et al., 1992; Borradori and Blanchet-Bardon, 1993]. No autopsy studies have been reported, but morphological anomalies are very important in elucidating the underlying pathophysiology. We describe clinical and autopsy findings with immunohistochemical studies in a new case of severe CFC syndrome and review previous cases for evidence of malnutrition and congenital neuropathy.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

Autopsy tissues were processed routinely. Histological stains included hematoxylin-and-eosin, periodic acid Schiff, luxol fast blue and immunohistochemistry for S100 and epithelial membrane antigen. Appropriate controls were employed for each special stain. Weight-for-height z scores were calculated using the National Health and Nutrition Examination Service 2000 reference population data at the Center for Disease Control National Center for Health Statistics [Kuczmarski et al., 2000].

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

Clinical Report

This African-American boy was born to a 24-year-old, gravida 4, para 3 mother. This was the first pregnancy with this father. The father's age and history were unavailable but he was not consanguineous with the mother. The maternal family history included hypertension, but no diabetes or previous large-for-gestational age infants. Polyhydramnios was suspected at 36 weeks of gestation, but by ultrasonography the amniotic fluid volume was normal. Dilation of both fetal renal pelvices was noted. By amniocentesis; the fetal karyotype was 46,XY. Spontaneous vaginal, vertex delivery occurred at term; abnormalities included thin meconium and placentomegaly (779 g, trimmed) with chronic villitis. The umbilical cord was short (25 cm), coiled to the left and had a marked decrease in number of coils (one coil per 25 cm). The infant was macrosomic (weight 4,838 g, >95th centile; length 52 cm, >75th centile; chest circumference 40 cm, >95th centile) and macrocephalic (head circumference 37 cm, 95th centile). Apgar scores were 6 and 8 at 1 and 5 min, respectively. Perinatal problems included a cardiac murmur with cyanosis, feeding difficulty and abnormal craniofacial appearance.

Cardiac abnormalities at birth included hypertrophic cardiomyopathy with an asymmetrical interventricular septum, left ventricular outflow tract obstruction, abnormally thick and redundant atrioventricular valve leaflets, a small patent ductus arteriosus, and a small secundum atrial septal defect. On propranolol, the outflow tract obstruction resolved; the cardiomyopathy stabilized by age 18 months. Psychosocial factors caused failure of prophylactic antibiotics; at age 29 months staphylococcal endocarditis caused severe congestive heart failure, which resolved with treatment.

Feeding difficulties at birth included gastroesophageal reflux with no pyloric stenosis. At age 2 months evaluation for slow feeding (30–60 min per meal) demonstrated oral aversion, inadequate suck reflex, frequent spitting up/vomiting, flatulence and gastroparesis. D-xylose test and fecal assays for fat, reducing substance and trypsin ruled out malabsorption. A gastrostomy tube was placed. On a regime of oral and tube feedings his weight increased and was maintained normally during hospitalizations; but repeatedly, as an outpatient, he manifested severe weight loss due to nutritional deprivation of psychosocial origin.

At birth the infant had slight exophthalmos, hypertelorism, protruding tongue and apparently low-set, posteriorly angulated ears. Repeat karyotype results were normal. Cranial ultrasonography suggested deep white matter atrophy with mild enlargement of the ventricles in the occipital horn and trigonocephaly. Renal ultrasonography showed mild-moderate left hydronephrosis. Results of “screens” for inherited metabolic disorders (plasma organic acids and urine organic and amino acid profiles), plasma carnitine (free and total) and acylcarnitine (short-, middle-, and long-chain), cholesterol and bilirubin were normal. Skeletal surveys showed no abnormalities of the axial skeleton or limbs; bone age was normal. At age 10 months, sparse hair of abnormal texture, strabismus, ptosis, dry crusty skin with increased elasticity and respiratory difficulties were noted. No hepatosplenomegaly or skeletal abnormalities were noted. Mild tracheomalacia progressed to severe tracheobronchomalacia with subglottic and tracheobronchial stenosis, requiring tracheostomy at age 20 months. At age 29 months, hyperelastic redundant skin, large abnormally modeled ears, hypoplastic supraorbital ridges, small orbits, depressed nasal bridge and increased joint laxity were noted. A skin biopsy showed no evidence of Ehlers–Danlos syndrome.

