Pediatric Annals

"Floppy Baby" [Oppenheim's Disease, Amyotonia Congenita]

Peggy A Hanson, MD

Abstract

HISTORICAL IMPLICATIONS

The use of the term floppy baby in the medical vocabulary was adopted promptly following its first use. The reasons are obvious. This is a nonprejudicial, descriptive term, clear to the parent and doctor alike, that gives no implication of precise diagnosis or prognosis. Historically, the use of the term amyotonia congenita had culminated in a welter of confusion. Some used it as an equivalent for Werdnig-Hoffmann disease; others used it to imply a good outcome (equivalent to the earlier Oppenheim's disease or the currently popular phrase "benign congenital hypotonia") in the case of a floppy baby, only to discover that the outcome was not benign. The term floppy baby introduces no diagnostic bias and no implication of prognosis, and every parent can understand it; it has, therefore, become a thoroughly serviceable term in the medical vocabulary. The eponym "Oppenheim's disease" and the expression "amyotonia congenita," no longer useful, should be eliminated.

DEFERRED DIAGNOSIS

Deferring diagnosis based on observation alone is important in this category of disease because experience has shown that in many instances the diagnosis will depend on specific laboratory tests. Categories statistically common in the past, such as hypotonic cerebral palsy secondary to kernicterus, are now rare. On the other hand, with changes in the art of medicine and in the availability of newer and more refined techniques, a diagnosis such as hyperglycinemia in a newborn or of central core disease in a young child can now be made promptly. The diagnosis is precise and will cany implications regarding treatment, prognosis, and genetic counseling. When treatment for even one condition is available, the urgency of establishing a precise diagnosis is increased; therefore, differential diagnosis has assumed ever-increasing importance.

DIFFERENTIAL DIAGNOSIS

The simplest correlate in the diagnosis of the floppy baby is the age of the patient. The spectrum of diseases in the newborn is different from that in the infant, and it again changes in childhood. Thus, although a given category of disease may be present at any age, some are more common at a given period. Table 1 indicates the most common diagnosis in the newborn and infant, with the designation of the organ system most prominently affected.

Certain factors are important. In the newborn period, the "sick" child may appear floppy. If there is a history of perinatal stress, the likelihood that this is an expression of "cerebral hypotonia" is increased. Such a history and the presence of spasticity are important clues in infancy as well. The child suddenly sick, jaundiced, or hypotonic in the newborn period may be just that, and a search for sepsis, meningitis, or intracranial hemorrhage is important. On the other hand, if the condition of the infant changes after feeding has begun or the child has had a significant interval in which to metabolize endogenous protein - especially if there is a positive family history - an alteration of sensorium, when observed together with hypotonia, would suggest a diagnosis of an inborn error of metabolism. Such a diagnosis must be promptly established, since dialysis and restriction of protein intake may be lifesaving. It is important to determine blood ammonia and pH as well as to perform amino acid analysis.

Congenital abnormalities, such as Down's syndrome and other chromosomal disorders, may be accompanied by hypotonia. The reversibility of the "tone" with administration of 5-OH-tryptamine has raised interesting questions regarding the origin of cerebral hypotonia. These questions are unanswered. Congenital hypothyroidism may present as a case of floppy baby. The appearance of the cretin is characteristic and the reflexes are delayed conspicuously, so that the knee jerk may be "hung…

HISTORICAL IMPLICATIONS

The use of the term floppy baby in the medical vocabulary was adopted promptly following its first use. The reasons are obvious. This is a nonprejudicial, descriptive term, clear to the parent and doctor alike, that gives no implication of precise diagnosis or prognosis. Historically, the use of the term amyotonia congenita had culminated in a welter of confusion. Some used it as an equivalent for Werdnig-Hoffmann disease; others used it to imply a good outcome (equivalent to the earlier Oppenheim's disease or the currently popular phrase "benign congenital hypotonia") in the case of a floppy baby, only to discover that the outcome was not benign. The term floppy baby introduces no diagnostic bias and no implication of prognosis, and every parent can understand it; it has, therefore, become a thoroughly serviceable term in the medical vocabulary. The eponym "Oppenheim's disease" and the expression "amyotonia congenita," no longer useful, should be eliminated.

