Rational Diagnostic Evaluation of the Child With Mental Deficiency David W.
Smith, MD, F. Estelle R. Simons,
\s=b\ Evaluation of a mentally deficient child should be individualized, using findings from an appropriate history and physical examination. Depending on these findings the patient may be assigned to one of four subcategories, as determined by clinical indications and the patient's age at onset of the problem. These categories are (1) prenatal problem of morphogenesis, (2) perinatal insult to brain, (3) postnatal onset of brain dysfunction, and (4) undecided age at onset. This subcategorization has relevance to the type of diagnostic studies that may be indicated. Using this approach, a retrospective study of the diagnostic evaluations of 98 mentally deficient children was performed. Ninety percent of these children were considered to have had "nonrational" laboratory tests, and of these, none contributed to elucidation of the basic diagnosis. The only tests that were valuable had been indicated by a specific historical or physical finding in addition to mental deficiency. (Am J Dis Child 129:1285-1290, 1975)
MD
Given a patient with evidence of mental deficiency, what is a rational diagnostic evaluation? Which of the
myriad laboratory, roentgenographic, and other specialized studies that have been of diagnostic value in some patients with the sign of mental defi¬ ciency should be done in a particular patient? One approach toward a rational diagnostic evaluation of the child with mental deficiency is presented here. The evaluation begins with an appropriate history and physical ex¬ amination, as shown in the following outline, and does not include any rou¬ tine laboratory investigation. This outline is obviously biased by our ex¬ perience and approach. A.
Family (genetic) history: This is of in¬ creasing importance, both for diag¬ nosis and counseling. Kaveggia et al1 estimated that nearly one half of the 1,224 seriously mentally deficient pa¬ tients whom they evaluated had geneti¬ cally determined disorders. Many of these were sporadic occurrences, such autosomal trisomies. However, the history disclosed similarly affected in¬ dividuals in 9% of the families and it was estimated that 10% of the parents had a high (5% to 50%) recurrence risk for a similarly affected offspring in the future. 1. Pedigree: Search specifically for a problem similar to that of the pa¬ tient in first-degree relatives (sib¬ lings and parents) and second-de¬ gree relatives (aunts, uncles, first cousins, and grandparents). For au¬ tosomal dominant and X-linked dis¬ orders and for chromosomal translocation disorders, the pedigree should be more extensive. Mis¬ carriages and stillbirths should be noted and consanguinity excluded. 2. Parental ages at birth of patient: Older maternal age is a factor in chromosomal trisomy syndromes, and older paternal age is a factor in certain fresh mutant gene disorderssuch as the Apert syndrome and acas
is a sign of a in function. Though is often un¬ the least several hun¬ there are at known, dred recognized disorders in which mental deficiency is a feature. A spe¬ cific overall diagnosis may be of con¬ siderable value in delineating the prognosis and care of the patient and genetic counsel for his parents. This report is devoted only to the initial objective of diagnosis for the child with mental deficiency and does not deal with the broader objective of the habilitation of the mentally handi¬
deficiency Mental problem primary diagnosis
capped child. Received for publication Aug 5,1974; accepted Nov 4. From the Dysmorphology Unit, Department of Pediatrics, University of Washington, Seattle. Reprint requests to Department of Pediatrics, University of Washington School of Medicine, RR234 Health Sciences RD-20, Seattle, WA 98195 (Dr Smith).
rodysostosis.
Downloaded From: http://archpedi.jamanetwork.com/ by a UQ Library User on 06/16/2015
3. Parental levels of intelligence and head circumference: This informa¬ tion is especially important for in¬ stances of mild mental deficiency or mild microcephaly, which may be fa¬ milial. Also, particularly when the mother is mentally deficient, the possibility of her having unrecog¬
nized phenylketonuria (PKU) should be considered.' Such women, if un¬ treated during pregnancy, have a high frequency of mentally deficient
offspring.'
B. Cultural-social history: Low socioeconomic status may play a role in mild degrees of mental deficiency. It may also be a factor in the occurrence of
prematurity, prenatal cytomegalovirus
infection, maternal alcoholism, and en¬ vironmental and emotional depriva¬ tion, each of which may be associated with mental deficiency in the offspring. C. Prenatal history: 1. Fetal activity should be noted, both in terms of time of onset and vigor. 2. Gestational problems, such as early threatened miscarriage, severe tox¬ emia, diabetes mellitus with ketoaci-
dosis, chronic alcoholism,3
or
rubella
exposure or disease during the first four months, may be relevant. 3. Maternal gestational weight gain should be recorded. 4. Duration of gestation is pertinent. D. Perinatal history: 1. Birth presentation is noteworthy, since problems of morphogenesis and neurological function are more common in fetuses who fail to as¬ sume the vertex position. 2. The amount and character of amni¬ otic fluid is of interest. Polyhydramnios may occur with neuro¬ logical deficits resulting in impaired swallowing, and meconium-stained fluid may be evidence of perinatal distress. 3. Head circumference and body length and weight at birth are im¬ portant. Fetal growth deficiency represents a congenital anomaly of overall size and is not uncommonly accompanied by other problems in morphogenesis, including that of the
brain.
4. Note the
Apgar
scores
function in terms of
sucking.
and
crying
early and
EVIDENCE OF MENTAL DEFICIENCY
5. Problems such
as placenta previa, delivery, prolonged hypoxia, apneic spells, seizures, hyperbilirubinemia, symptomatic hypoglycemia, or sepsis should be
traumatic
recorded. Postnatal history: 1. Describe developmental progress and central nervous system (CNS) function, including presence or ab¬ sence of behavior problems, seizures and neurological aberrations, and the patient's age at onset of slow or
deteriorating developmental
APPROPRIATE HISTORY AND PHYSICAL EXAMINATION
1
PRENATAL ONSET OF PROBLEM IN MORPHOGENESIS
2
prog¬
3
POSTNATAL ONSET
PERINATAL ONSET OF INSULT TO BRAIN
4
UNDECIDED
ress.
2. Postnatal events that might have been a cause of the developmental lag should be recorded. 3. General growth rate, changes in physical features, and illnesses also merit inquiry. Examination: Length and weight as re¬ lated to normal standards should be noted. The remaining examination should be divided into the indirect eval¬ uation of brain and brain function and the non-CNS evaluation. 1. Indirect assessment of brain and brain function: Measure head cir¬ cumference and relate it to normal standards. Transilluminate, note shape of cranium, and evaluate scalp hair patterning. Recent studies have implied that scalp hair directional patterning is determined at 10 to 16 weeks of fetal life by the growth and shape of the underlying brain; hence, aberrant scalp hair pattern¬ ing may be used as a clue toward an early fetal problem in brain morphogenesis."-7 Examine the ocular fundus following dilation of the pu¬ pils, as this is the one area in which neural tissue can be directly viewed. Assess CNS function and record developmental age, neurological status, and behavioral patterns. 2. Complete non-CNS examination for major and minor anomalies: Scruti¬ nize the entire body carefully for anomalies, including sensory defi¬ ciencies. For any given minor anom¬ aly, including unusual dermatoglyphic findings, determine whether it is a usual feature in otherwise normal family members before as¬ cribing importance to the anomaly. For any major anomaly, an effort should be made to interpret whether it was of prenatal onset or not. Fi¬ nally, when there is a pattern of al¬ tered morphogenesis in the patient,
Initial
approach toward evaluation of child with mental deficiency.
