American Journal of Medical Genetics Part C (Seminars in Medical Genetics)
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The Study of Genetic Syndromes in a Rural Setting PHILIP D. PALLISTER
The syndromal and genetic biology reported and reviewed herein can be studied, analyzed and reported by any “GP” with the required gifts, enthusiasm, drive, and ability to work with collaborators of goodwill at University centers near or far; and most importantly, to continue lifelong education and retraining. Beginning individually in rural Boulder, MT in 1947 it was possible to train in phenotype analysis with methods available to any GP, somewhat later to enlist collaborators at the Universities of Wisconsin and Washington, and finally to establish a genetic services program at a regional medical center (Shodair Children's Hospital in Helena) with fiscal support from the State Legislature amending and extending the prior Newborn Screening Act of Montana. With such financial stability it was possible to attract another physician, genetic counselors and a cytogeneticist to the Shodair Program. This genetic center now has expanded to a staff of 22 with advanced capabilities in cytogenetics, biochemistry and molecular biology (q.v. Elias in this issue). In these past 50 years then I have seen the Montana Genetics Program grow from humble rural beginnings to the amazing center it is now providing statewide outreach services, genetic education and the most advanced diagnostics and research. Now, it may not be inappropriate for me to recommend the Montana model for implementation in other genetically underserved regions throughout the United States. © 2014 Wiley Periodicals, Inc. KEY WORDS: genetic services; genetic education; genetic research; cytogenetics; molecular genetics; phenotype analysis
How to cite this article: Pallister PD. 2014. The study of genetic syndromes in a rural setting. Am J Med Genet Part C Semin Med Genet 9999:1–11.
INTRODUCTION For the purposes of this talk I shall present 10 of the genetic syndromes or conditions that were delineated phenotypically or defined causally at the Boulder River School and Hospital, Boulder, Montana and at Shodair Hospital, Helena, Montana between 1969 and 2011. These include private syndromes (one patient), familial entities (one family), and public syndromes (seen in two or more families and proven or presumed to be due to the same genetic cause), the “same” being used with care here since different classes of mutations of the same gene may produce different
phenotypes, even with different names. These conditions/syndromes are: The H form of craniosynostosis and mental retardation [Herrmann et al., 1969], autosomal dominant. The AR (private) syndrome of severe to profound mental retardation, craniosynostosis and limb defects [in Herrmann et al., 1969]. The MLH (private) translocation/mosaicism syndrome [Pallister et al., Pallister et al., 1974a; 1974a,b]. The Pallister W syndrome [Pallister et al., Pallister et al., 1974a; 1974a,b], X‐linked dominant.
The KBG or Herrman–Pallister–Opitz syndrome [Herrmann et al., 1975], autosomal dominant. The Pallister ulnar‐mammary syndrome, autosomal dominant, Pallister et al. [Pallister et al., 1976a; 1976a,b]. The KOP (private) translocation [Pallister and Opitz, 1978]. The Pallister–Killian mosaic i(12p) syndrome [Pallister et al., 1977]. The Pallister–Hall syndrome, autosomal dominant [Hall et al., 1980]. The Adam (private) syndrome [Pallister et al., 2011]. In addition we have worked on gonadal dysgenesis [Opitz and Pallister,
Presented at the Pallister Commemorative Meeting (Conference on Clinical Genetecs), Shodair Hospital, Helena, Montana, on July 11, 2014. Philip D. Pallister was born September 20, 1920 in Owatonna, MN, grew up in Rochester, MN, graduated M.D. in the class of 1944 from the University of Minnesota and served in the U.S. Army in World War II which took the life of his brother in Hausen, Germany on March 1, 1945. Pallister left the Army as the Acting Post Surgeon at Camp McCoy, Wisconsin in 1947 and began work as a GP and general surgeon in Boulder, MT where he and his wife, Willie, had 15 children. Met John Opitz at a Genetics of Mental Retardation Conference at the University of Wisconsin on May 31, 1965 and later his postdoctoral fellow Jürgen Herrmann, persuaded the former to move to Montana in 1979 and the latter to marry his only daughter. Metamorphosed from GP to GP (genetic practitioner) while Clinical Director of the Boulder River School and Hospital (for the mentally retarded). Responsible also for the Montana Prenatal and Newborn Screening Laws and the establishment of the Montana Medical Genetics Program at Shodair Hospital. *Correspondence to: Philip D. Pallister, M.D., Box 86, Boulder, MT 59632. E‐mail: [email protected] DOI 10.1002/ajmg.c.31418 Article first published online in Wiley Online Library (wileyonlinelibrary.com).
ß 2014 Wiley Periodicals, Inc.
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1979], the Perrault syndrome [Pallister and Opitz, 1979] and the Möbius and Hanhart syndromes. In completing these studies for publication I owe much to John Opitz, the girl‐for‐all or Swiss army knife of early medical genetics, with true cacoethes scribendi (demon to write), meticulous attention to the middle name of co‐ authors, annoying tendency to clean up my prose and not to shorten his sentences. It may also have been his notoriety, which persuaded, I suspect somewhat against their better judgment, so many colleagues east of Seattle to participate in our summer genetics seminars.
CLINICAL ILLUSTRATIONS (1.) H‐form of craniosynostosis and mental retardation1 [Herrmann et al., 1969, Fig. 1]. The proposita (III‐7), institutionalized since age 4, was evaluated at age 8 years. She had a condition of shortness of stature, microbrachycephaly (OFC 49.8 cm), ankyloses of first metacarpophalangeal joints, genua valga, and premature closure of the coronal suture. Her brother (III‐4) had had striking scaphocephaly at birth, was operated on with final IQ of 82, and OFC of 60 cm. Her sister (III‐5), at 12 years had an OFC of 53.2, premature closure of all sutures, seizures, “normal” IQ with dropping grades. The condition in this family is an autosomal dominant, females having largely brachycephaly and males dolichocephaly. (2.) This paper [Herrmann et al., 1969] also contained illustrations of the syndromes of Apert and Crouzon and unclassified craniosynostosis syndromes including that of AR,1 an 11‐year‐old boy of white/Flathead Indian descent transferred from Montana’s Warm Springs Hospital for the mentally ill. He had a striking condition of (Fig. 2) microbrachycephaly (OFC 50.8 cm), earlier coronal craniosynostectomy, hypertelorism, par1
We have retained the terminology from the original paper throughout the article.
tially repaired cleft lip/palate, permanent flexion ankyloses of hips and knees, absent radii, 4th and 5th fingers, short ulnae, partially cleft 3rd finger with two nails, bilateral fibular agenesis, bilateral cryptorchidism, and profound mental retardation. He moved about by sliding on the floor, was aphasic but attempted communication with grunting and grimaces. This boy with a unique, private syndrome had “apparently” normal chromosomes in 1969, but if restudied now may very likely had had the kind of microdeletion/‐duplication discovered 50 years later in the last “patient” of this report. (3.) MLH translocation mosaicism. This severely to profoundly retarded woman (Fig. 3A) had had repair of cleft lip/palate with postoperative onset of seizures; she did not walk until 3 years and was aphasic at the time of our studies. She had downslanting palpebral fissures, strabismus and distorted nose and mouth. Prebanding cytogenetic studies showed apparently normal chromosomes in all fibroblasts and a translocation between a C and an F chromosome in virtually all lympho-
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cytes. Restudy of her chromosomes at the University of Wisconsin (Klaus Patau) and in the Cytogenetics Laboratory of the State Lab of Hygiene at the University of Wisconsin by Dr. Stan Inhorn uncovered mosaicism for an “unusual translocation chromosome” [Pallister et al., Pallister et al., 1974a; 1974a,b], Figure 3B. (4.) The Pallister W syndrome (OMIM 311450). This X‐linked, partially dominant condition was first published in 1974 [Pallister et al., Pallister et al., 1974a; 1974a,b]. Initially thought to be unique to the W family of Montana it has since been seen in a sporadic case from Michigan by John Opitz and in a Milwaukee family by Jürgen Herrmann when he was still in practice. But, it remains a rare condition.
RW (II‐3). Birthdate 10/6/1950, with birth weight 2,034 g, notch‐ like indicated upper midline lip cleft with maxillary alveolar and anterior submucous cleft of palate, crowding of maxillary teeth and lack of upper incisors. He was moderately to severely mentally retarded. SW (II‐5) has virtually
Figure 1. (A) The proposita (III‐7) in the H‐craniosynostosis kindred. Reprint from Herrmann et al. [1969]. (B) Her kindred. Affected males generally with dolichocephaly, females with brachycephaly. Redrawn (JMO) from Pallister slide.
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grand mal seizures. In this case their mother had had a history of mental illness, strabismus and preterm labor, all pregnancies delivered before eight months; their sister was also mildly affected but had a severely affected son (Fig. 4C). Bottani and Schinzel [1993] described a boy considered to have the Pallister W syndrome. Goizet et al. [1999] reported on two brothers and a sporadic case with this condition and reviewed findings in four families so far, most essentially a “boxer’s” facial appearance with prominent chin and CNS involvement with mental retardation, seizures, strabismus (and spasticity) (Fig. 4D).
