The discovery of phenylketonuria: the story of a young couple, two retarded children, and a scientist.

In the 1920s, a little girl 3 years of age was brought from China to the United States by her American mother. Although the child was beautiful, her mind was not developing. The grief-stricken mother had consulted doctors in China, but they could neither diagnose the problem nor provide treatment. Morning and night the same questions occupied her mind: "What is the matter with my little girl? What is causing it? Is there any doctor, anywhere, who can cure her?" In the United States, she also went from doctors to psychologists to clinics looking for someone who could help. Finally, she went to the Mayo Clinic in Rochester, Minnesota. When she had answered all of the doctor's questions, and all the tests were finished, they still could not tell her what was wrong. There was nothing they could do. The disease from which the little girl suffered was unknown at that time. The mother was Pearl Buck. In her book, The Child Who Never Grew,(1) she described her first infant: "I remember when she was only 3 months old she lay in her basket on the sun deck of a ship. I had taken her there for the morning air. The people who promenaded on deck often stopped to look at her, and my pride grew as they spoke of her unusual beauty and of the intelligent look of her deep, blue eyes. I do not know at what moment the growth of her intelligence stopped, nor to this day why it did." This is a classical description of the disease, phenylketonuria (PKU). A perfect infant seems to develop normally for several months, then the development slows and at some point seems to stop. "Look at Mommy-look at Daddy!" the parents say as they try to coax the treasured smiles. Instead, the child drifts into a dream world and into irreversible mental retardation. All Pearl Buck's devotion and determination was of no avail in finding the cause of her child's retardation. It was to be another mother with the same commitment to her beautiful but retarded children, who approximately 10 years later followed the same path until she found a special doctor who unlocked the secret of the fate of these children. When 1 of the authors (W.R.C.) visited Miss Buck at her Pennsylvania home in 1960, she talked about how her daughter, Carol, then a grown person, had recently been diagnosed as having PKU, as a result of screening tests at the New Jersey Vineland Training School for the Mentally Retarded. During my visit and without disclosing the reason, Pearl Buck was invited to sniff a vial of phenylacetate crystals (the odor of stale urine samples from PKU patients). Immediately she recalled that Carol, as a child, had the same unusual odor. She was relieved that the prophesy of the last words in her book had come true: "What has been, need not forever continue to be so. It is too late for some of our children, but if their plight can make people realize how unnecessary much of the tragedy is, their lives, thwarted as they are, will not have been meaningless." These could be the words of Borgny Egeland, the mother of the children through whom the mystery of PKU was brought to light. Or they could express the conviction of the physician and biochemist, Asbjörn Fölling, who believed that "what was not known could be known." Through the discovery of PKU in these children, hope has been given to thousands of other children and to their grateful parents ().

Chromosome identification of the rusty-spotted cat (Felis rubiginosa): one more down and four to go.

The chromosomes of the rusty-spotted cat, Felis rubiginosa, of Sri Lanka (Ceylon) were analyzed. Although the 38-chromosome complement of F rubiginosa closely resembles that of several other species, it seems to be unique with only minor variations in the D and F chromosomes. This reduces, from 5 to 4, the number of the 37 recognized world feline species not yet cytogenetically studied. Despite great differences in size and distribution, the feline species of the world are one of the most homogenous families of mammals, with only subtle chromosomal differences separating most species. By comparative cytogenetic analyses, it is becoming possible to map the probable evolutionary pathway of the world's cats.

Pachyonychia Congenita (Jadassohn-Lewandowsky syndrome): a seventeen-member, four-generation pedigree with unusual respiratory and dental involvement.

Pachyonychia Congenita (PC) is an autosomal dominant syndrome of thick nails and other epithelial defects. A hospitalization for severe respiratory distress in a 3-year-old boy with PC and an affected father led to the discovery of 17 affected persons in a kindred spanning four generations. Nine relatives had varying degrees of upper respiratory tract obstruction, and eleven had dental aberrations. We review PC and discuss other unusual findings in this kindred, ie, arthritis in four affected relatives and a discrepancy between expected and observed ratios of affected to unaffected offspring of mothers with PC.

The interrelationships of chromosome banding patterns in canids, mustelids, hyena, and felids.

The G-banding patterns of six canids, four mustelids, one hyena, and 12 felids have been studied, and data from the study of 30 felids are summarized. The canids are karyotypically very similar to one another, but minor differences have tentatively been identified. The mustelids show the greatest karyotypic diversity of all the carnivore families so far studied. They do display, however, considerable G-band conservatism, as is common throughout the Order, and appear karyotypically more closely related to the Feloidea than to the Canoidea. The hyena shares many autosomes with the felids, showing a close relationship to that family. The felids are for the first time divisible into small groups or individually identifiable on the basis of 16 different karyotypic patterns.

