Journal of Pediatric Ophthalmology and Strabismus

Ocular Findings in Arthrogryposis Multiplex Congenita

Juan H Paez, MD; Anja Tuulonen, MD; Rina Yarom, MD; Ilan Arad, MD; Arie Zelikovitch; David Benezra, MD, PhD

Abstract

Introduction

Arthrogryposis multiplex congenita (AMC) is characterized by congenital rigidity and deformation of multiple joints. Although AMC presents with a large range of neural and muscular clinical manifestations, there is a tendency to recognize two subgroups. The neural form is most probably correlated with an autosomal dominant genetic trait,1 although an autosomal recessive pattern also has been reported.' Characteristic to the neural form of AMC is the loss of anterior horn cells.'"1 The myopathic form of AMC is characterized by diffuse myopathic changes accompanied by an increasing serum CPK and Aldolase activities. This form has been associated with an autosomal recessive pattern of inheritance."

Musculoskeletal, genitourinary, cardiovascular, gastrointestinal, and otorhinolaringological anomalies have been associated with AMC and extensively reported in the literature."" Optic atrophy. Cataract, extraocular ophthalmoplegia, trichiasis, and congenital glaucoma were observed in a few cases with AMC.'""': However, to our knowledge, a close study of the ocular condition and ophthalmological follow-up of cases with arthrogryposis multiplex congenita has not been reported.

Case Report

A.M ., a 2 1 00 gm m ale infant delivered by C-section, was the product of 35 weeks of uneventful gestation. The 35year-old mother had four previous normal pregnancies resulting in four healthy daughters (one of whom suffered from c!ub feet) and eight miscarriages. A bicornate uterus was diagnosed by contrast studies. The parents were unrelated. The present delivery followed a difficult labor attempt. The Apgar was eight at one minute. Multiple skeletal distortions were observed on delivery. These included flexion contractures of both feet and hands, marked scoliosis, dislocation of the hip joints and micrognatia. The baby was flaccid with almost no movements and had pressure sores over his ankles. Fractures of the right h u merus and femur were noted and were most probably secondary to the difficulties in extracting the baby through the C-section. Coarse rales heard over the chest were due to upper airway obstruction caused by glossoptosie. No other cardiorespiratory malformations were noted.

Laboratory tests revealed the following: Hb 17.8 mg%, HCT 56.2%, WBC 10,500, Platelets 194,000, CPK 139 units, Aldolast 41 U, pH 7.3. The blood urea, glucose, Ca, P, and electrolytes were within normal limits. The electromyography revealed a relatively good nerve conduction with a complete failure of muscular activation. EMI scan and EEG did not disclose any abnormality.

A muscle needle biopsy was performed. The material was quick-frozen in isopentane cooled with liquid nitrogen. Cryostat sections were stained with hematoxylin and eosine. VG and Gomory trichrome. In addition, reactions for ATPase at pH 9.4 and 4.3 and NADH reductase were performed. Part of the needle biopsy was placed immediately into 2.5% glutaraldehyde buffered with 0.1 M cocodylate. After post fixation with osmium and dehydration in alcohol, the material was embedded in araldite. Ultrathin sections stained with uranyl and lead acetate were viewed with Phillips 400 Electron microscope.

Results

Ophthalmic Findings: Thorough ophthalmological examinations were performed for the first time 24 hours after delivery and once weekly thereafter. The globe and the palpebral fissures were normal and the eyelids showed full movements. The conjunctiva was normal, the corneas were clear, and the blinking reflex was brisk following a gentle touch on the center of the cornea in both eyes. The pupils were regular and reacted well to light. The lens and vitreous were normal. Indirect ophthalmoscopy disclosed slightly pale discs with sharp margins. A Bergmeister' s remnant on the papilla of the RE also was observed. The retinal reflexes, color, and vessels appeared within normal limits for this age (Figure 1).

Discussion

Miscellaneous ophthalmological manifestations have seldom been observed in association with AMC" : Among these, most…

Introduction

Arthrogryposis multiplex congenita (AMC) is characterized by congenital rigidity and deformation of multiple joints. Although AMC presents with a large range of neural and muscular clinical manifestations, there is a tendency to recognize two subgroups. The neural form is most probably correlated with an autosomal dominant genetic trait,1 although an autosomal recessive pattern also has been reported.' Characteristic to the neural form of AMC is the loss of anterior horn cells.'"1 The myopathic form of AMC is characterized by diffuse myopathic changes accompanied by an increasing serum CPK and Aldolase activities. This form has been associated with an autosomal recessive pattern of inheritance."

Musculoskeletal, genitourinary, cardiovascular, gastrointestinal, and otorhinolaringological anomalies have been associated with AMC and extensively reported in the literature."" Optic atrophy. Cataract, extraocular ophthalmoplegia, trichiasis, and congenital glaucoma were observed in a few cases with AMC.'""': However, to our knowledge, a close study of the ocular condition and ophthalmological follow-up of cases with arthrogryposis multiplex congenita has not been reported.

