Original Article

Congenital Hypotonia: Is There an Algorithm?

Darja Paro-Panjan, MD, MSc; David Neubauer, MD, PhD

ABSTRACT

This study was performed with the aim of determining the diagnostic profile of newborns with hypotonia and of analyz-
ing the usefulness of different procedures in the diagnostic process. One hundred thirty-eight hypotonic newborns were
identified through the search of hospital records in a 10-year period: 121 (88%) had central hypotonia and 13 (9%) had
peripheral hypotonia, whereas 4 (3%) remained unclassified. Analysis of the contribution of clinical data and results of
investigations led to the construction of an algorithm, by which all cases in the group were diagnosed. Step 1, which
included clinical data and results of examinations, solved 50% of all diagnosed cases. Neuroimaging techniques made up
step 2 and contributed to the diagnosis in 13%. Step 3 was accomplished by a search through Oxford Medical Databases,
which yielded the final diagnosis in 9%, whereas karyotyping and fluorescent in situ hybridization for Prader-Willi syn-
drome comprised step 4 and contributed to the diagnosis in 6.5%. Biochemical tests formed step 5 and contributed to the
diagnosis in 6%. Step 6, which included specific investigations of muscle and nerve, was diagnostic in 6%. The remaining
cases (6.5%) were diagnosed only after several follow-up examinations. These results could assist the neonatologist when

deciding the diagnostic approach to floppy newborns. ( J Child Neurol 2004;19:439-442).

Congenital hypotonia is a frequent diagnosis in the newborn tissue disorders. Because a knowledge of the relative fre-
period. However, it is rather poorly defmed as a &dquo;subjective quency of particular disorders that present with hypotonia
decrease of resistance to passive range of motion in a new- might help to select appropriate investigations, our aim
born.&dquo;1 It can involve different systems: brain, muscles, and was to gain an insight into the diagnostic profile of neonates
connective tissue. Because it can be a sign of a serious presenting with hypotonia and to ascertain whether a step-
abnormality with the possible risk of malignant hyperther- wise algorithm in the diagnostic process of hypotonic new-
mia or other specific risks in some neuromuscular disorders, born can be proposed.
it is essential that a specific diagnosis be made.2 Reasons for
an accurate diagnosis also include the genetic implications MATERIAL AND METHODS
for the family, prognosis, interventional approach, and
empowerment of the family in terms of their autonomy in A retrospective study of newborns with hypotonia was performed
making decisions in relation to their child. Several longitu- on the Neonatal Department of Ijubljana University Children’s
dinal studies support the opinion that the majority of hypo- Hospital through a search of hospital discharge records. New-

tonic newborns are floppy because of central nervous borns included in the study were bom between June 1992 and June
system dysfunction; some hypotonic newborns have genetic 2002, and their predominant problem was hypotonia, as confirmed
disorders and metabolic disturbances, whereas the minor- clinically by the attending neonatologist. Hypotonia was observed
ity of hypotonic infants have neuromuscular and connective throughout the child’s hospital stay at the Neonatal Department.
The criteria used by the neonatologist to define hypotonia were that
the hypotonic child looked floppy, felt floppy, and had hyperex-
tensible joints. The neonatologist reviewed all of the hospital
Received July 7, 2003. Received revised Oct 21, 2003. Accepted for publi-
cation Oct 28, 2003. charts of the identified patients, and the pediatric neurologist
From the Departments of Neonatology (Dr Paro-Panjan) and Child, searched through the registry of the Neurological Department’s out-
Adolescent and Developmental Neurology (Dr Neubauer), University patient files with the aim of gaining an insight into the carious
Children’s Hospital Ljubljana, Ljubljana, Slovenia.
pathologies contributing to the &dquo;congenital hypotonia complex.&dquo;
Address correspondence to Dr David Neubauer, Department of Child,
The final diagnosis of each patient was obtained from a review of
Adolescent and Developmental Neurology, University Children’s Hospital
Ljubljana, Vrazov trg 1, SI-1525 Ljubljana, Slovenia. Tel: + 386 1 5229273; the entire inpatient and outpatient charts by both investigators, who
fax: + 386 1 5229357; e-mail: [email protected]. then reached a consensus. Hypotonia was classified as central or

