Sjiigren-Larsson-like Syndrome with Bone Dysplasia and Normal Fatty Alcohol NAD + Oxidoreductase Activity E m m a n u e l Scalais, MD*, A l a i n V e r l o e s , M D t , J e a n - P a u l S a c r 6 , MD*, G 6 r a l d E. P i 6 r a r d , M D , PhD§, a n d W i l l i a m B. Rizzo, MD~ A

We report a boy and girl with a "new" multiple congenital anomalies/mental retardation syndrome which resemblances Sj6gren-Larsson syndrome. Both patients had a concordant pattern of anomalies consisting of congenital lamellar ichthyosis with spontaneous improvement, moderate mental retardation, mild pyramidal involvement, telecanthus, flat facies, stubby long bones, and coxa valga. Severe myopia, ventriculoseptal defect, and postaxial polydactyly were present in the girl who had more severe bone involvement with dense, enlarged metaphyses, vertebral dysplasia, and advanced skeletal maturation of the lower limbs. Longchain fatty alcohol NAD + oxidoreductase (FAO) and steroid sulfatase were normal. Scalais E, Verloes A, Sacr6 JP, Pi6rard GE, Rizzo WB. Sj6gren-Larsson-like syndrome with bone dysplasia and normal fatty alcohol NAD+ oxidoreductase activity. Pediatr Neurol 1992;8:459-65.

Introduction Since the initial description of a syndrome of congenital ichthyosis, mental retardation, and spastic di/tetraplegia by Sj6gren and Larsson in 1957 [1], about 150 patients have been recognized, mainly in the V~isterbotten county of

From the *Department of Pediatrics; tCentre for Human Genetics; Liege University; Centre Hospitalier Saint Joseph-Esp6runce; Rocourt, Belgium; Departments of ~:Dermatopathology and §Paediatrics; Salt Tilman University Hospital; Liege, Belgium; ~Department of Pediatrics; Medicine College of Virginia; Richmond, Virginia.

B

Figure 1. Patient 1 soon after birth. Note collodion membrane: (A) face and (B) right hand.

Communications should be addressed to: Dr. Verloes; Centre de G6n6tique Humaine; Pathologie B23; C.H.U. Sart Tilman. (B) 4000 Libge, Belgium. Received September 13, 1991; accepted March 31, 1992.

Scalais et al: Congenital Ichthyosis and MR 459

normal FAO activity suggesting that they were allecled b~ another genetically distinct disease. Case Reports Patient I. This patienl (genetic file #5235) was h~wn al 3~ weeks gestation after a normal pregnancy. Birth weight was 25110 gm (5()th percentile), length 46 cm (50th percentile), and head circumference 34 cm 175th percentile). Apgar score was 9 at 1 and 5 rain, She had the features of a collodion infant (Figs I A, I B), unilateral upper l imh postaxial polydactyly, and a ventriculoseptal defect (VSD). Fundus examination was unremarkable. Electroencephalography (EEGI demonstrated some sharp waves. Icbthyosis almost completely healed within a few weeks. At age 4 years, her VSD had closed, but mitral prolapse, grade I, was observed. High-grade myopia was observed (-14 D bilaterally), with horizontal fixation nystagmus, choroidal atrophy, and slight xerosis, but no cataract. Hearing was normal. Areas of scaly, dr3' skin remained only on the neck, abdomen, and genitalia. Hair and nails were normal. Psychomotor milestones were delayed. She first walked after 2 years of age. Speech development was abnormal with predominantly expressive disturbances. She did not have seizures. At age 9 years, her height was 124.5 cm (-1 S.D.), weight 25.6 kg (mean), and head circumference 51.9 cm (mean). No dysmorphic features were observed, except for a somewhat flat face with receding chin and small mandible (Figs 2A,2B). Fine, dry scales were present in the external auditory canal and on the scalp, but hardly visible on the trunk. Hair and nails were normal. She had genu valga. Neurologic examination revealed increased deep tendon reflexes and unsustained ankle clonus. Elicitation of plantar reflexes disclosed a mildly delayed dorsiflexion of the great toes, considered mildly extensor. Cranial nerves were normal. Horizontal nystagmus persisted. There was no dysmetria or ataxia, but a mild tremor was manifest. Alternating movements were slow; gait was not ataxic. Coordination of fine movements was poor and she was unable to tie her shoes. No glistening white dots

Table 1.

