We report on six infants with a neonatally lethal malformation syndrome of hypothalamic hamartoblastoma, postaxial polydactyly, and imperforate anus. Some, but not all, patients had laryngeal cleft, abnormal lung lobulation, renal agenesis and/or renal dysplasia, short 4th metacarpals, nail dysplasia, multiple buccal frenula, hypoadrenalism, microphallus, congenital heart defect, and intrauterine growth retardation. The infants also had hypopituitarism and hypoadrenalism. All were sporadic cases, parents were not consanguineous, chromosomes were apparently normal. Family histories were unremarkable. There was insecticide and/or herbicide exposure in several of the cases, but no exposures were common to all 6 mothers. Five of the patients were born within an 8-month period, but all in different geographic locations. It is postulated that this is a previously apparently unreported syndrome of presently unknown cause.

Pallister-Killian syndrome is a rare, multi-system developmental diagnosis typically caused by tetrasomy of chromosome 12p that exhibits tissue-limited mosaicism. The spectrum of clinical manifestations in Pallister-Killian syndrome is wide and includes craniofacial anomalies, clefts, ophthalmologic, audiologic, cardiac, musculoskeletal, diaphragmatic, gastrointestinal, genitourinary, and cutaneous anomalies in association with intellectual disability and seizures. Growth parameters are often normal to elevated at birth with deceleration of growth postnatally. No formal estimate of the prevalence of Pallister-Killian syndrome has been made. Here, we report the clinical findings in 59 individuals with Pallister-Killian syndrome who were ascertained at Pallister-Killian syndrome Foundation family meetings held in the summers of 2006, 2008, 2009, and 2010. In addition, the clinical findings of 152 cases reported in the medical literature were reviewed and compared to the cohort examined here. Several novel clinical characteristics were identified through detailed dysmorphology examinations of this cohort and reassertion of a mild developmental variant is described. This report expands the clinical manifestations of Pallister-Killian syndrome and highlights the variable expressivity of this diagnosis with important implications for diagnosis and counseling.

Identification of the isochromosome 12p (i(12p)) associated with Pallister-Killian syndrome is complicated by the low frequency of this supernumerary chromosome in PHA stimulated peripheral blood lymphocytes, and frequently requires cytogenetic analysis of fibroblast cells. Recently, it has been shown that array CGH techniques are able to detect tetrasomy 12p in peripheral blood, even when not identified by traditional cytogenetic techniques. We studied 15 patients with a previous cytogenetic and clinical diagnosis of Pallister-Killian syndrome using genome-wide SNP arrays to investigate the ability of this platform to identify the i(12p) in blood and tissue. Array analysis verified tetrasomy 12p in all samples from fibroblasts, but was only able to detect it in 46% of blood samples. The genotyping information available from the SNP arrays allowed for the detection of as low as 5% mosaicism, as well as suggesting a Meiosis II origin for the isochromosome in the majority of patients. Analysis of the percentage of abnormal cells with patient age at time of study suggests that the frequency of the i(12p) decreased with age in blood, but not in fibroblasts. These highlight the power of SNP arrays in detecting and characterizing the isochromosome 12p in Pallister-Killian syndrome as well as underscoring the important utility of traditional cytogenetic techniques.

We report four patients with Nager acrofacial dysostosis (AFD) syndrome and review all previous cases. This leads to an extended characterization of the Nager syndrome—eg, description of lower limb defects—and also to a discussion of the differential diagnosis which includes AFD postaxial defect syndrome, Fontaine syndrome, distal 2q duplication syndrome, hemifacial microsomia/Goldenhar radial defect syndrome, and some others.

We reviewed etiologic and phenotypic aspects of those orofacial and limb anomalies usually diagnosed as Hanhart syndrome and Mobius syndrome but also those described, among others, under names such as aglossia-adactylia syndrome, gloss-palatine ankylosis, ankyloglossia superior, peromelia and micrognathia, cleft palate/lateral synechiae syndrome, and the Charlie M. syndrome. By coding the degree of severity of the limb defects it was possible to compare these cases quantitatively and to determine the nosologic significance of associated cranial nerve palsies and chest abnormalities. We analyzed 7 personal and 62 previously reported cases and found: 1. that the severity in the upper limbs and, particularly, malformations of the feet, but not the presence or absence of cranial nerve palsies, is a significant feature in the differentiation of cases, and 2. that the group of patients with cranial nerve palsies includes some with limb defects similar to those in the Hanhart syndrome and others with features which overlap the manifestations of the Poland syndrome. Still other cases had cranial nerve palsy as an isolated trait or as a component manifestation of several different syndromes. These findings permit re-definition and nosologic delimitation of the various syndromes as follows: 1. The Hanhart-syndrome: usually severe limb defect of at least one hand or foot, frequently associated with severe oral abnormalities and sometimes also with cranial nerve palsy. Most cases reported as aglossia-adactylia syndrome, aglossia-hypomelia syndrome, and some cases reported as glossopalatine ankylosis, ankyloglossia superior and Mobius syndrome describe instances of the Hanhart syndrome. 2. The Poland-Mobius syndrome: we suggest this term to refer to those cases of "Mobius syndrome" which have a chest defect and/or symbrachydactyly of the type seen in the Poland syndrome. We suspect that these cases of the "Mobius syndrome," and most of the cases which are usually diagnosed as Poland syndrome represent a different spectrum of the same condition, hence the term Poland-Mobius syndrome. 3. The autosomal dominant cleft palate/lateral synechiae syndrome delineated by Fuhrmann et al. and other apparently less frequent conditions are mentioned in the discussion. Cranial nerve palsy obviously occurs in several etiologically distinct conditions. An analogous situation is present, although less obvious, in the Hanhart and the Poland-Mobius syndrome. Both of these conditions are formal genesis malformation syndromes which implies that they are etiologically non-specific developmental field complexes. In the Hanhart syndrome Bersu et al. postulate a common pathogenetic disturbance for oral and limb defects, thus suggesting that the manifestations represent a single anomaly rather than a "syndrome." This anomaly, for which we suggest the term Kettner anomaly, may occur not only in the Hanhart syndrome but also in other conditions. Similarly, the Poland anomaly, i.e...

The cause of this syndrome remains unknown. Epidemiologic studies should be done by experts. The first two cases above gave a "muddy" history for possible teratogens--a "recall bias"--one of a vaginal foam spermicide, one of exposure over several days to a heavy residue of aviation diesel fuel exhaust. We do not think these are pertinent but they do point to the problem of getting a meaningful history. In addressing this problem (in a letter of 5/27/82) R.J. Berry, M.D., medical epidemiologist, Centers for Disease Control, Atlanta, Georgia, wrote "... a designed study providing standardized interview forms with controls could be designed if cases continue to appear." Since this seems to be the case, perhaps this approach should be embraced. A teratogen(s) appears to be a good bet since the condition was recognized suddenly with the first Montana case in February, 1978. Even though no record has been found in the files of the Armed Forces Institute of Pathology, Children's Hospital Automated Medical Programs (CHAMP), Montreal or Wisconsin and one or two other places, it might be worthwhile to look back at all cases of imperforate anus which have come to autopsy for possible associated CNS lesions. We may be deluding ourselves in considering the condition as "new." Chromosomes were usually studied in lymphocytes, once on the tumor and once or twice on marrow. It might be well to do more than one tissue in all new cases. Once again there appears to be no "obligatory" finding for any one syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)

No abstract

No abstract