On neurological examinations he was an irritable, but consolable, child with a flat affect and global developmental disabilities. He had normal extraocular movements with appropriate tracking, pupillary response, fundoscopic findings, myotactic reflexes, plantar reflex, and range of motion of all limbs. Eyelid fluttering was not present. Unilateral impairment of his response to auditory stimuli and aversive reaction to tactile stimuli were suspected. Computerized tomography showed trigonocephaly and normal corpus callosum and ventricles. By Early Learning Accomplishment Profiles at age 1 year delays were 36% in cognitive performance, 68% gross motor, 44% fine motor, 52% self-help, and 44% social-emotional skills; and by the Alberta Infant Motor Scale performance was less than the 5th centile. At age 29 months, gross motor development was at a 5 month level and at age 2½ years cognitive and self-help skills at an 11-month level. Finally, blood lead levels were nontoxic (1, 2, and 16 µg/dl at ages 1, 2, and 5 years, respectively).

Additional problems included multiple infections (otitis media, Hemophilus sp. sinusitis and gastroenteritis). No polyps or papillomas were present on multiple examinations of the oral and nasal cavities by multiple pediatricians. At 5 months, severe respiratory syncytial virus pneumonitis was followed closely by severe rotavirus gastroenteritis with acute dehydration, metabolic acidosis and shock. During attempts to secure an intravascular catheter, a vascular accident caused ischemia of the left foot with subsequent gangrene requiring a Syme amputation.

He was lost to follow-up for several years. At age 7 years, he was reported to be unresponsive and apneic at home. On arrival to the hospital, he was in cardiac arrest; resuscitation was of no avail. There was no history of recent fever, rhinorrhea, diarrhea, or vomiting.

Autopsy Findings

Growth failure was severe (Table I). Gross examination showed a high cranial vault, bitemporal constriction, hypertelorism, exophthalmos, hypoplasia of supraorbital ridges, depressed nasal bridge, anteverted nostrils, sparse thin curly dry hair, patchy alopecia, sparse eyebrows and eyelashes, apparently low-set, posteriorly angulated large thick ears with prominent helices, dysplastic teeth with an unusual saw-like shape and multiple foci of caries, short neck, keratosis pilaris atrophicans faciei, hyperpigmented and hypopigmented patches on shoulders and chest, excoriations in the diaper region and wrinkled palms (Fig. 1). Additional gross findings included severe periodontal disease, tenting of skin, dry mucous membranes and conjunctiva, edema of the hands, foot, penis and scrotum, extensive skin erosions, scant subcutaneous adipose tissue, 1–2 mm umbilical panniculus, muscular atrophy of all limbs, wrinkled soles, foot drop and pes cavus. He had no hypoplastic nails, hirsutism, “coarse” facial appearance, cutis laxa, inguinal or umbilical hernias, diverticuli of bladder or gastrointestinal tract, pulmonary emphysema, hiatus hernia or rectal prolapse. The body cavities contained serous effusions (right pleural 400 ml, left pleural 720 ml, pericardial 20 ml, and peritoneal 300 ml). There was dilation of the right atrium, right ventricle and left atrium, myxomatous tricuspid and mitral valve leaflets, fibrotic subendocardium, 1–2 cm secundum atrial septal defect, right ventricular wall thickness 3 mm, left ventricular wall thickness 11 mm, and valve circumferences as follows: tricuspid 7 cm, pulmonary 5.8 cm, mitral 6.8 cm, and aortic 4 cm. Both lungs were atalectatic. The gastric mucosa was atrophic with a flat, smooth surface. No polyps or papillomas were present in the nasal, oral, and rectal cavities. The adrenal glands and other viscera were normal in positions, external configurations and cut surfaces. On brain cutting, no gross abnormalities were identified.

Table I. Autopsy Measurements in a Case of Severe Phenotype Cardiofaciocutaneous Syndrome (CFC)
FindingPatientReference male age 7 years mean (95% CI)Z score
  • a

    Morphometric ranges from Kayser [1987] and Schonfield [1943].

Weight (kg)11.7522.6 (18.3, 29.9)−6.75
Stature (cm)95120.46 (111.74, 129.3)−4.87
Head circumference (cm)47  
Chest circumference (cm)55  
Abdominal circumference (cm)44  
Mid-upper arm circumference (cm)11.516.4 (14.1, 18.7)−4.21
Genitalia   
 Testis volume (cm3)11 (1.1, 0.9)a 
 Penis length (cm)46.1 (7.6, 4.8)a 
Heart (g)100106.6 (95.4, 117.8) 
Lungs   
 Right (g)151203.1 (174.6, 231.7) 
 Left (g)56189.6 (160.7, 218.5) 
Thyroid (g)5.3  
Liver (g)500752.6 (672.3, 832.9) 
Spleen (g)17.5103.3 (66.5, 140.1) 
Thymus (g)13  
Kidneys   
 Right (g)39.568.4 (59.6, 77.1) 
 Left (g)4267.8 (59.9, 75.7) 
Brain (g)10501381.4 (1194.2, 1568.5) 
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Figure 1. A: Frontal view of a boy age 7 years with cardiofaciocutaneous syndrome (CFC) and malnutrition. B: Close-up of keratosis pilaris atrophicans faciei on forehead and bridge of nose and a hypomelanotic macule (arrow). C: Furrowed palm. D: Dysplastic teeth. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