Electrophysiologic data of Patients 1 and 2 Patient 1 Right

Patient 2 Left

Right

Left

1.6 4.3 6.3 4.7* 1.1

1.9 4.2 6.5 4.6* 1.2

Brainstem Auditory Evoked Potentials (ms) Wave Wave Wave Wave Wave

I III V V-I W/I

1.6 3.9 6.0 4.3 1.5

1.7 4.0 6.0 4.3 0.7

Somatosensory Evoked Potentials (ms) Median nerve Erb point N13 N20 CCT

Figure 2. Patient 1, age 9 yearsu (A) face and (B) profile. Flat square face and receeding chin. Note normal appearance of the skin.

Sweden where its prevalence could be as high as 1 in 12,000. Sj6gren-Larsson syndrome (SLS) has also been found in many other parts of the world with a much lower frequency [2]. The recent discovery of the biochemical basis of the disease (i.e., fatty alcohol N A D + oxidoreductase [FAO] deficiency in typical SLS patients) has allowed assessment of the homogeneity of the syndrome. We report 2 siblings with a phenotype suggestive of SLS, but with

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Tibial nerve SNAP N19 (spinal) P1 CCT

7.4 10.0 20.0* 10.1"

7.6 19.1 20.8* 10.7"

8.0 9.8 20.0* 10.2"

8.0 t0.2 19.6" 9.4*

-16.6"

-16.8'

-13.8

6.7 t6.0

42.0* 25.4*

43.2* 26.4*

46:8* 33.0*

44.4* 28.4*

* Values exceeding the upper limits. Abbreviations: CCT = Central conduction time (N20-NI3, PI-NI9) SNAP = Sensory nerve action potential

Figure 3. Patient I at birth. (A) Lower left limb, and (B) lateral view of the spine. Note dark, stubby bones and widened metaphysis and advanced epiphyseal maturation. were observed on funduscopic examination. She had moderate mental deficiency. Computed tomography (CT) and EEG were normal. Magnetic resonance imaging was not performed. Brainstem auditory evoked potentials revealed a normal interpeak latency (interval I-V) and a conductive anomaly (mild threshold elevation; Table 1). Patternreversal visual evoked potentials demonstrated delayed latencies (PI: 116 ms - upper limit 110 ms), and somatosensory evoked potentials disclosed an increased central conduction time (Table 1) compatible with an impairment of myelinated tracts. At birth, radiography disclosed short, stubby long bones with enlarged and dense metaphyses, most impressive in the lower limbs, in which the maturation of the ossification centers was very advanced (Figs 3A,3B). Vertebral bodies were irregular and slightly flattened at the thoracic level. An anterior notch was visible. By age 4 years, the bone shape was less massive, but bilateral coxa valga persisted. Metaphyses remained enlarged. Epiphyses were normally shaped (Fig 4A). At 9 years of age, radiography demonstrated a minimal lumbar scoliosis and mild distal tibial bowing. Flat epiphyses were observed in the hands (Fig 4B). Premature fusion of a cone-shaped epiphysis was observed on the first distal phalanx. Bone age using the Tanner score was compatible with chronologic age. A shave skin biopsy was taken from the ann soon after birth. There was thick orthokeratosis with two superposed aspects. The superficial stratum corneum was lamellar to compact, while the deep portion was loose with a basket-weave appearance (Fig 5). Adnexal openings were hyperkeratotic. The stratum Malpighi and the stratum granulosum were unremarkable. Immunohistochemical stainings for cytokeratins 48-60 kD and 56-64 kD were normal. Hair was normal when examined under light and polarized microscopy. Metabolic studies, including serum amino acids, urinary organic acids, mucopolysaccharides, oligosaccharides, plasma phytanic acid, serum LH, and FSH, were normal. Plasma very long-chain fatty acid and phytanic acid were within the normal range. Lymphocytic karyotype using fluorescent (QFQ) banding was normal, 46,XX.