DEFERRED DIAGNOSIS

Deferring diagnosis based on observation alone is important in this category of disease because experience has shown that in many instances the diagnosis will depend on specific laboratory tests. Categories statistically common in the past, such as hypotonic cerebral palsy secondary to kernicterus, are now rare. On the other hand, with changes in the art of medicine and in the availability of newer and more refined techniques, a diagnosis such as hyperglycinemia in a newborn or of central core disease in a young child can now be made promptly. The diagnosis is precise and will cany implications regarding treatment, prognosis, and genetic counseling. When treatment for even one condition is available, the urgency of establishing a precise diagnosis is increased; therefore, differential diagnosis has assumed ever-increasing importance.

DIFFERENTIAL DIAGNOSIS

The simplest correlate in the diagnosis of the floppy baby is the age of the patient. The spectrum of diseases in the newborn is different from that in the infant, and it again changes in childhood. Thus, although a given category of disease may be present at any age, some are more common at a given period. Table 1 indicates the most common diagnosis in the newborn and infant, with the designation of the organ system most prominently affected.

Certain factors are important. In the newborn period, the "sick" child may appear floppy. If there is a history of perinatal stress, the likelihood that this is an expression of "cerebral hypotonia" is increased. Such a history and the presence of spasticity are important clues in infancy as well. The child suddenly sick, jaundiced, or hypotonic in the newborn period may be just that, and a search for sepsis, meningitis, or intracranial hemorrhage is important. On the other hand, if the condition of the infant changes after feeding has begun or the child has had a significant interval in which to metabolize endogenous protein - especially if there is a positive family history - an alteration of sensorium, when observed together with hypotonia, would suggest a diagnosis of an inborn error of metabolism. Such a diagnosis must be promptly established, since dialysis and restriction of protein intake may be lifesaving. It is important to determine blood ammonia and pH as well as to perform amino acid analysis.

Congenital abnormalities, such as Down's syndrome and other chromosomal disorders, may be accompanied by hypotonia. The reversibility of the "tone" with administration of 5-OH-tryptamine has raised interesting questions regarding the origin of cerebral hypotonia. These questions are unanswered. Congenital hypothyroidism may present as a case of floppy baby. The appearance of the cretin is characteristic and the reflexes are delayed conspicuously, so that the knee jerk may be "hung up." Screening of the newborn for thyroid deficiency is so important that it has been introduced into "routine" newborn screening.

Table

TABLE 1FLOPPY BABY SYNDROME: ANATOMIC CORRELATES

TABLE 1

FLOPPY BABY SYNDROME: ANATOMIC CORRELATES

NEUROMUSCULAR DISEASES

These are areas familiar to the pediatrician. The area in which he may feel more uncomfortable is in the diagnosis of diseases affecting the spinal cord, lower motor neuron, peripheral nerve, and muscle. In which of these can a specific diagnosis be made and on the basis of which tests? What is the reliability of the diagnosis?

A discrepancy between the alertness of the child and his immobility is often a first clue. This can be seen particularly in a spinal cord injury. Such patients are often alert, but with paralysis and absent reflexes, a sensory level may be difficult to establish in a newborn. In the severe case following a traumatic delivery, especially a breech delivery, diagnosis may be simple. But increasingly minor degrees of spinal cord injury have been observed at autopsy on newborns; therefore, the index of suspicion for spinal cord lesions should be increased. Suspicion generally permits a diagnosis to be made. Although laboratory studies are of limited use, the spinal fluid may contain blood, and patulous sphincters and abnormality of sensation confirm the diagnosis. After an initial period of spinal cord shock. the deep tendon reflexes may become hyperactive. The presence of an extensor plantar response, being normal in a young infant, is of no diagnostic help.

Statistically, spinal muscular atrophy, or Werdnig-Hoffmann disease, has been one of the most important diagnostic categories. Studies have changed our concepts in the spectrum of spinal muscular atrophy, and it is now apparent that many cases may not be fatal but may show progression or arrest of the disease.1,2 However, it is well established that the infant with onset of the disease under six months of age has a mortality of greater than 95 per cent.3 Parents may be appropriately counseled in this regard.