attempt should be made to deter¬ mine whether the non-CNS anom¬ alies are secondary to a primary brain defect, or whether they repre¬ sent multiple primary defects of morphogenesis. Hand and foot po¬ sitional deformities and scoliosis, for example, may be secondary to neu¬ an
rological deficits. If the combined findings of such a history and physical examination have not resulted in a specific diag¬ nosis, they will usually allow for subcategorization of the patient into one of the four clinical groupings outlined in the Figure, each of which merits a somewhat different approach toward further diagnostic evaluation. These four categories will be briefly dis¬ cussed, as will the types of diagnostic evaluation indicated within each of them. Cases of prenatal infectious disease or of hypothyroidism may oc¬ cur clinically in more than one of the four groups, and therefore these dis¬ orders will be discussed separately. Prenatal Problem in
Morphogenesis
Delineation.—This category is a large one, constituting 44% of the 1,224 more severely mentally defi¬ cient patients studied by Kaveggia et al.1 About one third of the patients in this category were considered to have a single defect in the develop¬ ment of the brain, such as primary
microcephaly, hydrocephaly, hydranencephaly, a defect of neural tube closure,
or
dysgenesis.
other types of cerebral The other two thirds had
Downloaded From: http://archpedi.jamanetwork.com/ by a UQ Library User on 06/16/2015
multiple major and minor malforma¬
tions of tissues other than the CNS. These malformations were inter¬ preted as evidence of a major problem in prenatal morphogenesis, and by implication the mental deficiency was also considered to be due to a defect in early morphogenesis. Within this multiple defect subcategory, 41% of patients had chromosomal abnormal¬ ities, most having trisomy 21. Eigh¬ teen percent had known syndromes of nonchromosomal cause, and the other 41% had unknown patterns of malfor¬ mation.
Diagnostic Laboratory Evaluation.— patients interpreted as having a single primary defect of brain de¬ velopment, a pneumoencephalogram In
may be indicated in
an
effort to
accurately determine the
more
nature and
extent of the defect in brain
mor¬
phogenesis, especially in hydrocephalus. In other defects it may pro¬ vide insight into the prognosis and may be helpful in genetic counseling. In patients with multiple congeni¬ tal anomalies, not interpreted as being secondary to a primary brain anomaly, the following steps should
be taken: 1. In patients with known chromo¬ somal abnormality syndromes, chro¬ mosomal studies should be done both to confirm the diagnosis and for genetic counseling purposes. If the patient has an unbalanced set of chromosomes because of chromosomal breakage, then both parents should
be studied to determine whether one of them is a balanced carrier of the chromosomal rearrangement with a consequent high recurrence risk. 2. In patients with known nonchromosomal abnormality syndromes, fur¬ ther studies, if any, are predomi¬ nantly indicated by the past findings for the specific syndrome. 3. In patients with unknown pat¬ terns of malformation, unless the pattern of altered morphogenesis is different in type from that which oc¬ curs with chromosomal abnormalities, a chromosomal study should be con¬ sidered, ideally using chromosomal
banding techniques.
Perinatal Insult to Brain Definition.—This
category includes
hypoxemia, kernicterus, severe neo¬ natal hypoglycemia, intracerebral hemorrhage, perinatal hypoxia, men¬ ingitis, and sepsis—all more common
in the premature infant. Caution should be exercised before assuming that problems of the birth process and of perinatal adaptation are the pri¬ mary cause of mental deficiency in patients who have evidence of pre¬ natal onset of a problem in mor¬ phogenesis. Such patients, especially those who have a severe defect of early brain development and those who have prenatal onset of growth deficiency, are more likely to have problems in neonatal adaptation in¬
cluding hypoxemia, hyperbilirubinemia, and hypoglycemia. Diagnostic Laboratory
Evaluation.—
This should be done as indicated the historical findings.
by
Postnatal Onset of Brain Dysfunction
Definition.—The history will
usually
indicate normal appearance and func¬
tion at birth and subsequent slowing or deterioration of developmental progress with signs of CNS dysfunc¬ tion, sometimes accompanied by al¬ tered growth and morphogenesis. Included in this grouping are en¬ vironmental insults such as trauma,
meningitis,
encephalitis, hyperintoxication, severe severe hypoxemia, hypoglycemia, lead encephalopathy, CNS degenera¬ tive disorders, and certain enzymatic natremia,
water
defects of amino acid, carbohydrate, uric acid, mucopolysaccharide, and brain lipid metabolism. Only a few rare inborn errors of metabolism such as the Leroy I-cell disease or general¬ ized gangliosidosis8 have gross clini¬ cal manifestations by the time of birth.
Diagnostic Laboratory
Evaluation.—
Evaluation should be germane to the overall problem, as indicated by his¬ tory and physical examination. Most of the patients with recog¬ nized inborn errors of a particular en¬ zyme function resulting in mental deficiency fall into this category.
They comprise a small but important subcategory. Of the 1,224 mentally deficient patients studied by Kaveggia et al,1 4.3% had established in¬
born errors of this type, of which one third were PKU and one was galactosemia. Besides these latter two con¬ ditions, in which early recognition with dietary therapy may be of value in preventing mental deficiency, few of the other disorders can be effec¬ tively managed at the present time. For some of these inborn errors of enzyme function, there are additional clues in the history and physical ex¬ amination that can lead to a specific rationale for the pertinent metabolic study of that patient. It is often diffi¬ cult to diagnose PKU from the clini¬ cal findings, and when it is not ex¬ cluded as a possibility by the overall
findings, a
serum phenylalanine level determination is indicated. The following list gives examples of features, in addition to mental deficiency, that often occur postnatally in certain inborn errors of metabolism.8
Phenylketonuria, (autosomal recessive): Light pigmentation; eczema in one third of patients; poor coordination, seizures in one fourth of patients, autistic classical
behavior
Sanfilippo syndrome (mucopolysacchari-
dosis type III) (autosomal recessive): De¬ velopmental lag after 1 year of age with deterioration toward restless behavior, clumsiness by age 6 to 7 years; develop¬ ment of coarse facies and hair by 2 to 3 years; gum hypertrophy, mild limitation in finger extension Hurler syndrome (mucopolysaccharidosis
type I) (autosomal recessive): Develop¬ mental
lag after 6 to 10 months with dete-
Downloaded From: http://archpedi.jamanetwork.com/ by a UQ Library User on 06/16/2015
rioration and growth
deficiency, coarse facies, stiff joints, gibbus, hepatosplenomegaly, cloudy corneas, rhinitis Hunter syndrome (mucopolysaccharidosis type
II),
severe
type (X-linked
reces¬
sive): Developmental lag after 6 to 12 months with growth deficiency, coarse facies, stiff joints, hepatosplenomegaly; no gibbus or cloudy corneas Galactosemia, severe type (autosomal recessive): Development in early infancy (while being fed cow's milk) of lethargy, hypotonia, hepatomegaly, icterus, hypogly¬ cemia, cataract, with failure to thrive. Lesch-Nyhan syndrome (X-linked reces¬ sive): Development after 6 to 8 months of spasticity, choreoathetosis, self-mutilation, autistic behavior, growth deficiency; tophi in late childhood.
Homocystinuria (automsomal recessive): arachnodactyly, pectus excavatum, genu valgum, pes cavus, mild limitation of finger extension; downward lens dis¬ location, usually by age 10 years; wide fa¬ cial pores, malar flush; thrombotic phenom¬ ena contributing to CNS problems. Arginosuccinicaciduria (autosomal re¬ cessive): Onset in first one to two years of growth deficiency, mild hepatomegaly, skin lesions, dry brittle hair with trichorrhexis nodosa, seizures. Undecided Age at Onset Mild
Definition.—This
was
the second
largest group in the study of Kaveggia et al,' making up about 37% of the more seriously mentally deficient patients. These patients show no evi¬ dence of a prenatal problem in mor¬ phogenesis, have no established his¬ tory of
a
gross insult to the brain in
the
perinatal period, and are rather consistently slow in postnatal devel¬ opment. They may or may not have other evidence of CNS dysfunction, such as spasticity, hypotonia, sei¬
zures, or aberrant behavior. Within this group it is unusual to arrive at an
etiologic diagnosis.