Figure 2. (A–G) Severely mentally retarded male with unique MCA syndrome (see text). In 1969 he had apparently normal chromosomes; if still living deserves restudy. From Herrmann et al. [1969].
identical findings to those of his brother (Fig. 4A, B). To some extent their condition resembles Gorlin’s OPD syndrome, however
ruled out on a visit by Dr. Gorlin for lack of hand involvement and deafness. In addition to mental retardation the affected males have
Figure 3. (A) The proposita of Pallister et al. [1971], at age 41. Reprinted from Proc II Int Congr Int Ass Sci Study Mental Deficiency [Warsaw, 1970]. Warsaw: Polish Medical Publishers, pp. 313–332. (B) Her translocation t(6p;19q). Original image by K. Patau, University of Wisconsin. From Pallister et al. [Pallister et al., 1974a; 1974a,b], Clin Genet 5:188–195.
(5.) The KBG (Herrmann, Pallister, Opitz) syndrome (OMIM 148060); the acronym representing the initials of the surnames of the first three families studied with this MR/MCA syndrome, not the former Soviet secret service. The phenotype includes: a
The KBG (Herrmann, Pallister, Opitz) syndrome (OMIM 148060); the acronym representing the initials of the surnames of the first three families studied with this MR/MCA syndrome, not the former Soviet secret service.
striking and characteristic facial appearance of prominent chin, broad eyebrows, with or without synophris, hypertelorism or telecanthus, anteversion of nostrils, long upper lip, smooth philtrum, diminished vermilion width of lips, macrodontia of upper central incisors with four to five mammelons, poly‐ or oligodontia, large ears, brachy‐ or turricephaly, and apparently short or webbed neck (Fig. 5). The physiognostic signs are so
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Figure 4. (A, B) W brothers (III‐5, ‐7 in D). From Pallister et al. [Pallister et al., 1974a; 1974a,b] Clin Genet 5:188–195. (C) Kindred of W brothers with manifesting mother and sister. Redrawn/modified from Pallister et al. [Pallister et al., 1974a; 1974a,b] and 2014 presentation. (D) Patient 1 of Goizet et al. at 16 years with W syndrome. From Goizet et al. [1999], Am J Med Genet. 87(5):446–449.
striking that as the third patient was walking towards me with his father I was able to predict to ophthalmologist/dentist Dr. Vince Amicucci standing beside me that the boy had at least four mammelons on his centrals. He looked and confirmed the finding. Most striking limb findings are brachydactyly of fingers/toes, clinodactyly of 5th finger, and cutaneous syndactyly of toes 2 and 3. Radiographically there may be cervical ribs, spina bifida occulta, vertebral segmentation defects, hip dysplasia, and delayed bone age. Affected males may have cryptorchidism; all patients are developmentally delayed.
KBG syndrome maps to 16q24.3, a site which may also harbor microdeletions with a predisposition to autistic disorders, so far not observed in the KBG
syndrome [Khalifa et al., 2013]. This autosomal dominant disorder, so far not heterogenous, is due to mutations or deletions (haploinsufficiency) of the ANKRD11 gene [Sirmaci et al., 2011], which is expressed in neurons and glial cells [Tunovic et al., 2014]. So far some 60 families have been described [Khalifa et al., 2013]. (6.) The Pallister ulnar‐mammary syndrome (OMIM 181450) was ascertained in a young woman with a limb malformation and a history of imperforate hymen, normal cognition, menarche and menses, no body odor or acne, and a decreased ability to sweat. Growth was normal. At 16 years she had slight left craniofacial hypoplasia with a wide midface; in retrospect I wonder if modern cephalometry methods might demonstrate increased fluctuating craniofacial asymmetry.
The Pallister ulnar‐mammary syndrome (OMIM 181450) was ascertained in a young woman with a limb malformation and a history of imperforate hymen, normal cognition, menarche and menses, no body odor or acne and a decreased ability to sweat.
She had congenital absence of all four canine teeth and of xiphisternum, a bifid uvula, minimal breast tissue even after mammary implants, somewhat
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normal; said to have had late sexual maturation with delayed growth spurt (height now about 188 cm) and not to produce body odor. III‐22: patient’s aunt had congenital absence of 5th finger; hymenotomy was performed at 16 years; breast is absent on right and hypoplastic on left but nipples are present bilaterally; no breast enlargement during pregnancy or by hormonal therapy; had C section for either cephalo‐pelvic disproportion or uterine “insufficiency”; has had mammary implants. IV‐19: patient’s cousin has small 5th finger fixed in extension.
Thus, after 1975 the condition in the proposita and her family impressed us as:
Figure 5. KBG syndrome. (A) Case 1 at 8 years. (B) Case 2 at 7 years. (C) Case 6: propositus of G family at 8‐1/2 years. (D) Macrodontia of case 1. From Herrmann et al. [1975], Birth Defects Orig Artic Ser XI(5):7–18.
attenuated left clavicle, and sparse axillary and pubic hair. Upper limbs were asymmetrically affected with hypoplasia of forearm bones more so on left than on right and absence of left fingers 4 and 5 (with metacarpals); 50% cutaneous syndactyly between digits two and three had been repaired—these digits were of normal size but the thumb was camptodactylous and dislocated at the metacarpophalangeal joint. On the right there was rudimentary postaxial hexadactyly but the hand was intact. Left ulna measured 12 cm and was attenuated distally; the right ulna was at the 10th centile for length. Left radius was correspondingly bowed and the wrist lacked the triquetrum, hamate, and pisiform bones. She had a moderately severe thoracic scoliosis. Intellect was normal as was that of all affected individuals (Fig. 6A,B).
The pedigree of the proposita (IV‐15) is in Figure 6C. Relatives were not examined, but historically the following information was provided: I‐2: had “stiff and crooked” 5th finger. I‐3: “affected.” II‐6: this man had “deformed and almost jointless” 5th finger; photos demonstrated delayed physical and sexual maturation with striking sexual (facial profile and beard) maturation during his 20s. II‐9: patient’s paternal grandmother is reported as not visibly affected but is said to have had no body odor and decreased sweating. III‐21: patient’s father had right 5th finger camptodactyly which was amputated in the PIP joint in childhood; left hand reportedly
An autosomal dominant or X‐linked incompletely recessive trait. As a complex pleiotropic condition arising early in gestation, to judge by upper limbs no later than GA day 26 or 28 when the limbbuds form, and causing apparently increased fluctuating asymmetry around the midline. Mosaic pleiotropy involving palate, dentition, xiphisternum, limbs, apocrine and mammary glands, hymen and sexual maturation. Some of the anomaly combinations perhaps representing polytopic defects or effects all due to regional or distant pathogenetic action and reaction analogous to the radial limb and cardiac involvement in the Holt–Oram syndrome (and most likely involving signal translocation cascades—added 2014). This condition is again a demonstration of Meckel’s original insight that duplication in one limb may be the developmental equivalent of deficiency in the contralateral one, most commonly affecting thumbs, much more rarely ulnar rays [q.v. Birch‐Jensen, 1949; and Temtamy and McKusick, 1978]. The former noted 19 ulnar defects in 625 individuals with upper limb defects (3%,
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the normal first venue for the publication of “new” syndromes. And so, two parallel traditions arose referring either to the Schinzel syndrome [e.g., Hecht and Scott, 1984] or the Pallister ulnar‐ mammary syndrome [e.g., Bamshad et al., 1996]. Clinicians generally are sloppier than zoologists in naming species, the latter, by international convention since Linnaeus, adhering strictly to priority of full publication, a practice natural to John M. Opitz, a card‐carrying zoologist. But, priority being a lesser concern to me than the full and accurate documentation of the biology, I may suggest the eponym Pallister–Schinzel, analogous to Pallister–Killian, etc., or simply UMS. In the above‐cited study of Bamshad et al. [1996] their patient II‐3 is patient I‐3 of Pallister et al. [Pallister et al., 1976a; 1976a,b] marked there with a ? since affected by history only; he can now be marked as fully affected transmitting his condition to 33 descendants in six generations. In that study the gene was mapped to HAS
Figure 6. Ulnar‐mammary syndrome. (A) Proposita. (B) Her forearms. (C) Her kindred modified from Pallister et al. [Pallister et al., 1976a; 1976a,b] marking I‐3 now affected and identical with II‐3 of Bamshad et al., 1996. From Pallister et al. [Pallister et al., 1976a; 1976a,b], Birth Defects Orig Artic Ser XII(5):247–254. (D) Pedigree of the family in C, updated and extended by Bamshad et al. [1996]. Unnumbered, to be read as if numbered from left to right. Thus, II‐3 here is Pallister I‐3, his descendants are in C, studied 20 years before Bamshad et al., Am J Med Genet 65:325–331.
1/211,789 incidence in the Danish population vs. 12% radial defects, 1/ 55,123).