Case Report

A.M ., a 2 1 00 gm m ale infant delivered by C-section, was the product of 35 weeks of uneventful gestation. The 35year-old mother had four previous normal pregnancies resulting in four healthy daughters (one of whom suffered from c!ub feet) and eight miscarriages. A bicornate uterus was diagnosed by contrast studies. The parents were unrelated. The present delivery followed a difficult labor attempt. The Apgar was eight at one minute. Multiple skeletal distortions were observed on delivery. These included flexion contractures of both feet and hands, marked scoliosis, dislocation of the hip joints and micrognatia. The baby was flaccid with almost no movements and had pressure sores over his ankles. Fractures of the right h u merus and femur were noted and were most probably secondary to the difficulties in extracting the baby through the C-section. Coarse rales heard over the chest were due to upper airway obstruction caused by glossoptosie. No other cardiorespiratory malformations were noted.

Laboratory tests revealed the following: Hb 17.8 mg%, HCT 56.2%, WBC 10,500, Platelets 194,000, CPK 139 units, Aldolast 41 U, pH 7.3. The blood urea, glucose, Ca, P, and electrolytes were within normal limits. The electromyography revealed a relatively good nerve conduction with a complete failure of muscular activation. EMI scan and EEG did not disclose any abnormality.

A muscle needle biopsy was performed. The material was quick-frozen in isopentane cooled with liquid nitrogen. Cryostat sections were stained with hematoxylin and eosine. VG and Gomory trichrome. In addition, reactions for ATPase at pH 9.4 and 4.3 and NADH reductase were performed. Part of the needle biopsy was placed immediately into 2.5% glutaraldehyde buffered with 0.1 M cocodylate. After post fixation with osmium and dehydration in alcohol, the material was embedded in araldite. Ultrathin sections stained with uranyl and lead acetate were viewed with Phillips 400 Electron microscope.

Results

Ophthalmic Findings: Thorough ophthalmological examinations were performed for the first time 24 hours after delivery and once weekly thereafter. The globe and the palpebral fissures were normal and the eyelids showed full movements. The conjunctiva was normal, the corneas were clear, and the blinking reflex was brisk following a gentle touch on the center of the cornea in both eyes. The pupils were regular and reacted well to light. The lens and vitreous were normal. Indirect ophthalmoscopy disclosed slightly pale discs with sharp margins. A Bergmeister' s remnant on the papilla of the RE also was observed. The retinal reflexes, color, and vessels appeared within normal limits for this age (Figure 1).

FIGURE 1: Posterior pole of both fundi at age of four weeks. A small Bergmeister papilla is observed on the disc of the right eye (A). The pattern in the left eye is within normal limits. No changes from these patterns were observed during the period of follow-up.

FIGURE 1: Posterior pole of both fundi at age of four weeks. A small Bergmeister papilla is observed on the disc of the right eye (A). The pattern in the left eye is within normal limits. No changes from these patterns were observed during the period of follow-up.

The intraocular pressure was 12 ± 3 mm Hg in both eyes. On skiascopy a slight hypermétropie of +2.50 spheres in both eyes was found. The ocular movements were full and doll's maneuver elicited normal responses. Figure 2 shows the child at four weeks of age. B-scan ultrasonography demonstrated that the two eye globes were of equal size with an AP diameter of 20.5 mm. No abnormal ultrasonic response was elicited from the left eye while in the right eye the hyaloid remnant could be demonstrated (Figure 3). The ERG and VEP responses at this stage were both within normal limits.

During the follow-up, we observed the development of a progressive esotropia at eight weeks of age. Along with the esotropia the corneal sensitivity decreased gradually; thus, by the age of 12 weeks a gross touch on the cornea failed to induce any blinking reflex. In order to prevent an exposure or neuropalytic keratitis, artificial tears were prescribed. Indirect ophthalmoscopy did not disclose any significant changes in the structure of the vitreous or in the appearance of the optic nerves. However, by the age of 16 weeks, while both the a and b waves of the ERG responses remained unchanged and within normal limits, a clear deterioration of the VEP responses was observed. This deterioration increased further on a longer follow-up, showing a lengthened latency and a gradual decrease in the amplitude of the VEP responses obtained on monocular and/ or binocular stimulations.

Muscle Biopsy Findings: Light microscopy revealed marked variability of muscle fiber diameter. Some fibers displayed a central nucleus, while others showed a piling up of a few nuclei per cell. There was an increase in interstitial cellularity. The enzyme stains failed to produce a distinct mosaic (Figure 4A). Electron microscopically, the myofibers varied in size and many appeared very small and immature with only rudimentary myofilaments (Figure 4B). In some myofibers there was degeneration of myofibrils with rows of triads and accumultation in the subsarcolemal region. In others, the myofilaments were in all directions with irregular and thickened Z lines. Folds of redundant basement membrane sometimes were seen around the myofibers and also in the interstitium (Figure 4C).

FIGURE 2: At four weeks of age, the multiple skeletal deformations, scoliosis, flexion contracture of feet and hands, and hypognatia are illustrated (A.B.C). Full and normal eye movements could be elicited at this stage (D).