Diagnostic Laboratory
Evaluation.—
There is seldom adequate information on which to base a rational laboratory diagnostic evaluation. It has been un¬ usual to achieve a specific diagnosis in the majority of those with severe spasticity and those with hypotonia, in the experience of Kaveggia et al.1 A buccal smear for X-chromatin is merited in boys to exclude XXY syn¬ drome, especially in those who are mildly mentally deficient and who ex¬ hibit subtle signs such as decreased
upper segment/lower segment ratio, small penis, and behavioral problems." In girls a buccal smear is merited to exclude XXX. For the other patients, exclusion of PKU is usually merited; however, there has been little value in a general screening for other recog¬
nized inborn errors of metabolism in such patients. Disorders Occurring Clinically in More Than One Category
A
patient with hypothyroidism prenatal infectious disease could set into any
one
normal size at
birth, often have os¬ immaturity of prenatal onset as evidenced by large fontanels, facial bone immaturity, and retardation in bone age.10 The diagnosis is unfortu¬ nately seldom entertained at birth, though we are aware of one unpub¬ seous
case
of Perinatal
detected at this age be¬
unusually large fontanels. problems not uncommonly include persistent indirect hyperbilirubinemia and poor feeding. Hypothyroid infants usually become increasingly sluggish in physical ac¬ tivity with slow growth and grossly retarded maturation. Myxedematous cause
fullness of the subcutaneous tissue and muscles develops in severe hypo¬ and is most noticeable in the lower part of the eyelids and tongue. Patients with such problems, compatible with hypothyroidism, mer¬ it specific thyroid function studies. The findings of mental deficiency and short stature alone, unaccompanied by other signs of hypothyroidism, are not sufficient indication for such studies. Prenatal Infectious Disease.—A his¬ tory of maternal rubella or exposure to the disease in the first four months of gestation may provide a clue to the possibility of fetal rubella disease, as may the findings of deafness, cata¬ racts, or cardiac defect in the patient. However, in cytomegalovirus and toxoplasmosis infections, the mother usually has no history of disease. One of these three disorders may be sus¬ pected on the basis of the following variable and nonspecific features in
thyroidism
retinitis, and deafness. Should some of these signs be present in a patient in whom prenatal infectious disease is suspected, tests such as direct cul¬
ture of virus
or demonstration of fluorescent IgM specific antibody or complement-fixation antibody studies are indicated.
Potential Indications for Other Studies
or
be of the above four
categories. with Hypothyroidism.—Patients congenital hypothyroidism, though of
lished
infancy: growth deficiency, micro¬ cephaly, hepatosplenomegaly, jaun¬ dice, poor feeding, petechiae, chorio-
We have alluded to indications for chromosomal studies, buccal smear for X-chromatin, pneumoencephalography, and tests for inborn errors of metabolism, hypothyroidism, and pre¬ natal infectious disease. Likewise, the following investigations should be done only when there is some indica¬ tion in addition to mental deficiency. 1. Skull roentgenograms merit con¬ sideration in a patient with clinical signs of craniosynostosis, evidence of increased incracranial pressure, cuta¬ neous signs of tuberous sclerosis or Sturge-Weber syndrome, or evidence of prenatal infectious disease, espe¬
cially toxoplasmosis. 2. Long bone roentgenograms may be indicated by clinical findings such
skeletal abnormalities. Bone age determination may be indicated in patients with decelerating growth, especially those for whom the overall findings are compatible with hypo¬ thyroidism, and in patients with ex¬ cessive rate of growth, but is of little practical value in patients with pre¬ natal onset of growth deficiency. 3. Electroencephalograms may be warranted in patients with a history of seizures or suspected seizure as
equivalent.
4. Determination of
fasting
blood glucose level merits consideration in patients with a history suggestive of hypoglycémie signs and symptoms but is not necessarily indicated for all patients with seizures. 5. Measurement of serum electro¬ lyte, uric acid, and blood urea ni¬ trogen levels; blood counts; and urinalysis should be performed only as prompted by findings in the history or examination in addition to mental
deficiency.
Downloaded From: http://archpedi.jamanetwork.com/ by a UQ Library User on 06/16/2015
SUBJECTS AND METHODS Based on the foregoing individualized approach toward the diagnostic evaluation of children with mental
deficiency, a retro¬
spective study of such children was done in
an effort to determine the number who had had "nonrational" diagnostic studies. We also wished to determine whether some of the nonrational studies did in fact contrib¬ ute to the diagnosis. One of us (F.E.R.S.) reviewed the data on 98 consecutive chil¬ dren with mental deficiency who were ex¬ amined as outpatients at the Child Devel¬ opment and Mental Retardation unit at the University of Washington from June 1970 to June 1972. These patients were se¬ lected from a total of 157 cases because they had been examined by both a pedia¬ trician and a psychologist on their initial clinic visit and had an IQ of 70 or less. The patients were not examined by us, except for some of those having patterns of mal¬ formation, who were seen in consultation. Thirty-two percent had an IQ below 50 and the other 68% had an IQ between 50 and 70. The evaluation was related to manage¬ ment and counseling as well as to diag¬ nosis, but only the diagnostic studies were reviewed for this report. The case histories and results of physical examinations were analyzed and on this basis a decision was made as to which of the aforementioned four categories the patient fit and which of the studies ordered were rational and which were considered nonrational. The re¬ sults were then reviewed and a determina¬ tion was made as to which studies had been of value relative to the overall diag¬ nosis, or at least of some ancillary value in the general health assessment of the pa¬ tient. Regarding the four age-at-onset categories, 53% of the patients were inter¬ preted as having a problem of prenatal on¬ set (category 1), 3% had mental deficiency as a result of a presumed perinatal insult (category 2), 4% were deficient because of postnatal damage (category 3), and in 40% the age at onset was undecided (category
4).
RESULTS
It was obvious that the diagnostic evaluation of these patients had been relatively individualized. Beyond a
urinalysis, no single laboratory study
had been done in more than half of the patients. The Table shows a sum¬ mation of the studies. None of the 87 patients having a nonrational diag¬ nostic test had a result that was valu¬ able toward a specific mental defi¬ ciency diagnosis, including the 47 who had nonrational urine studies search-
ing for evidence of an inborn error of metabolism. Only one nonrational test was of ancillary value for the patient: this child was discovered to have mild iron deficiency anemia, though the history and examination had not indicated such a possibility.
Laboratory Studies in 98 Children With Rational Indication*
The
foregoing approach
toward
Studies Urinary study for amino acids and abnormal metabolites Chromosome study Buccal smear
a
to
Diagnosis
No.
No. Valuable to Diagnosis
47 16
Skull roentgenograms Other skeletal roent¬ genograms
men¬
tal deficiency is corroborated by the small retrospective study cited above. More importantly, it is supported by studies in which routine diagnostic determinations were done on a much larger number of mentally deficient patients. Judith Dey, MD, of the Grosvenor Diagnostic and Assess¬ ment Clinic, which evaluates the ma¬ jority of individuals with mental defi¬ ciency in New South Wales, told one of us (D.W.S.) in 1973 that results of routine serum calcium, phosphorus, and uric acid tests and blood glucose tests have been normal in more than 2,000 patients except in those patients who had an indication for doing the study in addition to mental deficiency alone. As a result of this experience, the first three tests cited are no longer routinely performed. Routine skull and wrist roentgenograms have been normal in more than 4,000 pa¬ tients, except in those few patients in whom an abnormality was suspected prior to the roentgenographic study. Further comment is merited re¬ garding the largest group of patients, in category 1, who are considered to have a prenatal problem in morpho¬ genesis of the brain. This consid¬ eration may be based on direct evi¬ dence of brain malformation or on the indirect basis of multiple nonCNS congenital defects in morpho¬ genesis. The latter discrimination is often dependent on a careful total physical examination with the pur¬ pose of detecting minor as well as major anomalies. For example, Smith and Bostian11 studied 50 consecutive patients with idiopathic mental defi¬ ciency, 31 (62%) of whom had an IQ below 50, and found that 21 (42%) of them had three or more associated major or minor anomalies of prenatal onset vs none with three or more
No.
