668
2,
3.
Letters to the Editor
The Journal o f Pediatrics October 1975
Fisher DA: Neonatal detection of hypothyroidism, J PEDIATR 86:822, 1975. Klein AH, Agustin AV, Hopwood N J, PerriceUi A, Johnson L, and Foley rip Jr. Thyr0tropin (TSH) screening for congenital hypothyroidism, Pediatr Res 9:291, 1975 (abstr. 210).
Femoral hypoplasia-unusualfacies syndrome To the Editor." Daentl and associates' recently described a distinctive pattern of malformation which includes femoral hypoplasia and several abnormal facial features. This report of four unrelated individuals drew attention to two previously published reports of similarly affected individuals and represents the beginning of what may be,the delineation of a specific phenotype. In this process it is important to define the spectrum of the abnormalities. For that reason we would like to describe an infant who has the same~pattern of anomalies, but more severe shortening of the upper extremity than the individuals previously described.'
Fig. 2.
CASE REPORT Our patient was born after a 40-week, uncomplicated pregnancy to unrelated healthy parents ages 21 and 22. She has one normal sibling; no relatives have any skeletal anomalies. Her birth weight was 1.9 kg, length 34 cm, and head circumference 34 cm. At birth she had these congenital malformations: marked shortening of all four extremities without any elbow or knee flexion (Fig. 1), bilateral equinovarus deformity, clinodactyly of both fifth fingers, hypoplasia of the labia majora, micrognathia, cleft soft palate, long philtrnm, and small, cupped ears. Facial appearance is strikingly similar to Patient 4 in the report of Daenfl and associates. ~ Radiographs showed absence of both femurs, hypoplastic fibulas, a single irregularly shaped bone in the upper extremity (Fig. 2), only 11 pairs of ribs, a short sacrum, and a very narrow pelvis. Intravenous pyelography and chromosome analysis showed no abnormalities. At age 3V2 years she had normal intelligence and normal hearing. DISCUSSION
Fig. 1.
When this infant was born, her parents feared that her skeletal malformations would be associatedwith significant mental deficiency and were unable to be responsible for her care. The delineation of the femoral hypoplasis-unusual facies syndrome provides encouragement to the parents of an affected neonate with regard to the likelihood of normal intelligence, as well as the restricted nature of the associated malformations. Lewis B. Holmes Genetics Unit Massachusetts General Hospital Boston, Mass. 02114
Volume 87 Number 4
Letters to the Editor
REFERENCE
1. Daentl DL, Smith DW, Scott CI, Hall BD, and Gooding CA: Femoral hypoplasia-unusual facies syndrome, J PEDIATR 86:107, 1975.
Repty To the Editor: I agree that the patient described by Holmes probably has the same disorder as that reported by Daentl and associates. The severity o f expression is greater than usual for some features. Incomplete morphogenesis of the upper limbs is more striking in their patient, though synostosis o f the elbow has occurred in other individuals with this disorder. Hypoplasia of the labia majora and cupped ears have both been noted in other patients. To date all instances have been sporadic in otherwise normal families. David W. Smith, M.D. Professor of Pediatrics School o f Medicine University of Washington Seattle, Wash. 98105
Serum arylsulfatase A assay To the Editor: We have reported earlier a serum assay for arylsulfatase A that enabled us to detect e n z y m e deficiency in four patients with metachromatic leukodystrophy (MLD).' The diagnosis was documented by demonstration of absence of arylsulfatase A activity in the peripheral leukocytes of the patients. No overlap was observed between the serum activity in the patients and 44 controls, 19 of whom were affected with various neurologic diseases other than MLD. In their communication Singh and associates, ~ referring to our technique, state "a recently published method for arylsulfatase A assay could not be used as described because of formation of a heavy precipitate." These authors using a modification o f our assay system measured the arylsulfatase A activity in 15 normal subjects. No patients with MLD were studied. By comparing the enzyme activities obtained by the modified technique the same authors referring to our paper state later in their report that "the values for arylsulfatase A agree well with those obtained by other investigators who measured the enzyme activity on whole serum." It is not known at present whether the addition of ethylenediamine tetra-acetic acid increases the accuracy of the method. Study of patients with MLD and comparison of the obtained values in patients and control subjects with both techniques is required. As we have mentioned, use of fasting blood is indicated for the assay since it significantly reduces turbidity in the final digest. Since the publication of our serum assay for arylsulfatase A we