Addendum: The above is not to denigrate in the slightest the contribution of Werner Schinzel of Zürich to the study of this entity having finally published [Schinzel et al., 1987] details of the family he had communicated to
McKusick who in turn cited it in the 1973 MIM. Working from this personal communication Temtamy and McKusick referred to a “Schinzel syndrome of ulnar ray defects, hypogenitalism and anal atresia” in their book on the genetics of hand malformations [1978]. MIM, and its successor OMIM were then and still are not
TBX3 is a transcriptional repressor expressed early in ontogeny in lateral plate mesoderm, limb buds, mammary primordia, first arch mesenchyme and the genital tubercle. Whereas TBX5 is a transcriptional activator of upper limb and heart development.
12q23‐q24.1. It turned out to be TBX3, well known for its role in the Holt–Oram syndrome [HOS; Bamshad et al., 1997, 1999; Wollnik et al., 2002]. TBX3 is a transcriptional repressor expressed early in ontogeny in lateral plate mesoderm, limb buds, mammary primordia, first arch mesenchyme, and the genital tubercle.
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Whereas TBX5 is a transcriptional activator of upper limb and heart development. Loss of either gene is not compensated by the other and of both is expected to have severe effects. However, in a unique Czech family three individuals had a deletion of TBS3 and TBX5 with a mild phenotype partaking of HOS and UMS [Borozdin et al., 2006]. (7.) The KOP translocation. If I had to make a choice, it would probably be the KOP translocation among all of my studies that provided more refreshing BS,2 greater biological depth, more stimulating professional associations and intellectually satisfying conclusion than all the others, but not by much, since no condition in medical genetics is uninteresting or lacking its own unique pathos. Thus, the referral of the KOP propositus for vocational rehabilitation because of his mental deficiency overlooking his syndrome; local evaluation for delayed puberty overlooking his Klinefelter syndrome; cytogenetic study in Great Falls, MT reporting his chromosome abnormalities as “a type not uncommon in retarded persons” ignoring phenotype and buccal smear findings and missing X‐chromosome involvement; or the evaluation of his mother for six spontaneous miscarriages without chromosome analysis.
After confirmation of an X‐ autosome translocation in our propositus, which John Opitz shouted from the rooftops in Europe we fetched up in New York, the Albert Einstein College of Medicine of Yeshiva University with a preceding night at the Bronx Park Motel across from the zoo entrance, near Fordham University. John got there first, to inventory our six‐legged roommates when he heard someone whistling the theme from the film Dr. Zhivago outside announcing Pallister’s arrival. I flung my travel case on a low bench which promptly collapsed releasing an “Baloney & salami,” according to Erynn Johnson.
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astonishing swarm of several species of cockroaches. The night was disturbed not by lions or Jesuit priests but by the hourly activity in the adjacent room and the skittering of bad smelling cockroaches in our room. John spent much of the night occupying himself killing cockroaches. I spent my time trying to avoid them and listening to sounds from the adjoining room. Hurrying to leave the place in the morning I forgot my toilet kit which, when returned to me at the medical school was intact except for the straight razor, a wedding gift from my father. At Einstein we met a stellar faculty including Harold Nitowsky, Harold Klinger, and Marcello Siniscalco (who was also a faculty member at Leiden University). John also introduced me to the formidable and renowned Salome Glücksohn‐Waelsch who must have regarded me somehow as Darwin did the Fuegians in the last century (as usual I was dressed as a western rancher, cowboy boots and hat, no tie and beard. Coworkers were there from Leiden, Yale (Ruddle, Ricciuti), and Columbia University (O.J. Miller, P.W. Allderdice). The most junior colleague there, Andy L. Kosseff, then a medical student, later became one of John’s coworkers in Madison. But, the evaluation of this extraordinary patient ultimately also involved Drs. Inhorn, Meisner, Kosseff, and Jürgen Herrmann (Madison), H. Eldon Sutton (Austin, TX), Ruth Sanger and Rob Race and Elisabeth Robson (London). Details are provided by John Opitz, in this issue. (8.) The Pallister–Killian syndrome (OMIM 601803). When study of the first two patients at Boulder, recently transferred from the Warm Springs State Hospital for the Mentally Ill, made it likely that they had the same syndrome; then John Opitz, bursting with this new knowledge, importuned Elisabeth Kaveggia at Central
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Colony in Madison to find another severely retarded patient with severe epilepsy, microcephaly, supernumerary nipples, spasticity, and most importantly, with pigmentary streaking of the skin. She did; that patient’s surname was the same as my maternal grandfather’s Scotch clan name, raising the interesting possibility we might be related.
Results of chromosome studies of skin fibroblasts from these three individuals were initially interpreted as trisomy 20 by B. Rafael Elejalde in the Opitz group; however, a critical reinvestigation of the mother, by Uta Francke at Stanford, made it far more likely that the small extra chromosome in fibroblasts was, in fact an isochromosome 12p. Hence, our 1977 paper on the Pallister mosaic aneuploidy syndrome. Ian Krantz has since become the world expert on this condition with an authoritative series of research papers in the American Journal of Medical Genetics. His presentation is included in this issue. (9.) The Pallister–Hall syndrome (OMIM 146510). The index patient was not seen alive. He was delivered on February 27, 1978 by section for persistent breech presentation, birth weight, length and OFC at the 10th, 15th, and 50th centile, respectively. He lived 9 hr and was buried without autopsy or embalming. The attending pediatrician, Dr. Eric Livers of Bozeman, sent data and films to me in consultation. The infant had had multiple oral frenula, postaxial hexadactyly of left hand and foot, cutaneous syndactyly, microphallus, and imperforate anus. The films had suggested the Ellis‐van Creveld syndrome to local radiologists, something easily ruled out; however, gas in gut, essentially none in lungs suggested a TE fistula; the sella was broad and shallow; there was incipient polydactyly of the right thumb and an abnormal right 4th metacarpal.
At the annual Shodair Genetics Seminar on July 5, 1978 the infant
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was discussed with John Opitz, Jürgen Herrmann and Judy Hall without diagnosis, however, with imprinting of the phenotype in Judy Hall’s mind such that within a month after returning to Seattle she was able to make the diagnosis of this syndrome in her first patient who had the tumor. At that point I arranged exhumation. The baby had not eaten (no Gram‐negative bacteria in gut), was not decomposed, was put in formalin wraps and we drove it to the University of Washington, Seattle, was autopsied and was followed in October by a third case transferred from Alaska to Seattle. Initial investigations into potential teratogens were inconclusive. Hall et al. [1980] then reported on the first six infants with congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate anus, and postaxial polydactyly (Fig. 7A– C), followed a.o. by Iafolla et al. [1989] and by Pallister et al. [1989] on three cases respectively from
Montana, Arizona, and Wisconsin, so far all sporadic. The autosomal
Hall et al. then reported on the first six infants with congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate anus, and postaxial polydactyly (Fig. 7A–C), followed a.o. by Iafolla et al. and by Pallister et al. on three cases respectively from Montana, Arizona, and Wisconsin, so far all sporadic. dominant nature of the PHS did not become apparent until 1993/
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1994, setting aside teratological concerns. Hypothalamic tumor is in Figure 7D. The PHS gene was determined to be allelic with that of the Greig cephalopolysyndactyly syndrome (GCPS), namely GLI3, the phenotypic differences apparently being due to mutational differences. Table 24‐4 in Biesecker [2008] shows GCPS to be due to translocation, deletion, missense, splicing and frameshift/nonsense mutations with PHS essentially caused by frameshift/nonsense mutations 30 of the zincfinger domain. (10.) The Adam translocation syndrome. Speaking of “private” syndromes! The disorder under this head is “very” private in a double sense— involving my son Adam and an apparently unique, or at least previously undescribed, chromosome abnormality. The story was published so recently [Pallister et al., 2011] that interested readers are invited to look it over for essential details. However,
Figure 7. Postmortem images of infants with Pallister–Hall syndrome. (A) Patient 1. (B) Patient 2. (C) Patient 4 from Hall et al. [1980], Am J Med Genet 7:47–74. (D) Coronal and sagittal sections/views of brain respectively of Patient 2 and of Patient 3 showing hypothalamic hamartoblastoma replacing “hypothalamus and its related nuclei” from Clarren et al. [1980], Am J Med Genet 7:75–83.
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two important conclusions from that study bear repetition here.
In case of diagnostic unknowns the patient/family must be revisited periodically in light of recent diagnostic/nosologic advances, not just
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to satisfy someone’s curiosity, but most importantly to provide closure and essential reproductive information to the family. In such cases tissue or DNA must be archived for later reanalysis by ever more sensitive methods.
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In the case of Adam, it took a half century for such a reanalysis to finally document cause and to “settle” the case. You may want to learn the outcome of these studies (Fig. 8) in Pallister et al. [2011] and to relearn the old adage that results are always apparently normal until
Figure 8. (A) Propositus (Adam) with faithful companion (“Jasmine”) in Jaybird Ranch work. (B) Chromosome findings in Adam. (C) Their interpretation as t(14q;13q) with breakpoints at 14q32.2 and 13q34. From Pallister et al. [2011], Am J Med Genet Part A 155: 833–839.
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later proven otherwise. Adam’s smile (Fig. 8) can easily compete with that of Jasmine; he is always happy to autograph a copy of “his” report for others. His hugs are such you had better first take glasses out of breast pocket.