(X-chromatin)
individualized rational labora¬
tory evaluation of patients with
Nonrational Indication*
No. Valuable
COMMENT more
Mental Deficiency
Electroencephalogram
10
Serum protein-bound iodine or T, Serum electrolytes, etcf
Complete blood cell urinalysis
count
1*
27 75
Routine
Based on findings in history and physical examination. t Laboratory tests Including blood glucose, uric acid, blood *
level determinations. t One patient was found to have iron
nitrogen,
and
electrolyte
deficiency anemia.
anomalies in 100 control children without mental deficiency who were examined concurrently. This finding was interpreted as evidence that a large proportion of patients with seri¬ ous idiopathic mental deficiency have had a prenatal onset of the problem and that the prenatal cause of the non-CNS malformations, though un¬ known, was also the cause of the men¬ tal deficiency. The more direct find¬ ings of Crome12 strongly suggest that a high proportion of patients with undiagnosed severe mental deficiency have a malformation of early brain development. Crome examined brains at necropsy from 282 patients with severe mental deficiency. Two thirds of the group did not have a recog¬ nized syndrome, and of these all but 4.3% had a morphological brain alter¬ ation, the majority of which could be interpreted as being of prenatal on¬ set. Many patients with prenatal de¬ fects of brain development that are not apparent by physical examination probably fall into category 4, the "un¬ decided" group. Thus, the frequency with which mental deficiency is due to a prenatal problem in brain mor¬ phogenesis is probably higher than the 44% implicated by Kaveggia et al1 or the 53% in the present study. Diagnostic laboratory studies likely to prove useful in patients with pre¬ natal onset of a problem in morpho-
Downloaded From: http://archpedi.jamanetwork.com/ by a UQ Library User on 06/16/2015
urea
genesis are limited to chromosomal studies, viral or toxoplasmosis stud¬ ies, or roentgenograms. To our knowl¬ edge, there is seldom an indication for urinary and serum studies search¬ ing for known metabolic inborn er¬ rors of metabolism in patients in category 1. Kaveggia et al1 have re¬ ported studies of urinary amino acids, sugars, Índoles, and imidazoles, plus special determinations for PKU, cystine/homocystine, and mucopoly-
saccharides in more than 600 men¬ tally deficient patients with evidence of prenatal onset of altered mor¬ phogenesis, and not one study was of diagnostic value. Furthermore, though other investigators have screened for metabolic abnormali¬ ties in large numbers of mentally deficient patients, those with pre¬ natal onset of aberrant morpho¬ genesis have not been included in their positive results. Carson and Neill11 have emphasized the low yield of metabolic disorders in unselected screening of patients with mental
deficiency.
The experience of the MR-Metabolic Clinic at the University of Cali¬ fornia in San Francisco is of special relevance to the above comments, as related by Byran Hall, MD (written communication, 1973). This clinic was originally established for the meta¬ bolic evaluation of referred patients
with mental deficiency with no recog¬ nized syndrome and no evident cause for their mental deficiency. In this clinic, routine metabolic studies de¬ signed to detect virtually all known metabolic causes of mental deficiency include eight different serum chem¬ ical tests, six urine spot tests, urine amino acid analysis by ion exchange chromatography, and combined gas
chromatographic/mass spectrometric urine screening for abnormal organic acids. During an eight-month period 72 patients were evaluated, a few of whom had a previously established diagnosis, such as one with known PKU. The only new metabolic diag¬ nosis made during this time, that of the Sanfilippo syndrome, had been clinically suspected by Hall before the laboratory results were known. De¬ spite the nature of this clinic, 40% of the patients examined had a multiple congenital anomaly syndrome. Judg¬ ing from his experience in that clinic, Hall is in agreement with the individ¬ ualized diagnostic approach set forth in this article. As new knowledge has evolved re¬ garding the numerous causes of men-
tal
deficiency,
there has been an in¬ in the number of potential diagnostic studies that can be done. Some physicians and clinics tend to use a "complete battery" of diagnos¬ tic studies for almost all mentally deficient children. On the basis of ex¬ perience and the knowledge accrued in recent years, we believe that the diagnostic studies employed for a particular patient should be based on a rational interpretation of an appro¬ priate history and physical examina¬ tion on that patient. This approach rarely requires hospitalization of the patient, and metabolic, endocrinolog¬ ie, or roentgenographic studies are in¬ frequently indicated. This approach in no way detracts from the potential value of making a specific diagnosis in the child with mental deficiency. Such a diagnosis usually has value in management, prognosis, and genetic counseling. For cases of genetically determined inborn errors of metabolism, it is in¬ creasingly important to make a spe¬ cific diagnosis of the enzyme defect where feasible. For an ever greater number of such defects, it is possible crease
to detect the enzyme defect in cul¬ tured fetal fibroblasts obtained by amniocentesis in early gestation, ter¬ minate the affected prognancy, and thereby prevent the birth of another affected child in that family. This approach is presented both from a pragmatic standpoint and also as a challenge to those who might dis¬ agree with it. The rational diagnostic evaluation of the child with mental deficiency should continue to evolve on the basis of new knowledge and experience. We welcome additional knowledge or experience that would substantially support or change this
approach.
This investigation was supported by project 913 from the Maternal and Child Health Ser¬ vices, Health Services and Mental Adminis¬ tration, US Department of Health, Education and Welfare; by Public Health Service grant HD 05961; and by the National Foundation-March of Dimes. John M. Opitz, MD, and William L. Nyhan, MD, provided critical reviews of this article. Lyle Harrah provided library research; Mary Ann Harvey, editorial assitance; Christine Hansen, secretarial assistance. The University of Washington Child Development and Mental Re¬ tardation Unit gave their cooperation.
References 1. Kaveggia EG, Durkin MV, Pendleton E, et al: Diagnostic genetic studies on 1,224 patients with severe mental retardation. Read before the Third Congress of the International Association for Scientific Study of Mental Deficiency, The Hague, Sept 4-12, 1973. 2. Jones KL, Smith DW, Harvey MA, et al: Older paternal age and presumed fresh mutant gene disorders: Additional data. J Pediatr 86:84\x=req-\ 88, 1975. 3. Perry TL, Hansen S, Tischler B, et al: Unrecognized adult phenylketonuria. N Engl J Med 289:395-398, 1973. 4. Menkes JH, Aeberhard E: Maternal phenylketonuria. J Pediatr 74:924-931, 1969.
5. Jones KL, Smith DW, Ulleland CN, et al: Pattern of malformation in offspring of chronic alcoholic mothers. Lancet 1:1267-1271, 1973. 6. Smith DW, Gong BT: Scalp hair patterning as a clue to early fetal brain development. J Pediatr 83:374-378, 1973. 7. Smith DW, Gong BT: Scalp-hair patterning: Its origin and significance relative to early brain and upper facial development. Teratology 9:17\x=req-\ 34, 1974. 8. Holmes LB, Moser HW, Halld\l=o'\rssonS, et al: Mental Retardation: An Atlas of Diseases With Associated Physical Abnormalities. New York, Macmillan Co, 1972. 9. Caldwell PD, Smith DW: The XXY (Kline-
Downloaded From: http://archpedi.jamanetwork.com/ by a UQ Library User on 06/16/2015
felter's) syndrome in childhood: Detection and 80:250-258, 1972. 10. Smith DW, Popich G: Large fontanels in congenital hypothyroidism: A potential clue toward earlier recognition. J Pediatr 80:753-756, treatment. J Pediatr
1972. 11. Smith DW, Bostian KD: Congenital anomalies associated with idiopathic mental retardation. J Pediatr 65:189-196, 1964. 12. Crome L: The brain and mental retardation. Br Med J 1:897-904, 1960. 13. Carson NAJ, Neill DW: Metabolic abnormalities detected in a survey of mentally backward individuals in northern Ireland. Arch Dis Child 37:505-513, 1962.