439
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440

peripheral according to the clinical findings (quality of antigrav- Table 1. Types of Hypotonia, Diagnoses, and Number of Cases
ity limb movements, deep tendon reflexes, and the child’s psy-
chosocial response), the results of investigations, and the opinion
of the clinical geneticist. Central hypotonia included hypoxic-
ischemic encephalopathy and other encephalopathies, brain insults,
and intracranial hemorrhage, as well as chromosomal disorders,
congenital syndromes, inborn errors of metabolism, and neu-
rometabolic diseases. Among peripheral disorders, cases with a pri-
mary lesion in the motor unit-anterior hom cell, peripheral nerve,
neuromuscular junction, and muscle-were classified. After clas-
sification, the clinical data and all investigations relevant to the diag-
nosis were recorded, with the aim of performing a stepwise
algorithm of investigations by which all of the cases in the group
could be diagnosed.

RESULTS

The search through hospital records generated 138 hypotonic

newborns, 78 boys and 60 girls, with a gestational age
between 35 and 41 weeks. One hundred thirty-four cases
were classified, whereas 4 (3%) remained unclassifiable

and/or were lost to follow-up. The diagnostic findings are

summarized in Table 1. In 121 hypotonic newborns (88%),
the hypotonia was classified as central. Forty-one infants had
chromosomal abnormalities, 34 had hypoxic-ischemic
encephalopathy, 13 had different dysmorphic syndromes, 10
had intracranial hemorrhage, 8 had metabolic disorders, CDG congenital defect of glycosylation; CMD congenital myotonic dystrophy;
= =

CP cerebral palsy; DMD Duchenne muscular dystrophy; HIC intracranial

= = =

and 4 had Prader-Willi syndrome, whereas the other patholo- hemorrhage; HIE hypoxic-ischemic encephalopathy; PKU phenylketonuria;
= =

gies were less frequent. Thirteen children (9%) were clas- SMA spinal muscular atrophy.
=

sified as having a peripheral disorder: three cases had

anterior horn cell disease, one had neuropathy, and one
had a neuromuscular junction disorder. Eight children had
a muscle disorder. included specific nerve and muscle investigations: serum
After the analysis of the contribution of clinical data and creatine kinase levels, electromyography, and nerve con-
particular investigations to the final diagnosis in each patient, duction velocities, as well as DNA markers for spinal mus-
a stepwise algorithm was constructed. In the first step, cular atrophy, congenital myotonic dystrophy, Duchenne
which included family history, pregnancy and delivery data, muscular dystrophy, and muscle biopsy with mitochondri-
and clinical and neurologic examinations, 69 (50%) cases al enzymes. It comprised eight (6%) cases. The remaining
were classified. Within this step, a large proportion of hypo- nine cases (6.5%) were diagnosed only after several follow-
tonia cases were found to be due to central nervous system up examinations and some repeated investigations. Steps
impairment, but there were also 36 cases of trisomy 21 in the clinical pathway (algorithm) to the final diagnosis in
(because trisomy 21 was evident on clinical examination and the whole group are shown in Figure 1.
was later confirmed by karyotyping). Neuroradiologic inves-

tigations~omputed tomography (CT), magnetic resonance DISCUSSION

imaging (MRI), and magnetic resonance spectroscopy
(MRS)-which contributed to the diagnosis in 18 (13%) There are several possible approaches to the broad umbrella
children with central nervous system involvement, com- of the floppy newborn syndrome. The criteria for classifi-
prised the second step. The third step, which included a care- cation used were similar to those described in the study of
ful search through Oxford Medical DatabaseS7 (both Richer et ail. They studied a group of neonates admitted to
dysmorphology and neurogenetics) and consideration of the the intensive care unit and found that 66% had central
clinical geneticist’s opinion, yielded the fmal diagnosis in causes and 34% had peripheral causes of hypotonia. The