With what security can this diagnosis be made? The electromyogram is unreliable in the newborn period. The clinical pattern of weakness may be more reliable. This is generally characterized by proximal weakness and sparing of the extraocular muscles and the diaphragm. However, cases presenting with diaphragmatic paralysis have recently been described.4 Muscle biopsy may establish the diagnosis, but there are certain caveats. Sampling error often produces a biopsy with uniformly small fibers. Our recent experience with a patient with a reversible neuromuscular disorder characterized by small fibers makes the diagnosis on fiber size alone hazardous. For a firm diagnosis, one should clearly see two populations of fibers, one large and one small. The existence of a third population of medium size has been emphasized by Dubowitz. Interpretation of biopsies should, therefore, be made by someone competent and experienced in the examination of biopsies from infants. The problem of obtaining an appropriate sample in the infant may present a surgical challenge. Such surgery should be delegated to someone familiar with the problem. Before surgery, a soft-tissue x-ray of the thigh verifies the presence of muscle.

MYOTONIC DYSTROPHY

What other neuromuscular disorders are common in the newborn? Myotonic dystrophy has emerged as one of the commonest disorders in this period.5 Clinically, there tend to be two groups, the severely affected and the milder cases. In the former, death is not uncommon and respiratory support or tube feeding is often required. According to a recent analysis of these cases, it appears that only patients whose mother is the affected parent can present with the severe form of neonatal myotonic dystrophy. This suggests that there is an additional factor produced by intrauterine exposure to the maternal disorder. This is useful in establishing a diagnosis because the mother will have demonstrable myotonia even if the diagnosis was not established before her pregnancy. Therefore, examination of the parents assumes an important part in the study of these patients.

Electromyography and even muscle biopsy may be less reliable in establishing the diagnosis in the infant. Electrical myotonia is often not present at birth. In one patient whom we followed, electrical myotonia did not emerge until seven years of age and clinical myotonia was delayed even longer. Biopsy findings have been varied. Primary involvement of type I fibers is common to biopsies in every age group. In the severe neonatal myotonic dystrophy, signs of immaturity or growth arrest - namely, myotubes* and central nuclei - have been described. Thus, the muscle biopsy may well be suggestive but is never unequivocal in the diagnosis of myotonic dystrophy, and examination of the parents is important. In the milder form of myotonic dystrophy, either parent may carry the genetic defect; the patient usually shows spontaneous improvement for several years despite the eventual evolution of typical myotonic dystrophy.

FIBER-TYPE DISPROPORTION

Other diseases in which hypotonia and weakness are the major features may show disproportion in the size or number of muscle fiber types. Histochemical fiber typing of frozen muscle is the only way to establish the diagnosis of fiber-type disproportion.6 In such cases there may be only a single fiber type, with histochemical reactions common to both type 1 and type II fibers. Both type I and type II hypotrophy have been described. This diagnosis has clinical importance because, although initial weakness may be profound, patients with fiber-type disproportion usually have a nonprogressive course and tend to reach motor landmarks. Many cases are autosomal recessive.

CONQENrTAL MYOPATHIES

The same nonprogressive course is present in certain myopathies with characteristic morphologic and histochemical markers. These include central core fibers,7* myotubes,8 nemaline rods,9** and reducing bodies. 10+ These diagnoses depend primarily on morphologic studies of muscle biopsies. At least two patients have now been described in whom striking abnormalities of muscle biopsy at birth, accompanied by severe hypotonia, have had a regressive course, with eventual normalization of the biopsy and the clinical muscle strength. In one case, conspicuous abnormalities of mitochondria, glycogen, and lipid were present.11 Another was characterized by microfibers and ophthalmoplegia.12 Undoubtedly, further studies in the newborn will elucidate more such diseases.

CONGENITAL MUSCULAR DYSTROPHY

In general, proximal weakness is more common than distal weakness in childhood myopathies. In nemaline myopathy and myotonic dystrophy, there may be distal weakness as well. But distal weakness may be present in patients with myopathic diagnosis that does not fit one of the well-characterized diseases. We have observed a patient (Figure 1) with absence of flexor muscles of the hand and feet who had little evidence of proximal weakness. Biopsy disclosed generalized skeletal muscle involvement (Figure 2). Clinically, the feet were described as rocker-bottom because of the unique distribution of weakness, which was not appreciated by the examiners. Casts were applied to the feet at birth, and a diagnosis of a generalized disorder was overlooked .

Figure 1. Infant with "congenital muscular dystrophy" with absent flexor muscles of hands and feet.

Figure 1. Infant with "congenital muscular dystrophy" with absent flexor muscles of hands and feet.