COLOPHON In 1947 I arrived destined to be a GP and general surgeon in Boulder, Montana with my wife, Willie, after wartime medical studies and subsequent Army service. Little did I realize then that some 15–20 years later I would also become another kind of GP—genetic practitioner, always on the look‐out for pleiotropy, hence continually sharpening my skill in the evaluation of the entire patient, clothed or unclothed, dead or alive, young or old, male or female, with delayed or normal cognition. Victor McKusick once said that to me with some pride, “Phil, I am also a GP, like you, in the study and care of the entire patient—I call myself a Genetic Practitioner.” Sewing up wounds in the ER, repairing a hip, removing a malignant thyroid, handling a measles or chickenpox epidemic or delivering babies does not in the slightest preclude genetic analysis at all levels; but, I’m skeptical that any geneticists remain who can do the same while raising 14 sons and a daughter or create their own cattle breed or build a house, repair a truck engine or conduct archeological research into Native American prehistory. And none of this would have been possible without the help of the great geneticists and scientists who have brought me along on this journey as has John Opitz in this final effort who has graciously edited this story and brought it up to current standards of existing knowledge. And for the chance to have done or been all that and more I am grateful. September 20, 2014 on my 94th birthday. Auld Phil
REFERENCES Bamshad M, Roots S, Carey JC. 1996. Clinical analysis of a large kindred with the Pallister ulnar‐mammary syndrome. Am J Med Genet 65:325–331.
Bamshad M, Lin RC, Law DJ, Watkins WC, Krakowiak PA, Moore ME, Franceschini P, Lala R, Holmes LB, Gebuhr TC, Bruneau BG, Schinzel A, Seidman JG, Seidman CE, Jorde LB. 1997. Mutations in human TBX3 alter limb, apocrine and genital development in ulnar‐mammary syndrome. Nat Genet 16:311–315. Bamshad M, Le T, Watkins WS, Dixon ME, Kramer BE, Roeder AD, Carey JC, Root S, Schinzel A, Van Maldergem L, Gardner RJ, Lin RC, Seidman CE, Seidman JG, Wallerstein R, Moran E, Sutphen R, Campbell CE, Jorde LB. 1999. The spectrum of mutations in TBX3: Genotype/ phenotype relationship in ulnar‐mammary syndrome. Am J Hum Genet 64:1550– 1562. Biesecker LG. 2008. GLI3 and the Pallister–Hall and Greig cephalopolysyndactyly syndromes. Ch 24 In: Epstein CJ, Erickson RP, Wynshaw‐Boris A, editors. Inborn errors of development, the molecular basis of clinical disorders of morphogenesis. 2nd edition. Boulder, MT: Oxford University Press. pp 313–321. Birch‐Jensen A. 1949. Congenital deformities of the upper extremities. MD thesis, translated from the Danish. Acta Domus Biologiae Hereditariae Humanae Universitatis Hafniensis. Det danske Forlag and Andelsbogtrykkeriet i Odense. Borozdin W, Bravo‐Ferrer Acosta AM, Seemanova E, Leipoldt M, Bamshad MJ, Unger S, Kohlhase J. 2006. Contiguous hemizygous deletion of TBX5, TBX3, and RBM19 resulting in a combined phenotype of Holt–Oram and ulnar‐mammary syndromes. Am J Med Genet 140A:1880– 1886. Bottani A, Schinzel A. 1993. A third patient with median cleft upper lip, mental retardation and pugilistic facies (W syndrome): Corroboration of a hitherto private syndrome. Clin Dysmorphol 2:225–231. Clarren SK, Alvord EC, Hall JG. 1980. Congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate anus, and postaxial polydactyly—A new syndrome? Part II: Neuropathological considerations. Am J Med Genet 7:75–83. Goizet C, Bonneau D, Lacombe D. 1999. W syndrome: Report of three cases and review. Am J Med Genet 22; 87:446– 449. Hall JG, Pallister PD, Clarren SK, Beckwith JB, Wiglesworth FW, Fraser FC, Cho S, Benke PJ, Reed SD. 1980. Congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate anus and postaxial polydactyly—A new syndrome? Part I: Clinical, causal, and pathogenetic considerations. Am J Med Genet 7:47–74. Hall JG. 2014. This issue of AJMG. Herrmann J, Pallister PD, Opitz J. 1969. Studies of malformation syndromes XXII: Craniosynostosis and craniosynostosis syndromes. Rocky Mountain Med J 66:45–56. Herrmann J, Pallister PD, Opitz JM. 1975. The KBG syndrome: A syndrome of short stature, characteristic facies, mental retardation, macrodontia and skeletal anomalies. Birth Defects Orig Artic Ser XI(5); 7–18.
ARTICLE Iafolla K, Fratkin JD, Spiegel PK, Cohen MM Jr, Graham JM Jr. 1989. Case report and delineation of the congenital hypothalamic hamartoblastoma syndrome (Pallister– Hall syndrome). Am J Med Genet 33:489– 499. Khalifa M, Stein J, Gran L, Nelson V, Meck J, Aradhya S, Duby J. 2013. Partial deletion of ANKRD11 results in the KBG phenotype distinct from the 16q24.3 microdeletion syndrome. Am J Med Genet 161A:835– 840. Krantz I. 2014. This issue of AJMG. Opitz JM, Pallister PD. 1979. Brief historical note: The concept of gonadal dysgenesis. Am J Med Genet 4:333–343. Pallister PD, Patau K, Inhorn SL, Opitz JM. 1974. Studies of malformation syndromes of man XXX: A woman with multiple congenital anomalies, mental retardation and mosaicism for an unusual translocation chromosome t(6;19). Clin Genet 5:188– 195. Pallister PD, Herrmann J, Spranger JW, Langer LO, Gorlin RF, Opitz JM. 1974. Studies of malformation syndromes in man XXVIII: The W syndrome. Birth Defects Orig Artic Ser X(7):51–60(First delineation). Pallister PD, Herrmann J, Opitz JM. 1976. Studies of malformation syndromes in man XXXXII: A pleiotropic dominant mutation affecting skeletal, sexual and apocrine–mammary development. Birth Defects Orig Artic Ser XII(5):247–254. Pallister PD, Herrmann J, Meisner LF, Inhorn SL, Opitz JM. 1976. Trisomy‐20 syndrome in man. Lancet 1:431.(First delineation of so‐ called Pallister–Killian syndrome). Pallister PD, Meisner LF, Elejalde BR, Francke U, Herrmann J, Spranger J, Tiddy W, Inhorn SL, Opitz JM. 1977. Studies of malformation syndromes of man XLIIIC: The Pallister mosaic aneuploidy syndrome. Birth Defects Orig Artic Ser III(3)B:103– 110. Pallister PD, Opitz JM. 1978. Studies of malformation syndromes in Man LI: The KOP translocation. Birth Defects Orig Artic Ser XIV(6)C:133–146. Pallister PD, Opitz JM. 1979. Perrault syndrome: Autosomal recessive ovarian dysgenesis with facultative, non‐sex‐limited severe sensori‐ neural deafness. Am J Med Genet 4:239– 246. Pallister PD, Kaveggia EG, Inhorn SL, Meisner L, Opitz JM. 1971. Chromosome studies in malformation/retardation syndromes. Proc II Int Congr Int Ass Sci Study Mental Deficiency (Warsaw 1970). Warsaw: Polish Medical Publishers. pp. 313–332. Pallister PD, Hecht F, Herrmann J. 1989. Three additional cases of the congenital hypothalamic “hamartoblastoma” (Pallister– Hall) syndrome. Am J Med Genet 33:500– 501. Pallister PD, Pallister AB, South S, Toydemir R, Johnson JP, Beischel L, Opitz JM. 2011. A deletion 13q34/duplication 14q32.2‐ 14q32.33 syndrome diagnosed 50 years after neonatal presentation as infantile hypercalcemia. Am J Med Genet 155A: 833– 839. Schinzel A, Illig R, Prader A. 1987. The ulnar‐ mammary syndrome: An autosomal
ARTICLE dominant pleiotropic gene. Clin Genet 32:160–168. Sirmaci A, Spiliopoulos M, Brancati F, Powell E, Duman D, Abrams A, Bademci G, Agolini E, Guo S, Konuk B, Kavaz A, Blanton S, Digilio MC, Dallapiccola B, Young J, Zuchner S, Tekin M. 2011. Mutations in ANKRD11 cause KBG syndrome, characterized by intellectual disability, skeletal malformations,
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) and macrodontia. Am J Hum Genet 89:289– 294. Temtamy S, McKusick VA. 1978. The genetics of hand malformations. Alan R. Liss for the National Foundation—March of Dimes, Birth Defects Orig Artic Ser XIV (3),1978. Tunovic S, Barkovich J, Sherr EH, Slavotinek AM. 2014. De novo ANKRD11 and
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KDM1A gene mutations in a male with features of KBG syndrome and Kabuki syndrome. Am J Med Genet 164A:1744– 1749. Wollnik B, Kayserili H, Uyguner O, Tukel T, Yuksel‐Apak M. 2002. Haploinsufficiency of TBX3 causes ulnar‐mammary syndrome in a large Turkish family. Ann Genet 45:213– 217.