669
have studied 35 additional patients with various neurologic diseases. In one of them deficiency of arylsulfatase A was found in serum (6.5 nmoles 4-nitrocatechol/ml serum/4 hours). By using a modification of the arylsulfatase A assay 3 no enzyme activity was detected in peripheral leukoeytes o f the patient, whereas severe deficiency was demonstrated in cultured skin fibroblasts (19.3 nmoles 4-nitrocatechol/mg of protein/hour). In the 34 other cases studied the activity (mean _+ SD) in serum was 75.6 _+ 26.0, with a range from 34.4 to 134.5 The enzyme activity in these cases was also studied in peripheral leukocytes or cultured skin fibroblasts and was found to be within the normal range. Our findings do not support the statement o f Singh and associates2 that the serum arylsulfatase A assay reported by us cannot be used. We still feel that it is valuable for screening for MLD and the findings should be interpreted as indicated earlier by us? Finally, the superiority of the modified technique described by Singh and associates 2 for the identification o f MLD needs further documentation not provided presently by the authors. Nicholas G. Beratis, M.D. Kurt Hirsehhorn, M.D. Division o f Medical Genetics Department o f Pediatrics Mount Sinai School o f Medicine of the-City University o f New York Fifth Ave. and lOOth St. New York, N. Y. 10029
REFERENCES
1. Beratis NG, Aron AM, and Hirschhorn K: Metachromatic leukodystrophy: Detection in serum, J PEDIATR 83:824, 1973. 2. Singh J, Tavella D, and Di Ferrante N: Measurements of arylsulfatases A and B in human serum, J PEDIATR 86:574, 1975. 3. Beratis NG, Danesino C, and Hirschhorn K: Detection of homozygotes and heterozygotes for metachromatic leukodystrophy in lymphoid cell lines and peripheral leukocytes, Ann Hum Genet 38"485, 1975.
Repty To the Editor: Our recent communication 1 was intended to describe a simple and rapid method for the measurement in serum of arylsulfatases A and B. Having detected the formation o f turbidity and heavy precipitate in the execution o f the method proposed by Beratis and associates2 for the measurement of ARA in serum, we proposed a simple additional step to eliminate the inconvenience. There were no claims o f increased accuracy o f the method. Although in Beratis and associates '~ original paper there was no mention of turbidity in the final digest, its occurrence is now. mentioned in the above letter. If turbidity then occurs, what is objectionable to a technical
2,
3.
Letters to the Editor
The Journal o f Pediatrics October 1975
Fisher DA: Neonatal detection of hypothyroidism, J PEDIATR 86:822, 1975. Klein AH, Agustin AV, Hopwood N J, PerriceUi A, Johnson L, and Foley rip Jr. Thyr0tropin (TSH) screening for congenital hypothyroidism, Pediatr Res 9:291, 1975 (abstr. 210).
Femoral hypoplasia-unusualfacies syndrome To the Editor." Daentl and associates' recently described a distinctive pattern of malformation which includes femoral hypoplasia and several abnormal facial features. This report of four unrelated individuals drew attention to two previously published reports of similarly affected individuals and represents the beginning of what may be,the delineation of a specific phenotype. In this process it is important to define the spectrum of the abnormalities. For that reason we would like to describe an infant who has the same~pattern of anomalies, but more severe shortening of the upper extremity than the individuals previously described.'
Fig. 2.
CASE REPORT Our patient was born after a 40-week, uncomplicated pregnancy to unrelated healthy parents ages 21 and 22. She has one normal sibling; no relatives have any skeletal anomalies. Her birth weight was 1.9 kg, length 34 cm, and head circumference 34 cm. At birth she had these congenital malformations: marked shortening of all four extremities without any elbow or knee flexion (Fig. 1), bilateral equinovarus deformity, clinodactyly of both fifth fingers, hypoplasia of the labia majora, micrognathia, cleft soft palate, long philtrnm, and small, cupped ears. Facial appearance is strikingly similar to Patient 4 in the report of Daenfl and associates. ~ Radiographs showed absence of both femurs, hypoplastic fibulas, a single irregularly shaped bone in the upper extremity (Fig. 2), only 11 pairs of ribs, a short sacrum, and a very narrow pelvis. Intravenous pyelography and chromosome analysis showed no abnormalities. At age 3V2 years she had normal intelligence and normal hearing. DISCUSSION
Fig. 1.