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Microscopic Studies

Sections of intact skin showed hyperkeratosis with foci of parakeratosis and pigment incontinence. Sections of skin in the crusted and excoriated areas showed confluent parakeratosis with scattered neutrophils in the corneal layer and attenuation of the granular layer. In the skin and skeletal muscle from the chest, back, and buttock at autopsy, peripheral nerves were large and abundant with prominent onion bulb formations and no inflammatory infiltrates, granuloma, amyloid, abnormalities of elastic fibers, vasculitis, interstitial neuropathy or malignant changes (Fig. 2). Immunohistochemical stains of the onion bulb formations were typical of Schwann cells, rather than perineural cells and surrounded very small axons (Fig. 2). Atrophy of skeletal muscle was severe and extensive. Sections of skin and muscle retrieved from the foot amputated at age 5 months showed the same pattern of large nerves with early onion bulb formations. Cellularity of the bone marrow was increased. Sections of myocardium were normal. Sections of the pancreas demonstrated large central aggregates of hyperplastic islet cells without nuclear atypia, amyloid or inflammatory infiltrates (Fig. 3). Sections of thymus showed severe atrophy with marked loss of cortical lymphoid cells, sparse Hassell's corpuscles and increased fibrous connective tissue. In sections of hilar and mesenteric lymph nodes, splenic white pulp and intestinal lymphoid nodules, lymphoid cells were markedly decreased in numbers and fibrous connective tissue was relatively increased. Additional microscopic evidence of malnutrition included atrophy of the small intestinal mucosa with decreased numbers of goblet cells, decreased mitotic activity within epithelial crypts and minimal hepatic microvesicular steatosis. There was no evidence of cirrhosis or periodic acid-Schiff-positive macrophages. Hematoxylin-and-eosin and luxol fast blue stains of multiple sections of the cerebral cortex, basal ganglia, hippocampus, mammillary bodies, pons, cerebellum, and spinal cord showed no evidence of neuronal microdysgenesis, demyelination, inflammatory infiltrates, gliosis, degranulation of cerebellum, Purkinje cell migration defect, axonal degeneration or abnormalities of anterior horn cells or corticospinal tracts. There were no findings to suggest human immunodeficiency virus, leprosy, Lyme disease, diabetes, thyroid disease, uremia, liver disease, acromegaly, dysproteinemias, medication reaction or neoplasia.

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Figure 2. A: Hypertrophy of dermal nerve. B: Onion bulb formations stained for S100. C: Onion bulb formation with no staining for epithelial membrane antigen. A: H&E ×200; (B) immunohistochemical stain for S100 ×400; (C) immunohistochemical stain for epithelial membrane antigen ×400. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

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Figure 3. Islet cell hyperplasia (arrows) surrounds large pancreatic ducts and stains for insulin (inset). H&E ×200; inset, immunohistochemical stain for insulin ×400. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

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Special Studies

No fresh or frozen tissue was available for molecular studies. Attempts to extract DNA from the formalin-fixed, paraffin-embedded autopsy tissue blocks for assay for the PTPN11 gene were unsuccessful. Cardiofaciocutaneous syndrome was confirmed by the CFC index score of 16.408, which is within one standard deviation of the mean (12.1–17.3) for 68% of published cases [Kavamura et al., 2002]. In addition, this patient had all of the manifestations of the severe phenotype of CFC, except for polyhydramnios, which was reported in 57% of severely affected infants [Grebe and Clericuzio, 2000].