Interstitial deletion of the long arm of chromosome no. 5 in two unrelated children with congenital anomalies and mental retardation.

Two unrelated children with partial deletion of the long arm of a chromosome no. 5 are reported. The boy presented with severe hypotonia, developmental delay, and a few minor defects of the face including frontal bossing, antimongoloid slant of the palpebral fissures, depressed nasal bridge and bilateral epicanthal folds. With age, his hypotonia has improved. The parents have normal chromosomes; the mother has a 9qh+ variant. The second patient, a girl, presented at birth with multiple congenital anomalies including cleft palate, epicanthal folds, anteverted nostrils, horseshoe kidneys and club feet. At 4 years of age, she was small and severely retarded. The normal parents and the normal sister showed no chromosomal abnormalities. Gene mapping studies in both patients failed to define a specific gene locus to the deleted chromosome regions. Including these two patients, there appear to be only three reported cases of patients with 5q deletion. A comparative description of the third patient is included in this report. There are some clinical similarities but these are inadequate to identify a clinical syndrome. This perhaps is explained by some quantitative and qualitative differences in the deletions.

Chromosome identification of the flat-headed cat, Felis planiceps: one more down and five to go.

There are 38 recognized feline species in the world. With successful chromosome analysis of the flat-headed cat, Felis planiceps or Prionailurus planiceps, from the secluded river banks and lower mountain slopes of the jungles of Malasia, Borneo, and Sumatra, there remain only 5 rare and endangered species yet unstudied. Although some, including the flat-headed cat, have somewhat distinctive chromosome configurations, all cats thus far karyotyped show 38-chromosome counts, excepting 5 new world "tropicals" which have 36. A pattern of probable feline mutations can be read from the chromosome variations in the different species.

Effects of rapid increase of phenylalanine intake in older PKU children.

Twelve children formerly on strick low-phenylalanine diets were allowed to change to a moderate-protein diet over a five-week period. They were observed at home by parents, in school by teachers, and in the clinic by team members, and were evaluated periodically for phenylalanine intake, serum phenylalanine levels, activity, irritability, growth, and intelligence. Growth patterns were normal for age. Dietary phenylalanine increased sharply for all children at the end of three months, then dropped at about six months, after which it rose above the three month level. Serum phenylalanine levels followed dietary intakes, and in nine cases are staying at about 20 mg. per 100 ml. or less. The three subject above 20 mg. have serum phenylalanine of 21, 23, and 25 mg. per 100 ml. One of these has had behavioral problems and excessive weight gains in the past two years.

Familial 'partial 9p' trisomy: six cases and four carriers in three generations.

Six cases of translocation trisomy for the distal half of the short arm of a number 9 chromosome and four asymptomatic balanced translocation carriers are presented in a three-generation pedigree. The clinical features are remarkably similar to those recently recognized and increasingly reported in full short arm (9p) trisomy and should be considered a modification of the same syndrome. In addition to non-specific mental retardation and short stature, there is, in common, a characteristic facies, including down-turned corners of the mouth, a slightly bulbous nose, moderately large ears, suggestively wide-set eyes with an antimongoloid slant, dysplasia and hypolasis of the nails, clindactyly of the 5th fingers, and abnormal dermatoglyphs. It appears that the 'trisomy 9p syndrome' in its variant forms, including trisomies for more or less than just the short (p) arm, is one of the most common clinical autosome anomalies in humans, exceeded only by trisomy 21 (Down's syndrome) and possibly trisomies of chromosomes 13 and 18.

Radiologic signs of the 4p- (Wolf) syndrome.

The improved Giemsa-trypsin banding technique was used to differentiate the 4p- (Wolf) from the 5p- (cri du chat) syndrome. New radiographic findings of polydactyly, cervical ribs, and fusion defects of the elbows, ribs, and spine are presented in a girl with 4p- syndrome with 45 chromosomes and a B4/G22 translocation [45, XX, -4, -22, +t(4p22q)].

The trisomy 9p syndrome.