A R T I C L E
The Study of Genetic Syndromes in a Rural Setting PHILIP D. PALLISTER
The syndromal and genetic biology reported and reviewed herein can be studied, analyzed and reported by any “GP” with the required gifts, enthusiasm, drive, and ability to work with collaborators of goodwill at University centers near or far; and most importantly, to continue lifelong education and retraining. Beginning individually in rural Boulder, MT in 1947 it was possible to train in phenotype analysis with methods available to any GP, somewhat later to enlist collaborators at the Universities of Wisconsin and Washington, and finally to establish a genetic services program at a regional medical center (Shodair Children's Hospital in Helena) with fiscal support from the State Legislature amending and extending the prior Newborn Screening Act of Montana. With such financial stability it was possible to attract another physician, genetic counselors and a cytogeneticist to the Shodair Program. This genetic center now has expanded to a staff of 22 with advanced capabilities in cytogenetics, biochemistry and molecular biology (q.v. Elias in this issue). In these past 50 years then I have seen the Montana Genetics Program grow from humble rural beginnings to the amazing center it is now providing statewide outreach services, genetic education and the most advanced diagnostics and research. Now, it may not be inappropriate for me to recommend the Montana model for implementation in other genetically underserved regions throughout the United States. © 2014 Wiley Periodicals, Inc. KEY WORDS: genetic services; genetic education; genetic research; cytogenetics; molecular genetics; phenotype analysis
How to cite this article: Pallister PD. 2014. The study of genetic syndromes in a rural setting. Am J Med Genet Part C Semin Med Genet 9999:1–11.
INTRODUCTION For the purposes of this talk I shall present 10 of the genetic syndromes or conditions that were delineated phenotypically or defined causally at the Boulder River School and Hospital, Boulder, Montana and at Shodair Hospital, Helena, Montana between 1969 and 2011. These include private syndromes (one patient), familial entities (one family), and public syndromes (seen in two or more families and proven or presumed to be due to the same genetic cause), the “same” being used with care here since different classes of mutations of the same gene may produce different
phenotypes, even with different names. These conditions/syndromes are: The H form of craniosynostosis and mental retardation [Herrmann et al., 1969], autosomal dominant. The AR (private) syndrome of severe to profound mental retardation, craniosynostosis and limb defects [in Herrmann et al., 1969]. The MLH (private) translocation/mosaicism syndrome [Pallister et al., Pallister et al., 1974a; 1974a,b]. The Pallister W syndrome [Pallister et al., Pallister et al., 1974a; 1974a,b], X‐linked dominant.
The KBG or Herrman–Pallister–Opitz syndrome [Herrmann et al., 1975], autosomal dominant. The Pallister ulnar‐mammary syndrome, autosomal dominant, Pallister et al. [Pallister et al., 1976a; 1976a,b]. The KOP (private) translocation [Pallister and Opitz, 1978]. The Pallister–Killian mosaic i(12p) syndrome [Pallister et al., 1977]. The Pallister–Hall syndrome, autosomal dominant [Hall et al., 1980]. The Adam (private) syndrome [Pallister et al., 2011]. In addition we have worked on gonadal dysgenesis [Opitz and Pallister,
Presented at the Pallister Commemorative Meeting (Conference on Clinical Genetecs), Shodair Hospital, Helena, Montana, on July 11, 2014. Philip D. Pallister was born September 20, 1920 in Owatonna, MN, grew up in Rochester, MN, graduated M.D. in the class of 1944 from the University of Minnesota and served in the U.S. Army in World War II which took the life of his brother in Hausen, Germany on March 1, 1945. Pallister left the Army as the Acting Post Surgeon at Camp McCoy, Wisconsin in 1947 and began work as a GP and general surgeon in Boulder, MT where he and his wife, Willie, had 15 children. Met John Opitz at a Genetics of Mental Retardation Conference at the University of Wisconsin on May 31, 1965 and later his postdoctoral fellow Jürgen Herrmann, persuaded the former to move to Montana in 1979 and the latter to marry his only daughter. Metamorphosed from GP to GP (genetic practitioner) while Clinical Director of the Boulder River School and Hospital (for the mentally retarded). Responsible also for the Montana Prenatal and Newborn Screening Laws and the establishment of the Montana Medical Genetics Program at Shodair Hospital. *Correspondence to: Philip D. Pallister, M.D., Box 86, Boulder, MT 59632. E‐mail: [email protected] DOI 10.1002/ajmg.c.31418 Article first published online in Wiley Online Library (wileyonlinelibrary.com).
ß 2014 Wiley Periodicals, Inc.
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1979], the Perrault syndrome [Pallister and Opitz, 1979] and the Möbius and Hanhart syndromes. In completing these studies for publication I owe much to John Opitz, the girl‐for‐all or Swiss army knife of early medical genetics, with true cacoethes scribendi (demon to write), meticulous attention to the middle name of co‐ authors, annoying tendency to clean up my prose and not to shorten his sentences. It may also have been his notoriety, which persuaded, I suspect somewhat against their better judgment, so many colleagues east of Seattle to participate in our summer genetics seminars.
CLINICAL ILLUSTRATIONS (1.) H‐form of craniosynostosis and mental retardation1 [Herrmann et al., 1969, Fig. 1]. The proposita (III‐7), institutionalized since age 4, was evaluated at age 8 years. She had a condition of shortness of stature, microbrachycephaly (OFC 49.8 cm), ankyloses of first metacarpophalangeal joints, genua valga, and premature closure of the coronal suture. Her brother (III‐4) had had striking scaphocephaly at birth, was operated on with final IQ of 82, and OFC of 60 cm. Her sister (III‐5), at 12 years had an OFC of 53.2, premature closure of all sutures, seizures, “normal” IQ with dropping grades. The condition in this family is an autosomal dominant, females having largely brachycephaly and males dolichocephaly. (2.) This paper [Herrmann et al., 1969] also contained illustrations of the syndromes of Apert and Crouzon and unclassified craniosynostosis syndromes including that of AR,1 an 11‐year‐old boy of white/Flathead Indian descent transferred from Montana’s Warm Springs Hospital for the mentally ill. He had a striking condition of (Fig. 2) microbrachycephaly (OFC 50.8 cm), earlier coronal craniosynostectomy, hypertelorism, par1
We have retained the terminology from the original paper throughout the article.
tially repaired cleft lip/palate, permanent flexion ankyloses of hips and knees, absent radii, 4th and 5th fingers, short ulnae, partially cleft 3rd finger with two nails, bilateral fibular agenesis, bilateral cryptorchidism, and profound mental retardation. He moved about by sliding on the floor, was aphasic but attempted communication with grunting and grimaces. This boy with a unique, private syndrome had “apparently” normal chromosomes in 1969, but if restudied now may very likely had had the kind of microdeletion/‐duplication discovered 50 years later in the last “patient” of this report. (3.) MLH translocation mosaicism. This severely to profoundly retarded woman (Fig. 3A) had had repair of cleft lip/palate with postoperative onset of seizures; she did not walk until 3 years and was aphasic at the time of our studies. She had downslanting palpebral fissures, strabismus and distorted nose and mouth. Prebanding cytogenetic studies showed apparently normal chromosomes in all fibroblasts and a translocation between a C and an F chromosome in virtually all lympho-
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cytes. Restudy of her chromosomes at the University of Wisconsin (Klaus Patau) and in the Cytogenetics Laboratory of the State Lab of Hygiene at the University of Wisconsin by Dr. Stan Inhorn uncovered mosaicism for an “unusual translocation chromosome” [Pallister et al., Pallister et al., 1974a; 1974a,b], Figure 3B. (4.) The Pallister W syndrome (OMIM 311450). This X‐linked, partially dominant condition was first published in 1974 [Pallister et al., Pallister et al., 1974a; 1974a,b]. Initially thought to be unique to the W family of Montana it has since been seen in a sporadic case from Michigan by John Opitz and in a Milwaukee family by Jürgen Herrmann when he was still in practice. But, it remains a rare condition.
RW (II‐3). Birthdate 10/6/1950, with birth weight 2,034 g, notch‐ like indicated upper midline lip cleft with maxillary alveolar and anterior submucous cleft of palate, crowding of maxillary teeth and lack of upper incisors. He was moderately to severely mentally retarded. SW (II‐5) has virtually
Figure 1. (A) The proposita (III‐7) in the H‐craniosynostosis kindred. Reprint from Herrmann et al. [1969]. (B) Her kindred. Affected males generally with dolichocephaly, females with brachycephaly. Redrawn (JMO) from Pallister slide.
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grand mal seizures. In this case their mother had had a history of mental illness, strabismus and preterm labor, all pregnancies delivered before eight months; their sister was also mildly affected but had a severely affected son (Fig. 4C). Bottani and Schinzel [1993] described a boy considered to have the Pallister W syndrome. Goizet et al. [1999] reported on two brothers and a sporadic case with this condition and reviewed findings in four families so far, most essentially a “boxer’s” facial appearance with prominent chin and CNS involvement with mental retardation, seizures, strabismus (and spasticity) (Fig. 4D).