13 (9%) cases. Step 4, which included karyotyping and the study by Eng included infants between 0 and 3 years; his
fluorescent in situ hybridization test for Prader-Willi syn- results approaches ours because he found 85% central
drome, contributed to the diagnosis in nine (6.5°l0) cases. Bio- causes and 15% peripheral causes of muscle tone distur-
chemical investigations (including those for inborn errors bances.8 Because our group included more children with
of metabolism) formed the fifth step and were conclusive chromosomal abnormalities, the number of cases of cen-
for the final diagnosis in a further eight cases (6%). Step 6 tral hypotonia was higher. The same studies also revealed

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 441

Figure 1. Steps in the clinical pathway to the

final diagnosis. CDG congenital defect of glyco-
=

sylation ; CK serum creatine kinase; CMD con-

= =

genital myotonic dystrophy; CP cerebral palsy;

=

CT =
computed tomography; DMD Duchenne
=

muscular dystrophy; EMG =

electromyography;
FISH = fluorescent in situ hybridization; Gal-1-PUT
=
galactose-1-phosphouridyl transferase deficiency;
HIC = intracranial hemorrhage; HIE = hypoxic-
ischemic encephalopathy; MRI/MRS = magnetic
resonance imaging/magnetic resonance spec-

troscopy ; n.m neuromuscular; PKU phenylke-

= =

tonuria ; NCV nerve conduction velocity; SMA

= =

spinal muscular atrophy.

a high number of cerebral palsy cases,8 which could also most common in both studies The reason for the rather
be the case in our study if we reviewed the outcome because high number of cases of Prader-Willi syndrome is probably
45 of 53 cases with brain impairment showed encephalopa- due to the already well-established fact that this syndrome
thy owing to perinatal causes. The contribution of other primarily presents with prominent hypotonia during the
pathologies to the hypotonia complex in our group is sim- neonatal and infantile period&dquo; and also to the ax-aflability
ilar to that in the study of Richer et al; they found 9 of 50 of genetic testing by the fluorescent in situ hybridization
syndromic disorders, with Prader-Willi syndr ome being the technique.

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442

We share the opinion of authors who stressed that ation, and the use of dysmorphology databases enabled us

those rare newborns with a probable peripheral cause of flop- to recognize the majority (59%) of hypotonia cases in the
piness should be studied in detail: from simple clinical tests studied group during the newborn period. The selective
(shaking hands and other easily performed tests in moth- use of neuroimaging and genetic and biochemical meth-

ersl°) to neurophysiologic tests, muscle biopsy with mito- ods contributed to the diagnosis in another 25.5%, whereas
chondrial enzymes, and molecular DNA tests.:2-6 The highest neurophysiologic investigations, specific molecular tests, and
proportion of cases in our peripheral hypotonia group com- muscle biopsy contributed to the diagnosis in 6% of hypo-
prise cases of SMA and CMD.6 It is quite interesting that we tonic newborns. However, some cases (eg, congenital myas-
also found one case with Duchenne muscular dystrophy, thenic syndromes, some severe hypotonic forms of cerebral
which is usually not found so early because hypotonia is not palsy, and syndromes of joint hyperlaxity) were diagnosed
a presenting sign during the neonatal period. 1,11 This new- only after close follow-up and frequent repetition of some
born had mild axial hypotonia, exhibited the Marcus Gunn neurophysiologic investigations.
phenomenon, and was found to have an extremely high
serum creatine kinase level, which prompted DNA study for Acknowledgment
Duchenne muscular dystrophy. This proved positive, and the We thank Dr Dianne Jones for English revision of the manuscript.
diagnosis was definitely confirmed at about 1 year of age by
typical biopsy findings. 12 Contrary to the study of Dua et al, References
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