This girl was the first child of nonconsanguineous European (French/Belgian) parents. The father was 31-years-old and the mother age 16 years. She was 150 cm tall (-2 S.D.). Both were of borderline intelligence. Her karyotype had a pericentric inversion of the heterochromatic part of chromosome 19. She had two mentally deficient brothers, one of whom had an aortic coarctation and hydronephrosis. They were not examined by us. Patient 2. This boy is the only sibling of Patient 1. He was born 2 years after Patient 1, at 37 weeks gestation, by breech presentation: birth weight 3,310 gm (75th percentile), length 49.5 cm (75th percentile), and head circumference 36 cm (95th percentile). Apgar scores were 6 at 1 min and 9 at 5 min. He had the same features of a collodion infant as his sister, but had no other malformations. Neonatal fundus examination and EEG were unremarkable. Skin manifestations cleared within a few weeks with topical treatment, but areas of dry, scaly skin persisted throughout infancy. Hypotonia was prominent during the first months of life. Developmental milestones were delayed. He first walked after age 2 years. Walking ability improved with age but his gait remained unsteady. At age 3V2 years, his language was restricted to a few words. EEG was slow with some sharp waves. Spastic paraplegia was suspected at 4 years of age. Esophageal chalasia, responsible for recurrent bronchitis, required medical treatment. Ophthalmologic examination revealed a moderate myopia. When evaluated at age 7 years, height was 125 cm (+ 1 S.D.), weight 23.9 kg (mean), and head circumference 51.8 cm (mean). Physical findings were similar to his sister's and he had the same facial appearance (Fig 6). Thick, dry scales were observed in the external auditory canal. Cardiorespiratory status was normal. There was no visceromegaly. Genitalia were normally developed. Neurologic examination disclosed increased deep tendon reflexes and mild ankle clonus. Plantar reflexes were similar to his sister's. Cranial nerves were normal. There was no dysmetria or ataxia. Gait was not ataxic but he fell frequently; hopping on one foot was impossible on

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461

Figure 6.

B Figure 4. Patient 1. (A) Left lower limb at age 4 years. at age 5 years. Note flat epiphyses.

(B) Hand

the left side. Coordination was poor and he failed to isolate individual finger movements properly. He had a moderate mental deficiency. Funduscopic examination did not reveal glistening white dots. CT was normal. EEG was of the moderately abnormal range (slow-and-sharp-

Patient 2 at age 7 years.

waves), but a convulsive disorder was never ob~r~,ed. Brainstem auditory evoked potentials revealed increased interpeak latency (I-V; Table 1) suggestive of an impairment of the myelinated tracts. Pattern-reversal evoked potentials were not performed because of po~,r cooperation. Using flash visual evoked potentials after stimulation of each eye separately, a poorly reproducible waveform with normal cortical component latency was observed (N70:74 ms). Somatosensory evoked potenrials demonstrated an increased central conduction time compatible with an impairment of the conduction in the myelinated tracts. Bone anomalies were less striking than in his sister. In early infancy, bones were stubby, but metaphyses were not dense. A severe bilateral coxa valga was observed (Fig 7) but became less apparent with time. Bilateral hypoplasia of the internal aspect of the tibial epiphyseal plate was observed. Bone age was compatible with chronologic age. A shave skin biopsy of the arm revealed the presence of a striking lamellar orthokeratosis covering a stratum Malpighi of normal thickness (Fig 8). The stratum granulosum was focally 3-4 cells thick but otherwise apparently normal, hnmunohistochemical staining for cytokeratins 48-60 kD and 56-64 kD did not reveal any anomaly. Karyotype disclosed the inv(19) observed in his mother. The following results were normal: serum amino acids, cholesterol. HDL cholesterol, LDL cholesterol, triglycerides, fasting glucose, urinary organic acids, mucopolysaccharides, oligosaccharides, and plasma phytanic acid. Plasma very long-chain fatty acids were normal. Sweat test was repeatedly within the high normal range (chloride 40-60 mEq/L). Urine metabolic screening was normal. Enzymatic Investigations. In cultured fibroblasts of Patient 2, enzymatic activity of FAO was 57.6 - pmoles/min/mg protein (normal: 75.1 + 13.4 pmoles/mirdmg) and activity of fatty aldehyde dehydrogenase was 9.84 nmoles/min/mg protein (normal: 8.54 +-- 1.15 nmoles/min/mg).

Discussion Figure 5. Patient 1. Shave skin biopsy at 1 week. Note hyperkeratosis of the foUicle: original magnification, xlO0.

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Both children had a concordant pattern of anomalies, consisting of congenital lameUar ichthyosis with a benign