Figure 2. (A–G) Severely mentally retarded male with unique MCA syndrome (see text). In 1969 he had apparently normal chromosomes; if still living deserves restudy. From Herrmann et al. [1969].
identical findings to those of his brother (Fig. 4A, B). To some extent their condition resembles Gorlin’s OPD syndrome, however
ruled out on a visit by Dr. Gorlin for lack of hand involvement and deafness. In addition to mental retardation the affected males have
Figure 3. (A) The proposita of Pallister et al. [1971], at age 41. Reprinted from Proc II Int Congr Int Ass Sci Study Mental Deficiency [Warsaw, 1970]. Warsaw: Polish Medical Publishers, pp. 313–332. (B) Her translocation t(6p;19q). Original image by K. Patau, University of Wisconsin. From Pallister et al. [Pallister et al., 1974a; 1974a,b], Clin Genet 5:188–195.
(5.) The KBG (Herrmann, Pallister, Opitz) syndrome (OMIM 148060); the acronym representing the initials of the surnames of the first three families studied with this MR/MCA syndrome, not the former Soviet secret service. The phenotype includes: a
The KBG (Herrmann, Pallister, Opitz) syndrome (OMIM 148060); the acronym representing the initials of the surnames of the first three families studied with this MR/MCA syndrome, not the former Soviet secret service.
striking and characteristic facial appearance of prominent chin, broad eyebrows, with or without synophris, hypertelorism or telecanthus, anteversion of nostrils, long upper lip, smooth philtrum, diminished vermilion width of lips, macrodontia of upper central incisors with four to five mammelons, poly‐ or oligodontia, large ears, brachy‐ or turricephaly, and apparently short or webbed neck (Fig. 5). The physiognostic signs are so
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Figure 4. (A, B) W brothers (III‐5, ‐7 in D). From Pallister et al. [Pallister et al., 1974a; 1974a,b] Clin Genet 5:188–195. (C) Kindred of W brothers with manifesting mother and sister. Redrawn/modified from Pallister et al. [Pallister et al., 1974a; 1974a,b] and 2014 presentation. (D) Patient 1 of Goizet et al. at 16 years with W syndrome. From Goizet et al. [1999], Am J Med Genet. 87(5):446–449.
striking that as the third patient was walking towards me with his father I was able to predict to ophthalmologist/dentist Dr. Vince Amicucci standing beside me that the boy had at least four mammelons on his centrals. He looked and confirmed the finding. Most striking limb findings are brachydactyly of fingers/toes, clinodactyly of 5th finger, and cutaneous syndactyly of toes 2 and 3. Radiographically there may be cervical ribs, spina bifida occulta, vertebral segmentation defects, hip dysplasia, and delayed bone age. Affected males may have cryptorchidism; all patients are developmentally delayed.
KBG syndrome maps to 16q24.3, a site which may also harbor microdeletions with a predisposition to autistic disorders, so far not observed in the KBG
syndrome [Khalifa et al., 2013]. This autosomal dominant disorder, so far not heterogenous, is due to mutations or deletions (haploinsufficiency) of the ANKRD11 gene [Sirmaci et al., 2011], which is expressed in neurons and glial cells [Tunovic et al., 2014]. So far some 60 families have been described [Khalifa et al., 2013]. (6.) The Pallister ulnar‐mammary syndrome (OMIM 181450) was ascertained in a young woman with a limb malformation and a history of imperforate hymen, normal cognition, menarche and menses, no body odor or acne, and a decreased ability to sweat. Growth was normal. At 16 years she had slight left craniofacial hypoplasia with a wide midface; in retrospect I wonder if modern cephalometry methods might demonstrate increased fluctuating craniofacial asymmetry.
The Pallister ulnar‐mammary syndrome (OMIM 181450) was ascertained in a young woman with a limb malformation and a history of imperforate hymen, normal cognition, menarche and menses, no body odor or acne and a decreased ability to sweat.
She had congenital absence of all four canine teeth and of xiphisternum, a bifid uvula, minimal breast tissue even after mammary implants, somewhat
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normal; said to have had late sexual maturation with delayed growth spurt (height now about 188 cm) and not to produce body odor. III‐22: patient’s aunt had congenital absence of 5th finger; hymenotomy was performed at 16 years; breast is absent on right and hypoplastic on left but nipples are present bilaterally; no breast enlargement during pregnancy or by hormonal therapy; had C section for either cephalo‐pelvic disproportion or uterine “insufficiency”; has had mammary implants. IV‐19: patient’s cousin has small 5th finger fixed in extension.
Thus, after 1975 the condition in the proposita and her family impressed us as:
Figure 5. KBG syndrome. (A) Case 1 at 8 years. (B) Case 2 at 7 years. (C) Case 6: propositus of G family at 8‐1/2 years. (D) Macrodontia of case 1. From Herrmann et al. [1975], Birth Defects Orig Artic Ser XI(5):7–18.
attenuated left clavicle, and sparse axillary and pubic hair. Upper limbs were asymmetrically affected with hypoplasia of forearm bones more so on left than on right and absence of left fingers 4 and 5 (with metacarpals); 50% cutaneous syndactyly between digits two and three had been repaired—these digits were of normal size but the thumb was camptodactylous and dislocated at the metacarpophalangeal joint. On the right there was rudimentary postaxial hexadactyly but the hand was intact. Left ulna measured 12 cm and was attenuated distally; the right ulna was at the 10th centile for length. Left radius was correspondingly bowed and the wrist lacked the triquetrum, hamate, and pisiform bones. She had a moderately severe thoracic scoliosis. Intellect was normal as was that of all affected individuals (Fig. 6A,B).
The pedigree of the proposita (IV‐15) is in Figure 6C. Relatives were not examined, but historically the following information was provided: I‐2: had “stiff and crooked” 5th finger. I‐3: “affected.” II‐6: this man had “deformed and almost jointless” 5th finger; photos demonstrated delayed physical and sexual maturation with striking sexual (facial profile and beard) maturation during his 20s. II‐9: patient’s paternal grandmother is reported as not visibly affected but is said to have had no body odor and decreased sweating. III‐21: patient’s father had right 5th finger camptodactyly which was amputated in the PIP joint in childhood; left hand reportedly
An autosomal dominant or X‐linked incompletely recessive trait. As a complex pleiotropic condition arising early in gestation, to judge by upper limbs no later than GA day 26 or 28 when the limbbuds form, and causing apparently increased fluctuating asymmetry around the midline. Mosaic pleiotropy involving palate, dentition, xiphisternum, limbs, apocrine and mammary glands, hymen and sexual maturation. Some of the anomaly combinations perhaps representing polytopic defects or effects all due to regional or distant pathogenetic action and reaction analogous to the radial limb and cardiac involvement in the Holt–Oram syndrome (and most likely involving signal translocation cascades—added 2014). This condition is again a demonstration of Meckel’s original insight that duplication in one limb may be the developmental equivalent of deficiency in the contralateral one, most commonly affecting thumbs, much more rarely ulnar rays [q.v. Birch‐Jensen, 1949; and Temtamy and McKusick, 1978]. The former noted 19 ulnar defects in 625 individuals with upper limb defects (3%,
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the normal first venue for the publication of “new” syndromes. And so, two parallel traditions arose referring either to the Schinzel syndrome [e.g., Hecht and Scott, 1984] or the Pallister ulnar‐ mammary syndrome [e.g., Bamshad et al., 1996]. Clinicians generally are sloppier than zoologists in naming species, the latter, by international convention since Linnaeus, adhering strictly to priority of full publication, a practice natural to John M. Opitz, a card‐carrying zoologist. But, priority being a lesser concern to me than the full and accurate documentation of the biology, I may suggest the eponym Pallister–Schinzel, analogous to Pallister–Killian, etc., or simply UMS. In the above‐cited study of Bamshad et al. [1996] their patient II‐3 is patient I‐3 of Pallister et al. [Pallister et al., 1976a; 1976a,b] marked there with a ? since affected by history only; he can now be marked as fully affected transmitting his condition to 33 descendants in six generations. In that study the gene was mapped to HAS
Figure 6. Ulnar‐mammary syndrome. (A) Proposita. (B) Her forearms. (C) Her kindred modified from Pallister et al. [Pallister et al., 1976a; 1976a,b] marking I‐3 now affected and identical with II‐3 of Bamshad et al., 1996. From Pallister et al. [Pallister et al., 1976a; 1976a,b], Birth Defects Orig Artic Ser XII(5):247–254. (D) Pedigree of the family in C, updated and extended by Bamshad et al. [1996]. Unnumbered, to be read as if numbered from left to right. Thus, II‐3 here is Pallister I‐3, his descendants are in C, studied 20 years before Bamshad et al., Am J Med Genet 65:325–331.
1/211,789 incidence in the Danish population vs. 12% radial defects, 1/ 55,123).