A review documented 94 cases of CFC syndrome (CFCS), of which 23 were excluded [Innes and Chudley, 2000; Kavamura et al., 2002, 2003] because of inadequate documentation [Pierini and Pierini, 1979; Neild et al., 1984; Blanchet-Bardon et al., 1991] or controversial diagnoses [Fryns et al., 1991; Ward et al., 1994; Leichtman, 1996; Bisogno et al., 1999; Rauen et al., 2000, 2002; Rauen and Cotter, 2001]. The remaining 71 cases were reviewed for phenotype, sex, age-specific weight and height, neurological findings and nerve conduction studies. Z scores were calculated using the age and sex specific weight and height from 56 datasets [Reynolds et al., 1986; Neri et al., 1987; Verloes et al., 1988; Chrzanowska et al., 1989; Sorge et al., 1989; Gross-Tsur et al., 1990; Piérard et al., 1990; Bottani et al., 1991; Corsello and Giuffrè, 1991; Matsuda et al., 1991; Ades̀ et al., 1992; Fryns, 1992; Ghezzi et al., 1992; Kajii et al., 1992; Somer et al., 1992; Borradori and Blanchet-Bardon, 1993; Lopez-Rangel et al., 1993; Young et al., 1993; Haas et al., 1994; Krajewska-Walasek et al., 1996; Lecora et al., 1996; Manoukian et al., 1996; McDaniel and Fujimoto, 1997; Sabatino et al., 1997; Wieczorek et al., 1997; Legius et al., 1998; Van Den Berg and Hennekam, 1999; Grebe and Clericuzio, 2000] (Fig. 4). Neurological findings were reported in 69 CFC cases, which included all of the above CFC references plus [Navaratnam, 1973; Cantú et al., 1982; Baraitser and Patton, 1986; Graham et al., 1989; Mucklow, 1989; Piérard et al., 1990; Fryer et al., 1991; Turnpenny et al., 1992; Dunya et al., 1993; Mathews et al., 1993; Raymond and Holmes, 1993; Schepis et al., 1999; Ishiguro et al., 2002]. These neurological findings are summarized in Table II. Nerve conduction velocity and electromyography were reported in one case of the usual phenotype at age 15 months and was normal [Bottani et al., 1991]; other neurological findings in this case included mild, mainly motor, developmental delays and an intelligence quotient of 91 (Binet–Simon–Kramer intelligence test). No nerve conduction studies have been reported in a case of severe phenotype CFC syndrome. The remaining 2 CFC references did not report age-specific weight and height nor neurological findings [Della Monica et al., 1991; Palencia, 1995].

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Figure 4. Weight-for-height Z scores in CFC syndrome by phenotypes. Horizontal line 0.0 represents mean z scores of normal controls. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

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Table II. Neurological Findings in Cases of CFC
ParameterFindingN%
Cognitive/motor developmentNormal5/697
 Abnormal64/6993
Muscle toneNormal2/683
 Increased3/684
 Decreased29/6843
History of seizuresPositive11/6916
ElectroencephalogramAbnormal6/6100
Cranial imaging(CT 22, MRI 8, US 5)Normal8/3523
 Dilated ventricles15/3543
 Cortical atrophy17/3549
HearingNormal5/1050
 Decreased response to evoked stimuli/impaired hearing5/1050
FundiNormal9/1182
 Optic nerve atrophy2/1118
VisionNormal4/944
 Decreased response to evoked stimuli/impaired vision5/956
Eye/eyelid movementStrabismus31/6945
 Nystagmus16/6923
 Ptosis26/6938
Myotatic reflexesNormal6/1060
 Increased3/1030
 Decreased1/1010
Plantar reflexNormal4/4100
Tactile responseNormal2/633
 Decreased/altered3/650
 Increased1/617

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

The cause of death in this child with severe phenotype CFC syndrome and congenital demyelinating–remyelinating peripheral neuropathy was congestive heart failure due to untreated hypertrophic cardiomyopathy and nonorganic malnutrition of psychosocial origin.

Malnutrition is not typical of CFC syndrome children well cared for. Even though manifestations of CFC, especially the severe phenotype, include short stature and feeding problems (gastroesophageal reflux, vomiting and oral aversion gastroesophageal reflux, vomiting and/or oral aversion) requiring gastrostomy tube feedings [McDaniel and Fujimoto, 1997; Grebe and Clericuzio, 2000], weight-for-height z scores show body weight is usually proportionate to, if not increased for, height in both phenotypes. However, in the current case, weight-for-height z scores decreased progressively and were below those for both the usual and the severe phenotypes. The psychosocial pathogenesis of malnutrition in this case was evidenced by noncompliance with medications, feeding regimes and clinic appointments, severe weight loss during outpatient intervals, normal weight gain and maintenance during hospital admissions and absence of organic causes for malnutrition.