FIGURE 2: At four weeks of age, the multiple skeletal deformations, scoliosis, flexion contracture of feet and hands, and hypognatia are illustrated (A.B.C). Full and normal eye movements could be elicited at this stage (D).

FIGURE 3: Ultrasonographic patterns of both eyes. The B-scan of right eye (A) demonstrates the Bergmeister remnant (R) on the right papillae with a normal unterò posterior diameter of 20.5 mm. The A- and B-scans of the left eye (B) disclosed a normal pattern of response.

FIGURE 3: Ultrasonographic patterns of both eyes. The B-scan of right eye (A) demonstrates the Bergmeister remnant (R) on the right papillae with a normal unterò posterior diameter of 20.5 mm. The A- and B-scans of the left eye (B) disclosed a normal pattern of response.

FIGURE 4: Microscopic and electron microscopic findings of the muscle needle biopsy. (A): Cryostat section showing variability of fiber size and some fiber degeneration (hematoxylin and eosin X 250). (B): Electron micrograph showing immature and degeneration fibers. Upper left myofiber has sarcoplasmic sap (S) and subsarcolemnal accumulation of glycogen (G). Lower right shows disorganized depositions of myofibrils (F) (and inset in upper right) (x 7500. inset ? 50.000/. (C): Electron micrograph showing myofiber with disorganized myofibrils (M) and thick irregular Z lines (x 12,000).

FIGURE 4: Microscopic and electron microscopic findings of the muscle needle biopsy. (A): Cryostat section showing variability of fiber size and some fiber degeneration (hematoxylin and eosin X 250). (B): Electron micrograph showing immature and degeneration fibers. Upper left myofiber has sarcoplasmic sap (S) and subsarcolemnal accumulation of glycogen (G). Lower right shows disorganized depositions of myofibrils (F) (and inset in upper right) (x 7500. inset ? 50.000/. (C): Electron micrograph showing myofiber with disorganized myofibrils (M) and thick irregular Z lines (x 12,000).

Discussion

Miscellaneous ophthalmological manifestations have seldom been observed in association with AMC" : Among these, most interesting is the external ophthalmoplegia accompanying the Mobious Syndrome. However, follow-up of the ocular condition during the course of the disease has not been studied in any of these reports. In our case, a weekly thorough ophthalmological examination disclosed that some of the ocular symptoms observed in AMC develop at a later stage of the postnatal period. Thus, during the first month of life, ocular versions were full without any apparent muscle paresis and the corneal bunking reflexes were normal. Electrophysiological responses demonstrated a normal ERG and a normal VEP pattern for this age. By the end of the second month an esotropia with a progressive bilateral paresis of the lateral recti became apparent. The paresis gradually increased and by the third month no lateral ocular movement could be obtained even after monocular occlusion. Along with the progressing paresis of the lateral recti, a decreasing corneal blinking reflex was observed. Thus, by the age of 12 weeks even a gross touch of the cornea did not elicit a blinking reflex.

The electroretinogram responses remained within normal limits during all the follow-up period. On the other hand, the visual evoked potentials which were interpreted as normal during the first three months of life, became gradually abnormal on further follow-up. In the fourth month, the visual evoked responses showed both an increase of latency and a diminished amplitude of response.

The light and electron microscopy studies of the muscle biopsy were interpreted as nonspecific and compatible with bofh neural and myopathic changes. The level of the enzymes CPK (139 units) and aldolase (41 units) are in the high upper limit of normal values (90 and 40 respectively). However, none is diagnostic for a myopathic process, although in a purely neurogenic process lower values are expected. Our clinical observations demonstrate that the sensory nerve fibers also are affected along with the motor nerve fibers. The gradual deterioration in the functions of the I, V, and VI cranial nerves as observed in our case would favor the assumption that some of the neural and/ or myopathic changes in AMC are active processes that may take place during the post-natal period. The variety of expression in the two subgroups may lead to the assumption of a multifactorial influence in which the genetic pattern of transmission of the disease and the exact etiological factors are still debatable. The anatomy of the female uterus may have a crucial influence on the development of the syndrome and its severity.' In our case, the bicornate uterus of the mother was most probably the basic underlying cause for the many miscarriages, the sibling with club feet, and our patient with the full blown syndrome of AMC. As in most published cases of AMC, our case demonstrated mixed neural and myopathic abnormalities although clinically, the neural changes were more striking.

We believe that close ophthalmological follow-up of further cases of AMC could provide a better insight into the possible crucial inciting processes and some of the important etiological factors in this syndrome.

Summary

Close ophthalmological follow-up of a case of arthrogryposis multiplex congenita disclosed a progressing paresis of the lateral recti, a gradual decrease in the corneal blinking reflex by the age of eight weeks and a clear deterioration of the visual evoked responses by the first 16 weeks of life along with preservation of normal ERG responses.

These observations are believed to represent the gradual affection of the motor and sensorial cranial nerves occurring post-natally in this case of AMC.

References

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Bibliography

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10.3928/0191-3913-19820301-04

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