Children with muscle weakness and normal intelligence may compensate in various ways for their weakness, and specific muscle testing is required to demonstrate the characteristic pattern of distribution of the weakness. In many such patients the muscle biopsy changes are described as "myopathic," but they may be limited to variation in fiber size or replacement by connective tissue. To such patients, a diagnosis of congenital muscular dystrophy has often been applied. Many such patients have been inadequately studied and may actually have fibertype disproportion or congenital myopathies, described above. Generally, the course in these patients is nonprogressive, bearing out the probable relationship with other, more clearly defined entities. In the absence of demonstrable morphologic markers, this diagnosis will probably continue to be made. It is important with such patients, therefore, to pay special attention to the clinical characteristics, which may separate them from other groups.

MYASTHENIA GRAVIS

The diagnosis of myasthenia gravis in the newborn is important because treatment may be lifesaving. Two forms are described. In neonatal myasthenia, the mother is affected and the duration of the disease in the newborn is limited to six or eight weeks. Treatment with neostigmine prevents death, and the patient remains well thereafter. So-called congenital myasthenia is generally of later onset, but cases with neonatal onset have been described. In these patients, ocular involvement is more prominent - a feature generally absent in neonatal myasthenia. Again, specific treatment may be lifesaving.

Figure 2. Biopsy of the same patient, illustrating increase in fiber si2e variation and in amount of connective tissue.

Figure 2. Biopsy of the same patient, illustrating increase in fiber si2e variation and in amount of connective tissue.

ORTHOPEDIC DEFORMITIES

An orthopedic deformity may be the first clue to a diagnosis of neuromuscular disease. Arthrogryposis (persistent contraction of a muscle) is the result of intrauterine weakness and is associated with myopathy or neuropathy. In most cases there is little evidence of generalized muscle weakness, and the course is nonprogressive. Congenital dislocation of the hips is common in central core disease. As we have described above, patients with peripheral weakness may be diagnosed as having club foot and casts may be applied without adequate investigation. Patients and families with a history of orthopedic deformities may have a higher incidence of malignant hyperthermia. Therefore, adequate study of patients with orthopedic deformities is indicated, especially if they are accompanied by poor muscle tone or weakness.

GENETIC COUNSELING

A diagnosis of congenital muscular dystrophy is generally alarming to parents, who picture a relentlessly progressive disease, such as Duchenne's muscular dystrophy. Although some patients may be severely affected, a nonprogressive course is common, and cases with a good outcome have been described. It is, therefore, important to be careful in discussing the findings of muscle biopsy with the parents. In cases that are well delineated, genetic counseling may be appropriate. It is true that most neuromuscular diseases that appear in the newborn period have genetic implications. However, if one is in doubt about the implications of laboratory studies in such a patient, one must be careful not to apply the alarming term muscular dystrophy when talking with the parents. Less prejudicial terms, such as myopathy or congenital neuromuscular disorder, may prevent unnecessary panic.

BENIGN CONGENITAL HYPOTONIA

A last consideration is the child with apparently normal intelligence, severe hypotonia, and a normal muscle biopsy. In the infant, intelligence may be difficult to assess. A patient who subsequently develops PraderWilli syndrome may have profound hypotonia and areflexia and require tube feeding at birth. Only after recovery of motor function does the mild retardation accompanying this syndrome become apparent. One patient with profound hypotonia in the first six months of life had proven to have Ehlers-Danlos syndrome, due to a hydroxylysine deficiency. Thus, the patient in whom one is tempted to make a diagnosis of benign congenital hypotonia deserves careful study and repeated evaluation. It is likely that a precise diagnosis can be established in most of these patients. The category of benign congenital hypotonia represents a constantly dwindling group, and the diagnosis should be viewed with suspicion. The prognosis should remain guarded when one is counseling the parents.

CEREBRAL HYPOTONIA

We have emphasized the importance of adequate laboratory studies in newborns with weakness or hypotonia in whom there is no evidence of central nervous system abnormality. The infant who presents with weakness and hypotonia at six months to one year may represent a special circumstance. If there is a history of perinatal stress, one may make a tentative diagnosis of cerebral hypotonia. In the presence of spasticity and hyperreflexia, this diagnosis may be more certain.