Addendum: The above is not to denigrate in the slightest the contribution of Werner Schinzel of Zürich to the study of this entity having finally published [Schinzel et al., 1987] details of the family he had communicated to
McKusick who in turn cited it in the 1973 MIM. Working from this personal communication Temtamy and McKusick referred to a “Schinzel syndrome of ulnar ray defects, hypogenitalism and anal atresia” in their book on the genetics of hand malformations [1978]. MIM, and its successor OMIM were then and still are not
TBX3 is a transcriptional repressor expressed early in ontogeny in lateral plate mesoderm, limb buds, mammary primordia, first arch mesenchyme and the genital tubercle. Whereas TBX5 is a transcriptional activator of upper limb and heart development.
12q23‐q24.1. It turned out to be TBX3, well known for its role in the Holt–Oram syndrome [HOS; Bamshad et al., 1997, 1999; Wollnik et al., 2002]. TBX3 is a transcriptional repressor expressed early in ontogeny in lateral plate mesoderm, limb buds, mammary primordia, first arch mesenchyme, and the genital tubercle.
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Whereas TBX5 is a transcriptional activator of upper limb and heart development. Loss of either gene is not compensated by the other and of both is expected to have severe effects. However, in a unique Czech family three individuals had a deletion of TBS3 and TBX5 with a mild phenotype partaking of HOS and UMS [Borozdin et al., 2006]. (7.) The KOP translocation. If I had to make a choice, it would probably be the KOP translocation among all of my studies that provided more refreshing BS,2 greater biological depth, more stimulating professional associations and intellectually satisfying conclusion than all the others, but not by much, since no condition in medical genetics is uninteresting or lacking its own unique pathos. Thus, the referral of the KOP propositus for vocational rehabilitation because of his mental deficiency overlooking his syndrome; local evaluation for delayed puberty overlooking his Klinefelter syndrome; cytogenetic study in Great Falls, MT reporting his chromosome abnormalities as “a type not uncommon in retarded persons” ignoring phenotype and buccal smear findings and missing X‐chromosome involvement; or the evaluation of his mother for six spontaneous miscarriages without chromosome analysis.
After confirmation of an X‐ autosome translocation in our propositus, which John Opitz shouted from the rooftops in Europe we fetched up in New York, the Albert Einstein College of Medicine of Yeshiva University with a preceding night at the Bronx Park Motel across from the zoo entrance, near Fordham University. John got there first, to inventory our six‐legged roommates when he heard someone whistling the theme from the film Dr. Zhivago outside announcing Pallister’s arrival. I flung my travel case on a low bench which promptly collapsed releasing an “Baloney & salami,” according to Erynn Johnson.
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astonishing swarm of several species of cockroaches. The night was disturbed not by lions or Jesuit priests but by the hourly activity in the adjacent room and the skittering of bad smelling cockroaches in our room. John spent much of the night occupying himself killing cockroaches. I spent my time trying to avoid them and listening to sounds from the adjoining room. Hurrying to leave the place in the morning I forgot my toilet kit which, when returned to me at the medical school was intact except for the straight razor, a wedding gift from my father. At Einstein we met a stellar faculty including Harold Nitowsky, Harold Klinger, and Marcello Siniscalco (who was also a faculty member at Leiden University). John also introduced me to the formidable and renowned Salome Glücksohn‐Waelsch who must have regarded me somehow as Darwin did the Fuegians in the last century (as usual I was dressed as a western rancher, cowboy boots and hat, no tie and beard. Coworkers were there from Leiden, Yale (Ruddle, Ricciuti), and Columbia University (O.J. Miller, P.W. Allderdice). The most junior colleague there, Andy L. Kosseff, then a medical student, later became one of John’s coworkers in Madison. But, the evaluation of this extraordinary patient ultimately also involved Drs. Inhorn, Meisner, Kosseff, and Jürgen Herrmann (Madison), H. Eldon Sutton (Austin, TX), Ruth Sanger and Rob Race and Elisabeth Robson (London). Details are provided by John Opitz, in this issue. (8.) The Pallister–Killian syndrome (OMIM 601803). When study of the first two patients at Boulder, recently transferred from the Warm Springs State Hospital for the Mentally Ill, made it likely that they had the same syndrome; then John Opitz, bursting with this new knowledge, importuned Elisabeth Kaveggia at Central
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Colony in Madison to find another severely retarded patient with severe epilepsy, microcephaly, supernumerary nipples, spasticity, and most importantly, with pigmentary streaking of the skin. She did; that patient’s surname was the same as my maternal grandfather’s Scotch clan name, raising the interesting possibility we might be related.
Results of chromosome studies of skin fibroblasts from these three individuals were initially interpreted as trisomy 20 by B. Rafael Elejalde in the Opitz group; however, a critical reinvestigation of the mother, by Uta Francke at Stanford, made it far more likely that the small extra chromosome in fibroblasts was, in fact an isochromosome 12p. Hence, our 1977 paper on the Pallister mosaic aneuploidy syndrome. Ian Krantz has since become the world expert on this condition with an authoritative series of research papers in the American Journal of Medical Genetics. His presentation is included in this issue. (9.) The Pallister–Hall syndrome (OMIM 146510). The index patient was not seen alive. He was delivered on February 27, 1978 by section for persistent breech presentation, birth weight, length and OFC at the 10th, 15th, and 50th centile, respectively. He lived 9 hr and was buried without autopsy or embalming. The attending pediatrician, Dr. Eric Livers of Bozeman, sent data and films to me in consultation. The infant had had multiple oral frenula, postaxial hexadactyly of left hand and foot, cutaneous syndactyly, microphallus, and imperforate anus. The films had suggested the Ellis‐van Creveld syndrome to local radiologists, something easily ruled out; however, gas in gut, essentially none in lungs suggested a TE fistula; the sella was broad and shallow; there was incipient polydactyly of the right thumb and an abnormal right 4th metacarpal.
At the annual Shodair Genetics Seminar on July 5, 1978 the infant
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was discussed with John Opitz, Jürgen Herrmann and Judy Hall without diagnosis, however, with imprinting of the phenotype in Judy Hall’s mind such that within a month after returning to Seattle she was able to make the diagnosis of this syndrome in her first patient who had the tumor. At that point I arranged exhumation. The baby had not eaten (no Gram‐negative bacteria in gut), was not decomposed, was put in formalin wraps and we drove it to the University of Washington, Seattle, was autopsied and was followed in October by a third case transferred from Alaska to Seattle. Initial investigations into potential teratogens were inconclusive. Hall et al. [1980] then reported on the first six infants with congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate anus, and postaxial polydactyly (Fig. 7A– C), followed a.o. by Iafolla et al. [1989] and by Pallister et al. [1989] on three cases respectively from
Montana, Arizona, and Wisconsin, so far all sporadic. The autosomal
Hall et al. then reported on the first six infants with congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate anus, and postaxial polydactyly (Fig. 7A–C), followed a.o. by Iafolla et al. and by Pallister et al. on three cases respectively from Montana, Arizona, and Wisconsin, so far all sporadic. dominant nature of the PHS did not become apparent until 1993/
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1994, setting aside teratological concerns. Hypothalamic tumor is in Figure 7D. The PHS gene was determined to be allelic with that of the Greig cephalopolysyndactyly syndrome (GCPS), namely GLI3, the phenotypic differences apparently being due to mutational differences. Table 24‐4 in Biesecker [2008] shows GCPS to be due to translocation, deletion, missense, splicing and frameshift/nonsense mutations with PHS essentially caused by frameshift/nonsense mutations 30 of the zincfinger domain. (10.) The Adam translocation syndrome. Speaking of “private” syndromes! The disorder under this head is “very” private in a double sense— involving my son Adam and an apparently unique, or at least previously undescribed, chromosome abnormality. The story was published so recently [Pallister et al., 2011] that interested readers are invited to look it over for essential details. However,
Figure 7. Postmortem images of infants with Pallister–Hall syndrome. (A) Patient 1. (B) Patient 2. (C) Patient 4 from Hall et al. [1980], Am J Med Genet 7:47–74. (D) Coronal and sagittal sections/views of brain respectively of Patient 2 and of Patient 3 showing hypothalamic hamartoblastoma replacing “hypothalamus and its related nuclei” from Clarren et al. [1980], Am J Med Genet 7:75–83.
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two important conclusions from that study bear repetition here.
In case of diagnostic unknowns the patient/family must be revisited periodically in light of recent diagnostic/nosologic advances, not just
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to satisfy someone’s curiosity, but most importantly to provide closure and essential reproductive information to the family. In such cases tissue or DNA must be archived for later reanalysis by ever more sensitive methods.
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In the case of Adam, it took a half century for such a reanalysis to finally document cause and to “settle” the case. You may want to learn the outcome of these studies (Fig. 8) in Pallister et al. [2011] and to relearn the old adage that results are always apparently normal until
Figure 8. (A) Propositus (Adam) with faithful companion (“Jasmine”) in Jaybird Ranch work. (B) Chromosome findings in Adam. (C) Their interpretation as t(14q;13q) with breakpoints at 14q32.2 and 13q34. From Pallister et al. [2011], Am J Med Genet Part A 155: 833–839.
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later proven otherwise. Adam’s smile (Fig. 8) can easily compete with that of Jasmine; he is always happy to autograph a copy of “his” report for others. His hugs are such you had better first take glasses out of breast pocket.