Smith, MD, F. Estelle R. Simons,
\s=b\ Evaluation of a mentally deficient child should be individualized, using findings from an appropriate history and physical examination. Depending on these findings the patient may be assigned to one of four subcategories, as determined by clinical indications and the patient's age at onset of the problem. These categories are (1) prenatal problem of morphogenesis, (2) perinatal insult to brain, (3) postnatal onset of brain dysfunction, and (4) undecided age at onset. This subcategorization has relevance to the type of diagnostic studies that may be indicated. Using this approach, a retrospective study of the diagnostic evaluations of 98 mentally deficient children was performed. Ninety percent of these children were considered to have had "nonrational" laboratory tests, and of these, none contributed to elucidation of the basic diagnosis. The only tests that were valuable had been indicated by a specific historical or physical finding in addition to mental deficiency. (Am J Dis Child 129:1285-1290, 1975)
MD
Given a patient with evidence of mental deficiency, what is a rational diagnostic evaluation? Which of the
myriad laboratory, roentgenographic, and other specialized studies that have been of diagnostic value in some patients with the sign of mental defi¬ ciency should be done in a particular patient? One approach toward a rational diagnostic evaluation of the child with mental deficiency is presented here. The evaluation begins with an appropriate history and physical ex¬ amination, as shown in the following outline, and does not include any rou¬ tine laboratory investigation. This outline is obviously biased by our ex¬ perience and approach. A.
Family (genetic) history: This is of in¬ creasing importance, both for diag¬ nosis and counseling. Kaveggia et al1 estimated that nearly one half of the 1,224 seriously mentally deficient pa¬ tients whom they evaluated had geneti¬ cally determined disorders. Many of these were sporadic occurrences, such autosomal trisomies. However, the history disclosed similarly affected in¬ dividuals in 9% of the families and it was estimated that 10% of the parents had a high (5% to 50%) recurrence risk for a similarly affected offspring in the future. 1. Pedigree: Search specifically for a problem similar to that of the pa¬ tient in first-degree relatives (sib¬ lings and parents) and second-de¬ gree relatives (aunts, uncles, first cousins, and grandparents). For au¬ tosomal dominant and X-linked dis¬ orders and for chromosomal translocation disorders, the pedigree should be more extensive. Mis¬ carriages and stillbirths should be noted and consanguinity excluded. 2. Parental ages at birth of patient: Older maternal age is a factor in chromosomal trisomy syndromes, and older paternal age is a factor in certain fresh mutant gene disorderssuch as the Apert syndrome and acas
is a sign of a in function. Though is often un¬ the least several hun¬ there are at known, dred recognized disorders in which mental deficiency is a feature. A spe¬ cific overall diagnosis may be of con¬ siderable value in delineating the prognosis and care of the patient and genetic counsel for his parents. This report is devoted only to the initial objective of diagnosis for the child with mental deficiency and does not deal with the broader objective of the habilitation of the mentally handi¬
deficiency Mental problem primary diagnosis
capped child. Received for publication Aug 5,1974; accepted Nov 4. From the Dysmorphology Unit, Department of Pediatrics, University of Washington, Seattle. Reprint requests to Department of Pediatrics, University of Washington School of Medicine, RR234 Health Sciences RD-20, Seattle, WA 98195 (Dr Smith).
rodysostosis.
Downloaded From: http://archpedi.jamanetwork.com/ by a UQ Library User on 06/16/2015
3. Parental levels of intelligence and head circumference: This informa¬ tion is especially important for in¬ stances of mild mental deficiency or mild microcephaly, which may be fa¬ milial. Also, particularly when the mother is mentally deficient, the possibility of her having unrecog¬
nized phenylketonuria (PKU) should be considered.' Such women, if un¬ treated during pregnancy, have a high frequency of mentally deficient
offspring.'
B. Cultural-social history: Low socioeconomic status may play a role in mild degrees of mental deficiency. It may also be a factor in the occurrence of
prematurity, prenatal cytomegalovirus
infection, maternal alcoholism, and en¬ vironmental and emotional depriva¬ tion, each of which may be associated with mental deficiency in the offspring. C. Prenatal history: 1. Fetal activity should be noted, both in terms of time of onset and vigor. 2. Gestational problems, such as early threatened miscarriage, severe tox¬ emia, diabetes mellitus with ketoaci-
dosis, chronic alcoholism,3
or
rubella
exposure or disease during the first four months, may be relevant. 3. Maternal gestational weight gain should be recorded. 4. Duration of gestation is pertinent. D. Perinatal history: 1. Birth presentation is noteworthy, since problems of morphogenesis and neurological function are more common in fetuses who fail to as¬ sume the vertex position. 2. The amount and character of amni¬ otic fluid is of interest. Polyhydramnios may occur with neuro¬ logical deficits resulting in impaired swallowing, and meconium-stained fluid may be evidence of perinatal distress. 3. Head circumference and body length and weight at birth are im¬ portant. Fetal growth deficiency represents a congenital anomaly of overall size and is not uncommonly accompanied by other problems in morphogenesis, including that of the
brain.
4. Note the
Apgar
scores
function in terms of
sucking.
and
crying
early and
EVIDENCE OF MENTAL DEFICIENCY
5. Problems such
as placenta previa, delivery, prolonged hypoxia, apneic spells, seizures, hyperbilirubinemia, symptomatic hypoglycemia, or sepsis should be
traumatic
recorded. Postnatal history: 1. Describe developmental progress and central nervous system (CNS) function, including presence or ab¬ sence of behavior problems, seizures and neurological aberrations, and the patient's age at onset of slow or
deteriorating developmental
APPROPRIATE HISTORY AND PHYSICAL EXAMINATION
1
PRENATAL ONSET OF PROBLEM IN MORPHOGENESIS
2
prog¬
3
POSTNATAL ONSET
PERINATAL ONSET OF INSULT TO BRAIN
4
UNDECIDED
ress.
2. Postnatal events that might have been a cause of the developmental lag should be recorded. 3. General growth rate, changes in physical features, and illnesses also merit inquiry. Examination: Length and weight as re¬ lated to normal standards should be noted. The remaining examination should be divided into the indirect eval¬ uation of brain and brain function and the non-CNS evaluation. 1. Indirect assessment of brain and brain function: Measure head cir¬ cumference and relate it to normal standards. Transilluminate, note shape of cranium, and evaluate scalp hair patterning. Recent studies have implied that scalp hair directional patterning is determined at 10 to 16 weeks of fetal life by the growth and shape of the underlying brain; hence, aberrant scalp hair pattern¬ ing may be used as a clue toward an early fetal problem in brain morphogenesis."-7 Examine the ocular fundus following dilation of the pu¬ pils, as this is the one area in which neural tissue can be directly viewed. Assess CNS function and record developmental age, neurological status, and behavioral patterns. 2. Complete non-CNS examination for major and minor anomalies: Scruti¬ nize the entire body carefully for anomalies, including sensory defi¬ ciencies. For any given minor anom¬ aly, including unusual dermatoglyphic findings, determine whether it is a usual feature in otherwise normal family members before as¬ cribing importance to the anomaly. For any major anomaly, an effort should be made to interpret whether it was of prenatal onset or not. Fi¬ nally, when there is a pattern of al¬ tered morphogenesis in the patient,
Initial
approach toward evaluation of child with mental deficiency.