If there is developmental delay, a presumptive diagnosis of cerebral hypotonia may be made and laboratory investigation may be safely delayed. If an infant has good fine motor control and no clear-cut proximal weakness in the presence of modest hypotonia, no harm can be done by waiting for that child to stand and walk, whereupon muscle weakness will become more apparent. The presence of a progressive mental retardation and hypotonia should alert the pediatrician to the possibility of a degenerative disease, such as metachromatic leukodystrophy and Krabbe's disease.* In such patients, nerve conduction velocities may give a clue to peripheral nerve involvement while the child demonstrates a deteriorating or static mental development.

ACQUIRED WEAKNESS

Acquired muscle weakness is an urgent indication for diagnostic studies and an exception to the rule described above. The child who will not walk in the morning and has progressive muscle atrophy may well have juvenile rheumatoid arthritis. In young children, pain may not be a complaint. The same is true of dermatomyositis with prominent muscle weakness or dysphagia. The incidence of myositis increases after three years of age. Skin lesions should be carefully sought in children with acquired weakness at this age. Patients with modestly progressive proximal muscle weakness may turn out to have polyneuritis or even a form of spinal muscular atrophy, and it is urgent that diagnostic studies be undertaken. Distinction of these patients from those with classical Duchenne's muscular dystrophy is simple on the basis of serum creatine Phosphokinase (CPK) determination, which is much higher in the latter disease than in any of the other entities described. Pseudohypertrophy is not limited to Duchenne's muscular dystrophy but is more prominent in these patients.

With the increase of routine determinations of CPK as part of a "profile" of laboratory studies, there are patients in whom interpretation of an increased CPK may be the only diagnostic problem. The screening of these patients is important; if the elevation is significant and persistent, a thorough diagnostic workup may be indicated for the entire family. In one group of such patients, myopathic changes were found on biopsy but the clinical course was benign. Such families may be at risk for malignant hyperthermia. Careful explanation of the limits of our knowledge is important in counseling the families of such patients, and it is important that they be studied over long periods.

The floppy baby is, therefore, an increasingly important pediatric problem and a diagnostic challenge. He can no longer be dismissed with the reassuring attitude that he will outgrow it or with the more pessimistic outlook that the child really has cerebral palsy. Precise diagnosis should always be attempted, and the child should be followed carefully. Either the concern will be justified, because of the developmental delay for which the parents have been properly alerted, or the disease can be delineated by laboratory findings. With increasingly precise delineation of new syndromes, some may prove treatable and many will have genetic implications that can be outlined to the parents. In the long run, the parent will come to understand and be grateful for this conservative and careful approach.

BIBLIOGRAPHY

1 . Emery. A. E. H. The nosology of the spinal muscular atrophies. J. Med. Genet. 8 (1971). 481-495.

2. Munsat. T. L., et al. Neurogenic muscular atrophy of infancy with prolonged survival. Brain 92 (1969). 9-24.

3. Pearn, J. H.. Carter, C. 0.. and Wilson. J. The genetic identity of acute infantile spinal muscular atrophy. Brain 96 (1973), 463-470.

4. Nellis. R. B., et al. Respiratory distress as an initial manifestation of Werdnig-Hoffmann disease. Pediatrics 53 (1974), 33-40.

5. Dubowitz, V., and Brooke, M. H. Myotonic dystrophy. In Muscle Biopsy: A Modern Approach. Philadelphia: W. B. Saunders Company. 1973. pp. 213-227.

6. Dubowitz. V., and Brooke, M. H. Congenital fiber type disproportion. In Muscle Biopsy: A Modem Approach. Philadelphia: W. B. Saunders Company. 1973. pp. 280-288.

7. Shy. G. M., and Magee. K. R. A new congenital non- progressive myopathy. Brain 79 (1956), 610-621.

8. Spiro. A. J.. Shy. G. M.. and Gonatas, N. K. Myotubular myopathy. Arch. Neurol. 14 (1966), 1-14.

9. Shy, G. M-, et al. Nemaline myopathy: A new congenital myopathy. Brain 86 (1963). 793-810.

10. Brooke. M. H.. and Neville. H. E. Reducing body myopathy. Neurology 22 (1972), 829-840.

11. Jerusalem, F., et al. Mitochondria, lipid, glycogen (MLG) disease of muscle: A morphologically regressive congenital myopathy. Arch. Neurol. 29 (1973), 162-169.

12. Hanson. P. A.. Mastrianni. A. F., and Post. L Neonatal ophthalmoplegia with microfibers. Neurology (in press).

TABLE 1

FLOPPY BABY SYNDROME: ANATOMIC CORRELATES

10.3928/0090-4481-19770301-08

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