COLOPHON In 1947 I arrived destined to be a GP and general surgeon in Boulder, Montana with my wife, Willie, after wartime medical studies and subsequent Army service. Little did I realize then that some 15–20 years later I would also become another kind of GP—genetic practitioner, always on the look‐out for pleiotropy, hence continually sharpening my skill in the evaluation of the entire patient, clothed or unclothed, dead or alive, young or old, male or female, with delayed or normal cognition. Victor McKusick once said that to me with some pride, “Phil, I am also a GP, like you, in the study and care of the entire patient—I call myself a Genetic Practitioner.” Sewing up wounds in the ER, repairing a hip, removing a malignant thyroid, handling a measles or chickenpox epidemic or delivering babies does not in the slightest preclude genetic analysis at all levels; but, I’m skeptical that any geneticists remain who can do the same while raising 14 sons and a daughter or create their own cattle breed or build a house, repair a truck engine or conduct archeological research into Native American prehistory. And none of this would have been possible without the help of the great geneticists and scientists who have brought me along on this journey as has John Opitz in this final effort who has graciously edited this story and brought it up to current standards of existing knowledge. And for the chance to have done or been all that and more I am grateful. September 20, 2014 on my 94th birthday. Auld Phil
REFERENCES Bamshad M, Roots S, Carey JC. 1996. Clinical analysis of a large kindred with the Pallister ulnar‐mammary syndrome. Am J Med Genet 65:325–331.
Bamshad M, Lin RC, Law DJ, Watkins WC, Krakowiak PA, Moore ME, Franceschini P, Lala R, Holmes LB, Gebuhr TC, Bruneau BG, Schinzel A, Seidman JG, Seidman CE, Jorde LB. 1997. Mutations in human TBX3 alter limb, apocrine and genital development in ulnar‐mammary syndrome. Nat Genet 16:311–315. Bamshad M, Le T, Watkins WS, Dixon ME, Kramer BE, Roeder AD, Carey JC, Root S, Schinzel A, Van Maldergem L, Gardner RJ, Lin RC, Seidman CE, Seidman JG, Wallerstein R, Moran E, Sutphen R, Campbell CE, Jorde LB. 1999. The spectrum of mutations in TBX3: Genotype/ phenotype relationship in ulnar‐mammary syndrome. Am J Hum Genet 64:1550– 1562. Biesecker LG. 2008. GLI3 and the Pallister–Hall and Greig cephalopolysyndactyly syndromes. Ch 24 In: Epstein CJ, Erickson RP, Wynshaw‐Boris A, editors. Inborn errors of development, the molecular basis of clinical disorders of morphogenesis. 2nd edition. Boulder, MT: Oxford University Press. pp 313–321. Birch‐Jensen A. 1949. Congenital deformities of the upper extremities. MD thesis, translated from the Danish. Acta Domus Biologiae Hereditariae Humanae Universitatis Hafniensis. Det danske Forlag and Andelsbogtrykkeriet i Odense. Borozdin W, Bravo‐Ferrer Acosta AM, Seemanova E, Leipoldt M, Bamshad MJ, Unger S, Kohlhase J. 2006. Contiguous hemizygous deletion of TBX5, TBX3, and RBM19 resulting in a combined phenotype of Holt–Oram and ulnar‐mammary syndromes. Am J Med Genet 140A:1880– 1886. Bottani A, Schinzel A. 1993. A third patient with median cleft upper lip, mental retardation and pugilistic facies (W syndrome): Corroboration of a hitherto private syndrome. Clin Dysmorphol 2:225–231. Clarren SK, Alvord EC, Hall JG. 1980. Congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate anus, and postaxial polydactyly—A new syndrome? Part II: Neuropathological considerations. Am J Med Genet 7:75–83. Goizet C, Bonneau D, Lacombe D. 1999. W syndrome: Report of three cases and review. Am J Med Genet 22; 87:446– 449. Hall JG, Pallister PD, Clarren SK, Beckwith JB, Wiglesworth FW, Fraser FC, Cho S, Benke PJ, Reed SD. 1980. Congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate anus and postaxial polydactyly—A new syndrome? Part I: Clinical, causal, and pathogenetic considerations. Am J Med Genet 7:47–74. Hall JG. 2014. This issue of AJMG. Herrmann J, Pallister PD, Opitz J. 1969. Studies of malformation syndromes XXII: Craniosynostosis and craniosynostosis syndromes. Rocky Mountain Med J 66:45–56. Herrmann J, Pallister PD, Opitz JM. 1975. The KBG syndrome: A syndrome of short stature, characteristic facies, mental retardation, macrodontia and skeletal anomalies. Birth Defects Orig Artic Ser XI(5); 7–18.
ARTICLE Iafolla K, Fratkin JD, Spiegel PK, Cohen MM Jr, Graham JM Jr. 1989. Case report and delineation of the congenital hypothalamic hamartoblastoma syndrome (Pallister– Hall syndrome). Am J Med Genet 33:489– 499. Khalifa M, Stein J, Gran L, Nelson V, Meck J, Aradhya S, Duby J. 2013. Partial deletion of ANKRD11 results in the KBG phenotype distinct from the 16q24.3 microdeletion syndrome. Am J Med Genet 161A:835– 840. Krantz I. 2014. This issue of AJMG. Opitz JM, Pallister PD. 1979. Brief historical note: The concept of gonadal dysgenesis. Am J Med Genet 4:333–343. Pallister PD, Patau K, Inhorn SL, Opitz JM. 1974. Studies of malformation syndromes of man XXX: A woman with multiple congenital anomalies, mental retardation and mosaicism for an unusual translocation chromosome t(6;19). Clin Genet 5:188– 195. Pallister PD, Herrmann J, Spranger JW, Langer LO, Gorlin RF, Opitz JM. 1974. Studies of malformation syndromes in man XXVIII: The W syndrome. Birth Defects Orig Artic Ser X(7):51–60(First delineation). Pallister PD, Herrmann J, Opitz JM. 1976. Studies of malformation syndromes in man XXXXII: A pleiotropic dominant mutation affecting skeletal, sexual and apocrine–mammary development. Birth Defects Orig Artic Ser XII(5):247–254. Pallister PD, Herrmann J, Meisner LF, Inhorn SL, Opitz JM. 1976. Trisomy‐20 syndrome in man. Lancet 1:431.(First delineation of so‐ called Pallister–Killian syndrome). Pallister PD, Meisner LF, Elejalde BR, Francke U, Herrmann J, Spranger J, Tiddy W, Inhorn SL, Opitz JM. 1977. Studies of malformation syndromes of man XLIIIC: The Pallister mosaic aneuploidy syndrome. Birth Defects Orig Artic Ser III(3)B:103– 110. Pallister PD, Opitz JM. 1978. Studies of malformation syndromes in Man LI: The KOP translocation. Birth Defects Orig Artic Ser XIV(6)C:133–146. Pallister PD, Opitz JM. 1979. Perrault syndrome: Autosomal recessive ovarian dysgenesis with facultative, non‐sex‐limited severe sensori‐ neural deafness. Am J Med Genet 4:239– 246. Pallister PD, Kaveggia EG, Inhorn SL, Meisner L, Opitz JM. 1971. Chromosome studies in malformation/retardation syndromes. Proc II Int Congr Int Ass Sci Study Mental Deficiency (Warsaw 1970). Warsaw: Polish Medical Publishers. pp. 313–332. Pallister PD, Hecht F, Herrmann J. 1989. Three additional cases of the congenital hypothalamic “hamartoblastoma” (Pallister– Hall) syndrome. Am J Med Genet 33:500– 501. Pallister PD, Pallister AB, South S, Toydemir R, Johnson JP, Beischel L, Opitz JM. 2011. A deletion 13q34/duplication 14q32.2‐ 14q32.33 syndrome diagnosed 50 years after neonatal presentation as infantile hypercalcemia. Am J Med Genet 155A: 833– 839. Schinzel A, Illig R, Prader A. 1987. The ulnar‐ mammary syndrome: An autosomal
ARTICLE dominant pleiotropic gene. Clin Genet 32:160–168. Sirmaci A, Spiliopoulos M, Brancati F, Powell E, Duman D, Abrams A, Bademci G, Agolini E, Guo S, Konuk B, Kavaz A, Blanton S, Digilio MC, Dallapiccola B, Young J, Zuchner S, Tekin M. 2011. Mutations in ANKRD11 cause KBG syndrome, characterized by intellectual disability, skeletal malformations,
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) and macrodontia. Am J Hum Genet 89:289– 294. Temtamy S, McKusick VA. 1978. The genetics of hand malformations. Alan R. Liss for the National Foundation—March of Dimes, Birth Defects Orig Artic Ser XIV (3),1978. Tunovic S, Barkovich J, Sherr EH, Slavotinek AM. 2014. De novo ANKRD11 and
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KDM1A gene mutations in a male with features of KBG syndrome and Kabuki syndrome. Am J Med Genet 164A:1744– 1749. Wollnik B, Kayserili H, Uyguner O, Tukel T, Yuksel‐Apak M. 2002. Haploinsufficiency of TBX3 causes ulnar‐mammary syndrome in a large Turkish family. Ann Genet 45:213– 217.