attempt should be made to deter¬ mine whether the non-CNS anom¬ alies are secondary to a primary brain defect, or whether they repre¬ sent multiple primary defects of morphogenesis. Hand and foot po¬ sitional deformities and scoliosis, for example, may be secondary to neu¬ an
rological deficits. If the combined findings of such a history and physical examination have not resulted in a specific diag¬ nosis, they will usually allow for subcategorization of the patient into one of the four clinical groupings outlined in the Figure, each of which merits a somewhat different approach toward further diagnostic evaluation. These four categories will be briefly dis¬ cussed, as will the types of diagnostic evaluation indicated within each of them. Cases of prenatal infectious disease or of hypothyroidism may oc¬ cur clinically in more than one of the four groups, and therefore these dis¬ orders will be discussed separately. Prenatal Problem in
Morphogenesis
Delineation.—This category is a large one, constituting 44% of the 1,224 more severely mentally defi¬ cient patients studied by Kaveggia et al.1 About one third of the patients in this category were considered to have a single defect in the develop¬ ment of the brain, such as primary
microcephaly, hydrocephaly, hydranencephaly, a defect of neural tube closure,
or
dysgenesis.
other types of cerebral The other two thirds had
Downloaded From: http://archpedi.jamanetwork.com/ by a UQ Library User on 06/16/2015
multiple major and minor malforma¬
tions of tissues other than the CNS. These malformations were inter¬ preted as evidence of a major problem in prenatal morphogenesis, and by implication the mental deficiency was also considered to be due to a defect in early morphogenesis. Within this multiple defect subcategory, 41% of patients had chromosomal abnormal¬ ities, most having trisomy 21. Eigh¬ teen percent had known syndromes of nonchromosomal cause, and the other 41% had unknown patterns of malfor¬ mation.
Diagnostic Laboratory Evaluation.— patients interpreted as having a single primary defect of brain de¬ velopment, a pneumoencephalogram In
may be indicated in
an
effort to
accurately determine the
more
nature and
extent of the defect in brain
mor¬
phogenesis, especially in hydrocephalus. In other defects it may pro¬ vide insight into the prognosis and may be helpful in genetic counseling. In patients with multiple congeni¬ tal anomalies, not interpreted as being secondary to a primary brain anomaly, the following steps should
be taken: 1. In patients with known chromo¬ somal abnormality syndromes, chro¬ mosomal studies should be done both to confirm the diagnosis and for genetic counseling purposes. If the patient has an unbalanced set of chromosomes because of chromosomal breakage, then both parents should
be studied to determine whether one of them is a balanced carrier of the chromosomal rearrangement with a consequent high recurrence risk. 2. In patients with known nonchromosomal abnormality syndromes, fur¬ ther studies, if any, are predomi¬ nantly indicated by the past findings for the specific syndrome. 3. In patients with unknown pat¬ terns of malformation, unless the pattern of altered morphogenesis is different in type from that which oc¬ curs with chromosomal abnormalities, a chromosomal study should be con¬ sidered, ideally using chromosomal
banding techniques.
Perinatal Insult to Brain Definition.—This
category includes
hypoxemia, kernicterus, severe neo¬ natal hypoglycemia, intracerebral hemorrhage, perinatal hypoxia, men¬ ingitis, and sepsis—all more common
in the premature infant. Caution should be exercised before assuming that problems of the birth process and of perinatal adaptation are the pri¬ mary cause of mental deficiency in patients who have evidence of pre¬ natal onset of a problem in mor¬ phogenesis. Such patients, especially those who have a severe defect of early brain development and those who have prenatal onset of growth deficiency, are more likely to have problems in neonatal adaptation in¬
cluding hypoxemia, hyperbilirubinemia, and hypoglycemia. Diagnostic Laboratory
Evaluation.—
This should be done as indicated the historical findings.
by
Postnatal Onset of Brain Dysfunction
Definition.—The history will
usually
indicate normal appearance and func¬
tion at birth and subsequent slowing or deterioration of developmental progress with signs of CNS dysfunc¬ tion, sometimes accompanied by al¬ tered growth and morphogenesis. Included in this grouping are en¬ vironmental insults such as trauma,
meningitis,
encephalitis, hyperintoxication, severe severe hypoxemia, hypoglycemia, lead encephalopathy, CNS degenera¬ tive disorders, and certain enzymatic natremia,
water
defects of amino acid, carbohydrate, uric acid, mucopolysaccharide, and brain lipid metabolism. Only a few rare inborn errors of metabolism such as the Leroy I-cell disease or general¬ ized gangliosidosis8 have gross clini¬ cal manifestations by the time of birth.
Diagnostic Laboratory
Evaluation.—
Evaluation should be germane to the overall problem, as indicated by his¬ tory and physical examination. Most of the patients with recog¬ nized inborn errors of a particular en¬ zyme function resulting in mental deficiency fall into this category.
They comprise a small but important subcategory. Of the 1,224 mentally deficient patients studied by Kaveggia et al,1 4.3% had established in¬
born errors of this type, of which one third were PKU and one was galactosemia. Besides these latter two con¬ ditions, in which early recognition with dietary therapy may be of value in preventing mental deficiency, few of the other disorders can be effec¬ tively managed at the present time. For some of these inborn errors of enzyme function, there are additional clues in the history and physical ex¬ amination that can lead to a specific rationale for the pertinent metabolic study of that patient. It is often diffi¬ cult to diagnose PKU from the clini¬ cal findings, and when it is not ex¬ cluded as a possibility by the overall
findings, a
serum phenylalanine level determination is indicated. The following list gives examples of features, in addition to mental deficiency, that often occur postnatally in certain inborn errors of metabolism.8
Phenylketonuria, (autosomal recessive): Light pigmentation; eczema in one third of patients; poor coordination, seizures in one fourth of patients, autistic classical
behavior
Sanfilippo syndrome (mucopolysacchari-
dosis type III) (autosomal recessive): De¬ velopmental lag after 1 year of age with deterioration toward restless behavior, clumsiness by age 6 to 7 years; develop¬ ment of coarse facies and hair by 2 to 3 years; gum hypertrophy, mild limitation in finger extension Hurler syndrome (mucopolysaccharidosis
type I) (autosomal recessive): Develop¬ mental
lag after 6 to 10 months with dete-
Downloaded From: http://archpedi.jamanetwork.com/ by a UQ Library User on 06/16/2015
rioration and growth
deficiency, coarse facies, stiff joints, gibbus, hepatosplenomegaly, cloudy corneas, rhinitis Hunter syndrome (mucopolysaccharidosis type
II),
severe
type (X-linked
reces¬
sive): Developmental lag after 6 to 12 months with growth deficiency, coarse facies, stiff joints, hepatosplenomegaly; no gibbus or cloudy corneas Galactosemia, severe type (autosomal recessive): Development in early infancy (while being fed cow's milk) of lethargy, hypotonia, hepatomegaly, icterus, hypogly¬ cemia, cataract, with failure to thrive. Lesch-Nyhan syndrome (X-linked reces¬ sive): Development after 6 to 8 months of spasticity, choreoathetosis, self-mutilation, autistic behavior, growth deficiency; tophi in late childhood.
Homocystinuria (automsomal recessive): arachnodactyly, pectus excavatum, genu valgum, pes cavus, mild limitation of finger extension; downward lens dis¬ location, usually by age 10 years; wide fa¬ cial pores, malar flush; thrombotic phenom¬ ena contributing to CNS problems. Arginosuccinicaciduria (autosomal re¬ cessive): Onset in first one to two years of growth deficiency, mild hepatomegaly, skin lesions, dry brittle hair with trichorrhexis nodosa, seizures. Undecided Age at Onset Mild
Definition.—This
was
the second
largest group in the study of Kaveggia et al,' making up about 37% of the more seriously mentally deficient patients. These patients show no evi¬ dence of a prenatal problem in mor¬ phogenesis, have no established his¬ tory of
a
gross insult to the brain in
the
perinatal period, and are rather consistently slow in postnatal devel¬ opment. They may or may not have other evidence of CNS dysfunction, such as spasticity, hypotonia, sei¬
zures, or aberrant behavior. Within this group it is unusual to arrive at an
etiologic diagnosis.