When this infant was born, her parents feared that her skeletal malformations would be associatedwith significant mental deficiency and were unable to be responsible for her care. The delineation of the femoral hypoplasis-unusual facies syndrome provides encouragement to the parents of an affected neonate with regard to the likelihood of normal intelligence, as well as the restricted nature of the associated malformations. Lewis B. Holmes Genetics Unit Massachusetts General Hospital Boston, Mass. 02114
Volume 87 Number 4
Letters to the Editor
REFERENCE
1. Daentl DL, Smith DW, Scott CI, Hall BD, and Gooding CA: Femoral hypoplasia-unusual facies syndrome, J PEDIATR 86:107, 1975.
Repty To the Editor: I agree that the patient described by Holmes probably has the same disorder as that reported by Daentl and associates. The severity o f expression is greater than usual for some features. Incomplete morphogenesis of the upper limbs is more striking in their patient, though synostosis o f the elbow has occurred in other individuals with this disorder. Hypoplasia of the labia majora and cupped ears have both been noted in other patients. To date all instances have been sporadic in otherwise normal families. David W. Smith, M.D. Professor of Pediatrics School o f Medicine University of Washington Seattle, Wash. 98105
Serum arylsulfatase A assay To the Editor: We have reported earlier a serum assay for arylsulfatase A that enabled us to detect e n z y m e deficiency in four patients with metachromatic leukodystrophy (MLD).' The diagnosis was documented by demonstration of absence of arylsulfatase A activity in the peripheral leukocytes of the patients. No overlap was observed between the serum activity in the patients and 44 controls, 19 of whom were affected with various neurologic diseases other than MLD. In their communication Singh and associates, ~ referring to our technique, state "a recently published method for arylsulfatase A assay could not be used as described because of formation of a heavy precipitate." These authors using a modification o f our assay system measured the arylsulfatase A activity in 15 normal subjects. No patients with MLD were studied. By comparing the enzyme activities obtained by the modified technique the same authors referring to our paper state later in their report that "the values for arylsulfatase A agree well with those obtained by other investigators who measured the enzyme activity on whole serum." It is not known at present whether the addition of ethylenediamine tetra-acetic acid increases the accuracy of the method. Study of patients with MLD and comparison of the obtained values in patients and control subjects with both techniques is required. As we have mentioned, use of fasting blood is indicated for the assay since it significantly reduces turbidity in the final digest. Since the publication of our serum assay for arylsulfatase A we
669
have studied 35 additional patients with various neurologic diseases. In one of them deficiency of arylsulfatase A was found in serum (6.5 nmoles 4-nitrocatechol/ml serum/4 hours). By using a modification of the arylsulfatase A assay 3 no enzyme activity was detected in peripheral leukoeytes o f the patient, whereas severe deficiency was demonstrated in cultured skin fibroblasts (19.3 nmoles 4-nitrocatechol/mg of protein/hour). In the 34 other cases studied the activity (mean _+ SD) in serum was 75.6 _+ 26.0, with a range from 34.4 to 134.5 The enzyme activity in these cases was also studied in peripheral leukocytes or cultured skin fibroblasts and was found to be within the normal range. Our findings do not support the statement o f Singh and associates2 that the serum arylsulfatase A assay reported by us cannot be used. We still feel that it is valuable for screening for MLD and the findings should be interpreted as indicated earlier by us? Finally, the superiority of the modified technique described by Singh and associates 2 for the identification o f MLD needs further documentation not provided presently by the authors. Nicholas G. Beratis, M.D. Kurt Hirsehhorn, M.D. Division o f Medical Genetics Department o f Pediatrics Mount Sinai School o f Medicine of the-City University o f New York Fifth Ave. and lOOth St. New York, N. Y. 10029
REFERENCES
1. Beratis NG, Aron AM, and Hirschhorn K: Metachromatic leukodystrophy: Detection in serum, J PEDIATR 83:824, 1973. 2. Singh J, Tavella D, and Di Ferrante N: Measurements of arylsulfatases A and B in human serum, J PEDIATR 86:574, 1975. 3. Beratis NG, Danesino C, and Hirschhorn K: Detection of homozygotes and heterozygotes for metachromatic leukodystrophy in lymphoid cell lines and peripheral leukocytes, Ann Hum Genet 38"485, 1975.
Repty To the Editor: Our recent communication 1 was intended to describe a simple and rapid method for the measurement in serum of arylsulfatases A and B. Having detected the formation o f turbidity and heavy precipitate in the execution o f the method proposed by Beratis and associates2 for the measurement of ARA in serum, we proposed a simple additional step to eliminate the inconvenience. There were no claims o f increased accuracy o f the method. Although in Beratis and associates '~ original paper there was no mention of turbidity in the final digest, its occurrence is now. mentioned in the above letter. If turbidity then occurs, what is objectionable to a technical