Since the first description of trisomy 9p in 1970, there has been a rapidly increasing recognition and reporting of new cases. The physical and mental features of retarded growth and development, down-turned corners of the mouth, mildly globular nose, slightly wide-set and deep-set eyes with anti-Mongoloid slant, and unusual dermatoglyphics are distinctive enough to establish trisomy 9p as a clinical chromosomal entity--one which may prove to be the fourth most common autosomal syndrome (after trisomies 21, 13, and 18). This paper includes a review and tabulation of features seen in the 20 reported cases and photographs of the faces of ten of these children. A new case included in this survey demonstrates the practical application of four types of chromosome banding identification (C, G, Q, and R). The confirmation of the chromosomal aberration in this syndrome is dependent on the use of one or more of these special laboratory techniques. Most of the clinical characteristics distinctive of the trisomy 9p syndrome are seen also in other trisomies involving more or less of the number 9 chromosome. From these observations it is determined that the crucial determinants of the classical features of this syndrome lie within the distal half of the number 9 short arm.

Trisomy 9q-. a variant of the 9p trisomy syndrome.

A low-birth-weight near-term male infant was found to have a non-familial 47,XY chromosome complement with an extra medium-sized metacentric chromosome slightly larger than a number 16. By Giemsa-trypsin (G-banding) this extra chromosome was determined to be a number 9 with deletion of approximately half of the long arm at region q 22. Chromosome studies on the clinically normal 38-year-old mother showed a balanced translocation with the deleted portion attached onto the distal end of a number 8 short arm, i.e. 46,XX,t(8;9)(p23;q22). Nondisjunction during meiosis of this woman's normal and deleted number 9 chromosomes is the basis of the child's abnormalities. One half-sibling of the child has a balanced translocation similar to that in the mother. Chromosome analyses on 4 others of the child's maternal half-siblings and on the maternal grandmother all showed normal patterns.

An animal model for the XXY Klinefelter's syndrome in man: tortoiseshell and calico male cats.

A review of the chromosome findings in 25 male tortoiseshell or calico (T-C) cats showed a variety of aneuploidy, polyploidy, mosaicism, and chimerism. An XXY-complement was included in the chromosome makeup of 16 of the 25 cats. Almost all of these cats were sterile. Testicular pathologic changes, when recorded, appeared comparable with that of human XXY Klinefelter's syndrome. The findings in 2 male T-C cats were presented as representative models of XXY Klinefelter's syndrome in man. Other findings in human Klinefelter's syndrome have not been looked for in the feline models, but a plan for this is underway. A review also was made of the historical steps leading to our present understanding of the Klinefelter syndrome including the role of Felis catus. An explanation of cat coat-color genetics clarified why "black" and sex-linked "orange" coloration can appear together normally in XX females and in rare males with 2 different X chromosomes. Thus, male T-C cats were only convenient indicators of underlying sex-chromosome aberrations which were occurring completely independent of coloration.

Translocation 4p-- syndrome: a general review.

The casee presented here may be the first fully identified and verified cas of translocation 4p-- syndrome, a B4/G22 translocation, ie, 45,XX,-4,-22,+t(4q 22q). Thirty-nine other cases of the 4p--syndrome, including one other possible translocation case, have been found in the medical literature. Conventional chromosome studies cannot distinguish between 4p-- (Wolf) syndrome and 5p-- (cri-du-chat) syndrome, and the clinical features, as in our case, may not be sufficiently characteristic to permit differentiation. The newer chromosome banding techniques have made specific identification possible.

Familial D/D translocation t(13q;14q). Eight members in four generations.

Eight family members spanning four generations were found to have 45 chromosome count D/D trnaslocation identified by Giemsa-trypsin banding as t(13q;14q). The only mature male is believed to be infertile on the basis of a very low sperm count with reduced motility. This is believed to be related to the chromosome aberration and not to be coincidental. Aside from this, all were clinically normal except the index case, a young girl with unusual facies and moderate to severe retardation of growth and development. It is believed that her abnormalities were coincidental to the chromosome translocation and fortuitous in locating this family and initiating the pedigree. This example of essentially benign (some males are fertile) Robertsonian centric fusion in humans lends itself to interesting speculations about the results from chance matings between such translocation carriers.

Partial D 15 trisomy. A case and general review.

A profoundly retarded girl with cyanotic congenital heart disease, recurrent myoclonic seizures, an external strabismus and not very unusual facial features was found to have a 47, XX chromosome complement. The extra chromosome is a small G-size chromosome with small projections extending from the ends of the long arms and no satellites observed on the short arms. By Geimsa-trypsin banding techniques this aberrant chromosome appears to be a partially deleted D 15 chromosome. A comparison of the clinical features is made with those described in the nine other reported specifically identifies cases of 'partial trisomy 15'. For clinical and chromosome morphology reasons, this was felt not to be trisomy in the G group nor an extra Y. We speculate that the long arm projections are satellites derived from a ring-type intrachromosomal translocation.