Diagnostic Laboratory
Evaluation.—
There is seldom adequate information on which to base a rational laboratory diagnostic evaluation. It has been un¬ usual to achieve a specific diagnosis in the majority of those with severe spasticity and those with hypotonia, in the experience of Kaveggia et al.1 A buccal smear for X-chromatin is merited in boys to exclude XXY syn¬ drome, especially in those who are mildly mentally deficient and who ex¬ hibit subtle signs such as decreased
upper segment/lower segment ratio, small penis, and behavioral problems." In girls a buccal smear is merited to exclude XXX. For the other patients, exclusion of PKU is usually merited; however, there has been little value in a general screening for other recog¬
nized inborn errors of metabolism in such patients. Disorders Occurring Clinically in More Than One Category
A
patient with hypothyroidism prenatal infectious disease could set into any
one
normal size at
birth, often have os¬ immaturity of prenatal onset as evidenced by large fontanels, facial bone immaturity, and retardation in bone age.10 The diagnosis is unfortu¬ nately seldom entertained at birth, though we are aware of one unpub¬ seous
case
of Perinatal
detected at this age be¬
unusually large fontanels. problems not uncommonly include persistent indirect hyperbilirubinemia and poor feeding. Hypothyroid infants usually become increasingly sluggish in physical ac¬ tivity with slow growth and grossly retarded maturation. Myxedematous cause
fullness of the subcutaneous tissue and muscles develops in severe hypo¬ and is most noticeable in the lower part of the eyelids and tongue. Patients with such problems, compatible with hypothyroidism, mer¬ it specific thyroid function studies. The findings of mental deficiency and short stature alone, unaccompanied by other signs of hypothyroidism, are not sufficient indication for such studies. Prenatal Infectious Disease.—A his¬ tory of maternal rubella or exposure to the disease in the first four months of gestation may provide a clue to the possibility of fetal rubella disease, as may the findings of deafness, cata¬ racts, or cardiac defect in the patient. However, in cytomegalovirus and toxoplasmosis infections, the mother usually has no history of disease. One of these three disorders may be sus¬ pected on the basis of the following variable and nonspecific features in
thyroidism
retinitis, and deafness. Should some of these signs be present in a patient in whom prenatal infectious disease is suspected, tests such as direct cul¬
ture of virus
or demonstration of fluorescent IgM specific antibody or complement-fixation antibody studies are indicated.
Potential Indications for Other Studies
or
be of the above four
categories. with Hypothyroidism.—Patients congenital hypothyroidism, though of
lished
infancy: growth deficiency, micro¬ cephaly, hepatosplenomegaly, jaun¬ dice, poor feeding, petechiae, chorio-
We have alluded to indications for chromosomal studies, buccal smear for X-chromatin, pneumoencephalography, and tests for inborn errors of metabolism, hypothyroidism, and pre¬ natal infectious disease. Likewise, the following investigations should be done only when there is some indica¬ tion in addition to mental deficiency. 1. Skull roentgenograms merit con¬ sideration in a patient with clinical signs of craniosynostosis, evidence of increased incracranial pressure, cuta¬ neous signs of tuberous sclerosis or Sturge-Weber syndrome, or evidence of prenatal infectious disease, espe¬
cially toxoplasmosis. 2. Long bone roentgenograms may be indicated by clinical findings such
skeletal abnormalities. Bone age determination may be indicated in patients with decelerating growth, especially those for whom the overall findings are compatible with hypo¬ thyroidism, and in patients with ex¬ cessive rate of growth, but is of little practical value in patients with pre¬ natal onset of growth deficiency. 3. Electroencephalograms may be warranted in patients with a history of seizures or suspected seizure as
equivalent.
4. Determination of
fasting
blood glucose level merits consideration in patients with a history suggestive of hypoglycémie signs and symptoms but is not necessarily indicated for all patients with seizures. 5. Measurement of serum electro¬ lyte, uric acid, and blood urea ni¬ trogen levels; blood counts; and urinalysis should be performed only as prompted by findings in the history or examination in addition to mental
deficiency.
Downloaded From: http://archpedi.jamanetwork.com/ by a UQ Library User on 06/16/2015
SUBJECTS AND METHODS Based on the foregoing individualized approach toward the diagnostic evaluation of children with mental
deficiency, a retro¬
spective study of such children was done in
an effort to determine the number who had had "nonrational" diagnostic studies. We also wished to determine whether some of the nonrational studies did in fact contrib¬ ute to the diagnosis. One of us (F.E.R.S.) reviewed the data on 98 consecutive chil¬ dren with mental deficiency who were ex¬ amined as outpatients at the Child Devel¬ opment and Mental Retardation unit at the University of Washington from June 1970 to June 1972. These patients were se¬ lected from a total of 157 cases because they had been examined by both a pedia¬ trician and a psychologist on their initial clinic visit and had an IQ of 70 or less. The patients were not examined by us, except for some of those having patterns of mal¬ formation, who were seen in consultation. Thirty-two percent had an IQ below 50 and the other 68% had an IQ between 50 and 70. The evaluation was related to manage¬ ment and counseling as well as to diag¬ nosis, but only the diagnostic studies were reviewed for this report. The case histories and results of physical examinations were analyzed and on this basis a decision was made as to which of the aforementioned four categories the patient fit and which of the studies ordered were rational and which were considered nonrational. The re¬ sults were then reviewed and a determina¬ tion was made as to which studies had been of value relative to the overall diag¬ nosis, or at least of some ancillary value in the general health assessment of the pa¬ tient. Regarding the four age-at-onset categories, 53% of the patients were inter¬ preted as having a problem of prenatal on¬ set (category 1), 3% had mental deficiency as a result of a presumed perinatal insult (category 2), 4% were deficient because of postnatal damage (category 3), and in 40% the age at onset was undecided (category
4).
RESULTS
It was obvious that the diagnostic evaluation of these patients had been relatively individualized. Beyond a
urinalysis, no single laboratory study
had been done in more than half of the patients. The Table shows a sum¬ mation of the studies. None of the 87 patients having a nonrational diag¬ nostic test had a result that was valu¬ able toward a specific mental defi¬ ciency diagnosis, including the 47 who had nonrational urine studies search-
ing for evidence of an inborn error of metabolism. Only one nonrational test was of ancillary value for the patient: this child was discovered to have mild iron deficiency anemia, though the history and examination had not indicated such a possibility.
Laboratory Studies in 98 Children With Rational Indication*
The
foregoing approach
toward
Studies Urinary study for amino acids and abnormal metabolites Chromosome study Buccal smear
a
to
Diagnosis
No.
No. Valuable to Diagnosis
47 16
Skull roentgenograms Other skeletal roent¬ genograms
men¬
tal deficiency is corroborated by the small retrospective study cited above. More importantly, it is supported by studies in which routine diagnostic determinations were done on a much larger number of mentally deficient patients. Judith Dey, MD, of the Grosvenor Diagnostic and Assess¬ ment Clinic, which evaluates the ma¬ jority of individuals with mental defi¬ ciency in New South Wales, told one of us (D.W.S.) in 1973 that results of routine serum calcium, phosphorus, and uric acid tests and blood glucose tests have been normal in more than 2,000 patients except in those patients who had an indication for doing the study in addition to mental deficiency alone. As a result of this experience, the first three tests cited are no longer routinely performed. Routine skull and wrist roentgenograms have been normal in more than 4,000 pa¬ tients, except in those few patients in whom an abnormality was suspected prior to the roentgenographic study. Further comment is merited re¬ garding the largest group of patients, in category 1, who are considered to have a prenatal problem in morpho¬ genesis of the brain. This consid¬ eration may be based on direct evi¬ dence of brain malformation or on the indirect basis of multiple nonCNS congenital defects in morpho¬ genesis. The latter discrimination is often dependent on a careful total physical examination with the pur¬ pose of detecting minor as well as major anomalies. For example, Smith and Bostian11 studied 50 consecutive patients with idiopathic mental defi¬ ciency, 31 (62%) of whom had an IQ below 50, and found that 21 (42%) of them had three or more associated major or minor anomalies of prenatal onset vs none with three or more
No.
(X-chromatin)
individualized rational labora¬
tory evaluation of patients with
Nonrational Indication*
No. Valuable
COMMENT more
Mental Deficiency
Electroencephalogram
10
Serum protein-bound iodine or T, Serum electrolytes, etcf
Complete blood cell urinalysis
count
1*
27 75
Routine
Based on findings in history and physical examination. t Laboratory tests Including blood glucose, uric acid, blood *
level determinations. t One patient was found to have iron
nitrogen,
and
electrolyte
deficiency anemia.
anomalies in 100 control children without mental deficiency who were examined concurrently. This finding was interpreted as evidence that a large proportion of patients with seri¬ ous idiopathic mental deficiency have had a prenatal onset of the problem and that the prenatal cause of the non-CNS malformations, though un¬ known, was also the cause of the men¬ tal deficiency. The more direct find¬ ings of Crome12 strongly suggest that a high proportion of patients with undiagnosed severe mental deficiency have a malformation of early brain development. Crome examined brains at necropsy from 282 patients with severe mental deficiency. Two thirds of the group did not have a recog¬ nized syndrome, and of these all but 4.3% had a morphological brain alter¬ ation, the majority of which could be interpreted as being of prenatal on¬ set. Many patients with prenatal de¬ fects of brain development that are not apparent by physical examination probably fall into category 4, the "un¬ decided" group. Thus, the frequency with which mental deficiency is due to a prenatal problem in brain mor¬ phogenesis is probably higher than the 44% implicated by Kaveggia et al1 or the 53% in the present study. Diagnostic laboratory studies likely to prove useful in patients with pre¬ natal onset of a problem in morpho-
Downloaded From: http://archpedi.jamanetwork.com/ by a UQ Library User on 06/16/2015
urea
genesis are limited to chromosomal studies, viral or toxoplasmosis stud¬ ies, or roentgenograms. To our knowl¬ edge, there is seldom an indication for urinary and serum studies search¬ ing for known metabolic inborn er¬ rors of metabolism in patients in category 1. Kaveggia et al1 have re¬ ported studies of urinary amino acids, sugars, Índoles, and imidazoles, plus special determinations for PKU, cystine/homocystine, and mucopoly-
saccharides in more than 600 men¬ tally deficient patients with evidence of prenatal onset of altered mor¬ phogenesis, and not one study was of diagnostic value. Furthermore, though other investigators have screened for metabolic abnormali¬ ties in large numbers of mentally deficient patients, those with pre¬ natal onset of aberrant morpho¬ genesis have not been included in their positive results. Carson and Neill11 have emphasized the low yield of metabolic disorders in unselected screening of patients with mental
deficiency.
The experience of the MR-Metabolic Clinic at the University of Cali¬ fornia in San Francisco is of special relevance to the above comments, as related by Byran Hall, MD (written communication, 1973). This clinic was originally established for the meta¬ bolic evaluation of referred patients
with mental deficiency with no recog¬ nized syndrome and no evident cause for their mental deficiency. In this clinic, routine metabolic studies de¬ signed to detect virtually all known metabolic causes of mental deficiency include eight different serum chem¬ ical tests, six urine spot tests, urine amino acid analysis by ion exchange chromatography, and combined gas
chromatographic/mass spectrometric urine screening for abnormal organic acids. During an eight-month period 72 patients were evaluated, a few of whom had a previously established diagnosis, such as one with known PKU. The only new metabolic diag¬ nosis made during this time, that of the Sanfilippo syndrome, had been clinically suspected by Hall before the laboratory results were known. De¬ spite the nature of this clinic, 40% of the patients examined had a multiple congenital anomaly syndrome. Judg¬ ing from his experience in that clinic, Hall is in agreement with the individ¬ ualized diagnostic approach set forth in this article. As new knowledge has evolved re¬ garding the numerous causes of men-
tal
deficiency,
there has been an in¬ in the number of potential diagnostic studies that can be done. Some physicians and clinics tend to use a "complete battery" of diagnos¬ tic studies for almost all mentally deficient children. On the basis of ex¬ perience and the knowledge accrued in recent years, we believe that the diagnostic studies employed for a particular patient should be based on a rational interpretation of an appro¬ priate history and physical examina¬ tion on that patient. This approach rarely requires hospitalization of the patient, and metabolic, endocrinolog¬ ie, or roentgenographic studies are in¬ frequently indicated. This approach in no way detracts from the potential value of making a specific diagnosis in the child with mental deficiency. Such a diagnosis usually has value in management, prognosis, and genetic counseling. For cases of genetically determined inborn errors of metabolism, it is in¬ creasingly important to make a spe¬ cific diagnosis of the enzyme defect where feasible. For an ever greater number of such defects, it is possible crease
to detect the enzyme defect in cul¬ tured fetal fibroblasts obtained by amniocentesis in early gestation, ter¬ minate the affected prognancy, and thereby prevent the birth of another affected child in that family. This approach is presented both from a pragmatic standpoint and also as a challenge to those who might dis¬ agree with it. The rational diagnostic evaluation of the child with mental deficiency should continue to evolve on the basis of new knowledge and experience. We welcome additional knowledge or experience that would substantially support or change this
approach.
This investigation was supported by project 913 from the Maternal and Child Health Ser¬ vices, Health Services and Mental Adminis¬ tration, US Department of Health, Education and Welfare; by Public Health Service grant HD 05961; and by the National Foundation-March of Dimes. John M. Opitz, MD, and William L. Nyhan, MD, provided critical reviews of this article. Lyle Harrah provided library research; Mary Ann Harvey, editorial assitance; Christine Hansen, secretarial assistance. The University of Washington Child Development and Mental Re¬ tardation Unit gave their cooperation.
References 1. Kaveggia EG, Durkin MV, Pendleton E, et al: Diagnostic genetic studies on 1,224 patients with severe mental retardation. Read before the Third Congress of the International Association for Scientific Study of Mental Deficiency, The Hague, Sept 4-12, 1973. 2. Jones KL, Smith DW, Harvey MA, et al: Older paternal age and presumed fresh mutant gene disorders: Additional data. J Pediatr 86:84\x=req-\ 88, 1975. 3. Perry TL, Hansen S, Tischler B, et al: Unrecognized adult phenylketonuria. N Engl J Med 289:395-398, 1973. 4. Menkes JH, Aeberhard E: Maternal phenylketonuria. J Pediatr 74:924-931, 1969.
5. Jones KL, Smith DW, Ulleland CN, et al: Pattern of malformation in offspring of chronic alcoholic mothers. Lancet 1:1267-1271, 1973. 6. Smith DW, Gong BT: Scalp hair patterning as a clue to early fetal brain development. J Pediatr 83:374-378, 1973. 7. Smith DW, Gong BT: Scalp-hair patterning: Its origin and significance relative to early brain and upper facial development. Teratology 9:17\x=req-\ 34, 1974. 8. Holmes LB, Moser HW, Halld\l=o'\rssonS, et al: Mental Retardation: An Atlas of Diseases With Associated Physical Abnormalities. New York, Macmillan Co, 1972. 9. Caldwell PD, Smith DW: The XXY (Kline-
Downloaded From: http://archpedi.jamanetwork.com/ by a UQ Library User on 06/16/2015
felter's) syndrome in childhood: Detection and 80:250-258, 1972. 10. Smith DW, Popich G: Large fontanels in congenital hypothyroidism: A potential clue toward earlier recognition. J Pediatr 80:753-756, treatment. J Pediatr
1972. 11. Smith DW, Bostian KD: Congenital anomalies associated with idiopathic mental retardation. J Pediatr 65:189-196, 1964. 12. Crome L: The brain and mental retardation. Br Med J 1:897-904, 1960. 13. Carson NAJ, Neill DW: Metabolic abnormalities detected in a survey of mentally backward individuals in northern Ireland. Arch Dis Child 37:505-513, 1962.