The autopsy findings in the current case included changes that have not been reported previously in CFC. Some of these are nonspecific findings and may be associated with CFC syndrome and/or malnutrition. Specifically, pancreatic islet cell hyperplasia may be associated with the neonatal macrosomia and subsequent growth failure of CFC and/or with malnutrition. As an important growth factor, insulin would be expected to play an important role in pathogenesis of islet cell hyperplasia, macrosomia at birth and malnutrition. Likewise, thymic atrophy and lymphoid depletion were probably secondary to the multiple infections typical of both CFC and malnutrition. The severity of these findings, however, may be greater than would be seen with either CFC or malnutrition alone. However, the onion bulb hypertrophy is a specific histologic hallmark for segmental demyelinating-remyelinating neuropathies. A congenital, rather than acquired, neuropathy was present in this case because the onion bulb lesions were demonstrated at age 5 months prior to the onset of malnutrition (Fig. 4). The differential diagnosis of a congenital neuropathy with onion bulb hypertrophy includes infantile phytanic acid storage disease (MIM266510 Hereditary Motor and Sensory Neuropathy type IV; infantile Refsum disease) and Charcot–Marie–Tooth hereditary neuropathy (CMT), types 1A, 1B, and 1D (MIM118220, MIM118200 Hereditary Motor and Sensory Neuropathy type I and Recessive or type III) or type 4E (MIM605253 congenital hypomyelinating neuropathy). In the absence of cerebral and cerebellar demyelination and astrocytic gliosis, other forms of infantile demyelinating neuropathies (metachromatic leukodystrophy and Krabbe disease) are untenable.

Infantile phytanic acid storage disease is a peroxisomal disease that is similar to CFC syndrome with respect to mental retardation, failure to thrive, ichthyosis, cardiomyopathy and minor facial anomalies (redundant skin folds at the neck, epicanthal folds, abnormal ears, and flattened facial profile). However, unlike CFC syndrome, it includes hypocholesterolemia, retinitis pigmentosa, accumulation of the very long chain fatty acid phytanic acid in tissues, cirrhosis and periodic acid-Schiff-positive tissue macrophages. In the current case, levels of phytanic acid were not measured, but there were no central nervous system abnormalities, retinitis pigmentosa, cirrhosis or periodic acid-Schiff-positive macrophages. In previous studies of peroxisomal function in four cases of CFC, very long chain fatty acids were normal in 100%, plasma pipecolate was normal in 75%, and medium chain free fatty acids were normal in 25% and increased in 75% of cases [Graham et al., 1989]. These findings suggest a primary abnormality of mitochondrial metabolism rather than a peroxisomal defect in cases of CFC syndrome.

The alternate differential diagnosis, Charcot–Marie–Tooth neuropathy (CMT), refers to a clinically and genetically heterogeneous group of disorders characterized by chronic motor and sensory polyneuropathy, distal muscle weakness and atrophy, frequent mild-moderate sensory loss, depressed tendon reflexes and foot deformities. Previously, the CMT variants were classified by age-of-onset, nerve conduction studies and histopathology. Currently, CMT classification is undergoing modification to focus on the mode of inheritance and the causative gene or chromosomal locus. Using the old classification, the current case is CMT3, Dejerine–Sottas syndrome/neuropathy (MIM145900) or Congenital Hypomyelinating Neuropathy. Using the new classification, the current case is CMT1 or CMT4 depending upon results of electrophysiological studies [Boerkoel et al., 2002].

Whereas some findings in this case are specific for CMT (hypertrophic peripheral neuropathy with abundant onion bulb formations in limbs and trunk and foot deformities that may precede the loss of myotatic reflexes by a few years) and some manifestations are specific for CFC (craniofacial anomalies and abnormalities of hair and teeth), there are several traits that overlap between CFC and CMT (motor and speech developmental delays, short stature, hypotonia, ptosis, strabismus, hyperkeratotic skin abnormalities, and cardiomyopathy).

Review of neurological findings in previous cases of CFC showed that the neurological signs and symptoms were nonspecific, severe, diffuse (motor and sensory, pyramidal and extra-pyramidal, cerebellar and complex cognitive functions) and inconclusive for congenital peripheral neuropathy. Nevertheless, it is interesting that despite the inherent difficulties of testing sensory functions in young mentally retarded patients, decreased responses to evoked stimuli (visual, auditory and tactile) were documented in 50% of cases tested, suggesting that the actual occurrence may be higher.

The evidence of a congenital demyelinating–remyelinating peripheral neuropathy in the current case may be a coincidental finding, or may be a previously unrecognized factor responsible for some of the manifestations typical of CFC syndrome (for example, hypotonia, polyhydramnios, sensory impairments, developmental delays in motor and speech skills, muscular atrophy, short stature, ptosis, nystagmus, strabismus, feeding difficulties and respiratory difficulties), or may be a component of a subset of CFC cases (for example, the severe phenotype). Studies of additional cases are needed.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

With great reverence we acknowledge this child, whose life must have been most unhappy and whose death, a liberation and a redeeming gift to mankind.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES