Evolutionary morphology of the Tenrecoidea (Mammalia) carpal complex

The mammalian carpus can be difficult to interpret both phylogenetically and functionally. It is evolutionarily constrained in terms of functional morphology, yet there is considerable variation among many eutherian and metatherian lower and higher level taxa. The ecologically diverse Tenrecoidea (Mammalia) is a useful model for morphological interpretation of the interplay between function and phylogenetic constraint. Elements from the wrist and hand of 13 tenrecoid species, and one species each from Macroscelididae, Solenodontidae, and Erinaceidae, were compared to test form–function hypotheses of specific carpal, metacarpal, and phalangeal characters. Qualitative comparisons illustrate that several aspects of the tenrecoid carpus can be correlated with positional behaviour. Convergences within Tenrecoidea, and between tenrecoids and nontenrecoids with similar locomotor regimes, confirm a small number of carpal characters and a larger number of distal forearm, metacarpal, and phalangeal characters that reliably correspond with functional expectations. In addition, several features of the carpus appear to be phylogenetically constrained and indicate specific affinities within Tenrecoidea. Finally, there are a significant number of carpal features that vary among the studied taxa and remain ambiguous in terms of phylogenetic and/or functional significance.  © 2008 The Linnean Society of London, Biological Journal of the Linnean Society , 2008, 93 , 267–288.     

Two cases of digital defects in Macaca mulatta infants and a survey of the literature

Although congenital digital defects, particularly polydactyly, have been reported frequently in humans, their occurrence in rhesus macaques is relatively rare. We observed two cases of spontaneous digital defects in male rhesus monkey infants recently born at the California Regional Primate Research Center. One infant exhibited bilateral postaxial polydactyly and the other infant had bilateral oligodactyly with unilateral phalangeal duplication. In this report, we present the clinical/pathological details of these cases as well as discuss the embryology of normal and abnormal limb development. We will also summarize a variety of spontaneous and experimentally induced digital defects that have been reported in several nonhuman primate species.     

The association of split hand foot malformation (SHFM) and congenital heart defects

BACKGROUND: Split hand foot malformation (SHFM) (cleft hand, central ray deficiency) is a highly variable malformation that shows genetic heterogeneity with at least five loci mapped to date. SHFM occurs as an isolated finding or in association with other anomalies, including congenital heart defects (CHDs). METHODS: In total 48 SHFM1, 52 SHFM3, 48 SHFM4, 21 SHFM5, and four chromosome 8 patients were evaluated. In addition, we performed a literature review to identify “unmapped” SHFM patients with CHD to evaluate the various etiologies of this combination of findings. The London Dysmorphology Database also served as a resource to identify syndromes with this combination of phenotypic findings. Only patients presenting with both SHFM and CHD were included in the analysis. Classification of CHD among mapped and unmapped SHFM patients was performed utilizing the revised Clark classification. A closer inspection of the types of CHD found in this patient group was performed in order to investigate possible pathogenetic mechanisms. RESULTS: CHDs were found in 10% of SHFM1 patients, 47% of SHFM5 patients, but were not reported in SHFM2, SHFM4 patients, or patients mapped to chromosome 8. Forty‐two syndromic cases and 15 cases of unrecognized syndromes were identified. CONCLUSIONS: The higher frequency of heart defects seen in SHFM1 and SHFM5 of the mapped patient group raises the question as to whether common mechanisms/genetic players are involved. Candidate genes for SHFM1 and SHFM5 include members of the DLX homeobox gene family. Birth Defects Research (Part A), 2008. © 2008 Wiley‐Liss, Inc.     

Associated malformations in cases with congenital diaphragmatic hernia

The etiology of congenital diaphragmatic hernia (CDH) is unclear and its pathogenesis is controversial. Because previous reports have inconsistently noted the type and frequency of malformations associated with CDH, we assessed these associated malformations ascertained between 1979 and 2003 in 334,262 consecutive births. Of the 115 patients with the most common type of CDH, the posterolateral, or Bochdalek-type hernia, 70 (60.8%) had associated malformations. These included: chromosomal abnormalities (n = 21, 30.0%); non-chromosomal syndromes (Fryns syndrome, fetal alcohol syndrome, De Lange syndrome, CHARGE syndrome, Fraser syndrome, Goldenhar syndrome, Smith-Lemli-Opitz syndrome, multiple pterygium syndrome, Noonan syndrome, and spondylocostal dysostosis); malformation sequences (laterality sequence, ectopia cordis); malformation complexes (limb body wall complex) and non syndromic multiple congenital anomalies (MCA) (n = 30, 42.9%). Malformations of the cardiovascular system (n = 42, 27.5%), urogenital system (n = 27, 17.7%), musculoskeletal system (n = 24, 15.7%), and central nervous system (n = 15, 9.8%) were the most common other congenital malformations. We observed specific patterns of malformations associated with CDH which emphasizes the need to evaluate all patients with CDH for possible associated malformations. Geneticists and pediatricians should be aware that the malformations associated with CDH can often be classified into a recognizable malformation syndrome or pattern (57.1%).     

Appendicular skeletal morphology in minute salamanders,genus Thorius (amphibia: Plethodontidae): Growth regulation,adult size determination,and natural variation

Patterns of growth and variation of the appendicular skeleton were examined in Thorius, a speciose genus of minute terrestrial plethodontid salamanders from southern Mexico. Observations were based primarily on ontogenetic series of each of five species that collectively span the range of adult body size in the genus; samples of adults of each of seven additional species provided supplemental estimates of the full range of variation of limb skeletal morphology. Limbs are generally reduced, i.e., pedomorphic, in both overall size and development, and they are characterized by a pattern of extreme variation in the composition of the limb skeleton, especially mesopodial elements, both within and between species. Fifteen different combinations of fused carpal or tarsal elements are variably present in the genus, producing at least 18 different overall carpal or tarsal arrangements, many of which occur in no other plethodontid genus. As many as four carpal or tarsal arrangements were observed in single population samples of each of several; five tarsal arrangements were observed in one population of T. minutissimus. Left-right asymmetry of mesopodial arrangement in a given specimen is also common. In contrast, several unique, nonpedomorphic features of the limb skeleton, including ossification of the typically cartilaginous adult mesopodial elements and ontogenetic increase in the degree of ossification of long bones, are characteristic of all species and distinguish Thorius from most related genera. They form part of a mechanism of determinate skeletal growth that restricts skeletal growth after sexual maturity. Interspecific differences in the timing of the processes of appendicular skeletal maturation relative to body size are well correlated with interspecific differences in mean adult size and size at sexual maturity, suggesting that shifts in the timing of skeletal maturation provide a mechanism of achieving adult size differentiation among species. Processes of skeletal maturation that confer determinate skeletal growth in Thorius are analogous to those typical of most amniotes – both groups exhibit ontogenetic reduction and eventual disappearance of the complex of stratified layers of proliferating and maturing cartilage in long bone epiphyses – but, unlike most amniotes, Thorius lacks secondary ossification centers. Thus, the presence of secondary ossification centers cannot be used as a criterion for establishing determinate skeletal growth in all vertebrates.     

Multiple ophthalmic anomalies and digital hypoplasia.

Multiple congenital eye and hand anomalies occurred in a young female born to normal but consanguineous parents. Both eyes were microphthalmic with severe corneal, iris lens pathology. Ultrasonography revealed multiple echos from the vitreous. The ocular findings are suggestive of retinal dysplasia. A skeletal dysplasia, presenting as distal phalangeal hypoplasia, was found in both hands. There was no history of intrauterine exposure to drugs. This appears to be a unique association of congenital malformations, without other systemic involvement. Diagnostic and genetic implications are discussed.     

Disruption of teashirt zinc finger homeobox 1 is associated with congenital aural atresia in humans

Congenital aural atresia (CAA) can occur as an isolated congenital malformation or in the context of a number of monogenic and chromosomal syndromes. CAA is frequently seen in individuals with an 18q deletion, which is characterized by intellectual disability, reduced white-matter myelination, foot deformities, and distinctive facial features. Previous work has indicated that a critical region for CAA is located in 18q22.3. We studied four individuals (from two families) with CAA and other features suggestive of an 18q deletion, and we detected overlapping microdeletions in 18q22.3 in both families. The minimal region of deletion overlap (72.9-73.4 Mb) contained only one known gene, TSHZ1, which was recently shown to be important for murine middle-ear development. Sequence analysis of the coding exons in TSHZ1 in a cohort of 11 individuals with isolated, nonsyndromic bilateral CAA revealed two mutations, c.723G>A (p.Trp241X) and c.946_947delinsA (p.Pro316ThrfsX16), and both mutations predicted a loss of function. Together, these results demonstrate that hemizygosity of TSHZ1 leads to congenital aural atresia as a result of haploinsufficiency.     

The many faces of RET dysfunction in kidney

Signaling pathways that are activated upon interaction of glial cell-line derived neurotrophic factor (Gdnf), its coreceptor Gfrα1, and receptor tyrosine kinase Ret are critical for kidney development and ureter maturation. Outside the kidney, this pathway is implicated in a number of congenital diseases including Hirschsprung disease (intestinal aganglionosis, HSCR) and hereditary cancer syndromes (MEN 2). Total lack of Gdnf, Gfrα1 or Ret in mice results in perinatal lethality due to bilateral renal agenesis or aplasia. In humans, RET mutations have been identified in a spectrum of congenital malformations involving the RET axis including isolated HSCR, isolated congenital anomalies of kidney or urinary tract (CAKUT), or CAKUT and HSCR together. The molecular basis for these pleiotropic effects of RET has just begun to be unraveled. In an effort to delineate the pathogenetic mechanisms that underlie these congenital malformations, we and others have characterized Ret’s role in early kidney and urinary system development. Here we present a brief overview of the “many faces” of Ret dysfunction in kidney with particular emphasis on Ret’s signaling specificity and intergenic interactions that confer normal urinary system development.     

The community of human malformation syndromes that shares ectodermal dysplasia and deformities of the hands and feet.

Syndromes of human congenital malformation may be classified be recognizing communities of syndromes that share multiple phenotypic similarities involving their principal diagnostic features. A community of syndromes that shares various expressions of ectodermal dysplasia and various deformities of the hands and feet is proposed; these syndromes are divisible into two classes according to the presence or absence of anomalies in the nasal or labial regions of the face. The dysmorphogenetic validity of the division is supported by the fact that the syndromes without nasal or labial anomalies have a high frequency of sensorineural deafness as one expression of ectodermal dysplasia whereas those without such anomalies do not. The usefulness of such a syndromal community as a base for evolving a taxonomic scheme of dysmorphogenetic relatedness amongst different syndromes is illustrated.     

Morphological observations on the congenital malformation of limbs in the Japanese monkey

Congenital malformation of limbs is found in many troops of the Japanese monkey. The author morphologically examined more than ten monkeys with such malformations by means of palpation and Röntgenographing. Anatomical dissection was performed on two of these monkeys. Malformation manifests a considerable variety of forms, from the reduction or absence of fingers to almost total lack of limbs, and is prone to occur in the region of the third finger, the center of malformation, occasionally showing a “split” or “cleft” hand or foot. The latter tendency is more conspicuous in the hand than in the foot. In a word, most of the malformations are characterized by congenital amputation, though the degree varies considerably. The occurrence of supernumerary digits was not found and fusion between fingers was rare. One of the most interesting anatomical results found may be the continuation or fusion between muscles which are normally opposed to each other in action. The occurrence of malformation is more frequent in the male than in the female, and in the hand than in the foot. Little is known about the causes of such malformations, except that they do not occur, at least, according to dominant inheritance.     

ACTIVATION OF THE CORPORA ALLATA IN RELATION TO OVARIAN MATURATION IN THE SEASONAL FORMS OF THE BUTTERFLY, POLYGONIA C-AUREUM L.

In Polygonia c-aureum , there are two seasonal forms, viz. , the summer form and the autumn form. Previous experiments (E ndo , 1970) showed that the corpora allata of the summer form accelerate the maturation of ovarian follicles soon after imaginal ecdysis. On the other hand, the corpora allata of the autumn form do not stimulate ovarian maturation during a period of 2 to 3 weeks after the emergence.
In the summer form (S) as well as in the autumn form (A), the corpora allata remained in an inactive state for about 15 days after emergence when they had been isolated microsurgically from the brain and the corpora cardiaca during the larval period. Further, when separation of the brain into the right and left hemispheres or ablation of the medial neurosecretory group cells of the pars intercerebralis had been carried out on S-pupae of 28 hr after pupation or of earlier ages, they developed into autumn form in respect to wing pattern and their corpora allata did not stimulate ovarian maturation until 2 to 3 weeks after emergence. On the other hand, when the above operations had been performed 34 hr after the pupation or of later ages, they developed into summer form in respect to wing pattern and ovarian maturation was evident soon after the emergence. In these cases, stimulation of the corpora allata is closely connected with the development of seasonal-forms of wing pattern.
From these experiments, it is clear that the medial neurosecretory group cells of the pars intercerebralis in S-insects stimulate the corpora allata about 30 hr after pupation by way of the nervi corporis cardiaci and the activated corpora allata promote ovarian maturation throughout adult life. In A-insects, on the other hand, the medial neurosecretory group cells of the brain are inactive and fail to activate the corpora allata which in turn have no influence on ovarian maturation.     

The many faces of RET dysfunction in kidney

Signaling pathways that are activated upon interaction of glial cell-line derived neurotrophic factor (Gdnf), its coreceptor Gfra1, and receptor tyrosine kinase Ret are critical for kidney development and ureter maturation. Outside the kidney, this pathway is implicated in a number of congenital diseases including Hirschsprung disease (intestinal aganglionosis, HSCR) and hereditary cancer syndromes (MEN 2). Total lack of Gdnf, Gfra1 or Ret in mice results in perinatal lethality due to bilateral renal agenesis or aplasia. In humans, RET mutations have been identified in a spectrum of congenital malformations involving the RET axis including isolated HSCR, isolated congenital anomalies of kidney or urinary tract (CAKUT), or CAKUT and HSCR together. The molecular basis for these pleiotropic effects of RET has just begun to be unraveled. In an effort to delineate the pathogenetic mechanisms that underlie these congenital malformations, we and others have characterized Ret''s role in early kidney and urinary system development. Here we present a brief overview of the “many faces” of Ret dysfunction in kidney with particular emphasis on Ret''s signaling specificity and intergenic interactions that confer normal urinary system development.Key words: RET, GDNF, kidney, RTK, CAKUT, branching morphogenesis, ureter     

Diagnosis of late puberty

Late puberty is defined as the lack of pubertal development at two standard deviations above the mean age for the general population of the geographical area. In practical terms, this is a chronological age of 14 years for males (testicular volume <4 ml) and 13 years for girls (lack of thelarche). The goal of the assessment is to determine whether the delay or lack of development is due to a lag in normal pubertal maturation or represents an abnormality that must be investigated. Etiologies of pubertal delay and pubertal failure include: a) Constitutional delay of puberty (healthy patients with a clinical history of delayed growth and development; b) Hypogonadotropic states (congenital abnormalities, tumours, endocrinopathies); c) Hypergonadotropic states (chromosomal alterations, syndromes, genetic disorders, radiotherapy/chemotherapy); d) Secondary to chronic illness (organic abnormalities, oncological diseases, malnutrition, eating disorders and endocrinopathies). Diagnostic evaluation must include: a detailed physical examination, including auxological parameters (height and bone maturation), personal and familial antecedents, measurements of general hematological and biochemical parameters, gonadotropins, prolactin, thyroid hormones, sex steroids, growth hormone and growth factors. When necessary, an MRI must be performed. A karyotype is indicated in girls with delayed puberty and short stature and in boys who have small testes and hypergonadotropism.     

A case with bilateral radio-ulnar synostosis

Congenital radio-ulnar synostosis may be an isolated abnormality or additional abnormalities may accompany it. It may also be found as a part of well-known syndromes. We present a case with bilateral congenital radio-ulnar synostosis, speech delay, dimple on shoulders, café au lait spot and characteristic facial appearance. The proband has a brother with similar clinical findings with the exception of congenital radio-ulnar synostosis. We discuss the possible relationship between our case and previously described syndromes with congenital radio-ulnar synostosis, and distinct phenotypic features of the presented case.     

Tubular hand bone growth during the latter half of the prenatal period: an allometric analysis

The growth of the 19 tubular hand bones from fetal months 5 to 9 was studied by the allometric method. The hand bones were carefully dissected under a low power stereoscopic microscope. The length and breadth of all bones was found to be monophasic in relation to crown-rump length. In general, maximum bone and ossified shaft lengths in the same row group demonstrate similar allometric coefficients. The specific growth rate of ossified shaft length for all fetal hand bones is greater than the growth rate of maximum length. The highest allometric coefficients for both maximum length and ossified shaft length were obtained from the middle phalanges. The shape of the metacarpals and distal phalanges becomes thinner, while the other bones become thicker or maintain their length-breadth ratio. The relative growth pattern of the first proximal phalanx differed from the middle phalangeal group of the other digits. This suggests that current nomenclatures for the three bones of the pollex is appropriate.     

Smith‐Lemli‐Opitz syndrome in trisomy 13: How does the mix work?

BACKGROUND: Trisomy 13 and Smith-Lemli-Opitz syndrome (SLOS) are both well-recognized multiple congenital anomaly/mental retardation syndromes. CASE: In this report we describe a male newborn with trisomy 13 who also has features of SLOS, such as 2/3 toe syndactyly and a shawl-like scrotum. Biochemical analysis was consistent with SLOS, and limited molecular analysis revealed 1 mutation in the DHCR7 gene. CONCLUSIONS: The challenges in establishing the diagnosis of SLOS in this patient are presented and the unique coexistence of the 2 major malformation syndromes is discussed. Given the overlapping phenotype of the 2 syndromes, our report should encourage further research on cholesterol biosynthesis in patients with trisomy 13.     

Secondary centers of ossification of the human toes: exceptional polymorphism and evolutionary perspectives

As great morphological variability characterizes the phalanges of the human toes in adults, we hypothesized for a possible variability in the presence or absence of their secondary (= epiphyseal) centers of ossification linked to the unique morphology of the human foot within primates. The aim of this study was thus to provide original and detailed data on the occurrence of these centers. Classically, the big toe or hallux (I) presents two secondary centers and the lateral toes (II-V) three centers, and consequently the five toes present a total of 14 secondary centers. The material studied consisted of 261 foot radiographs from 261 young individuals of European origin (202 males and 59 females; 6-16 years). The presence (or absence) of the secondary centers of the phalanges of the toes was assessed for each foot. Feet presenting a biphalangeal variant in one or more lateral toes were studied separately. The theoretical possibilities of association of the three secondary centers in a given lateral toe (II-V) are eight in number; these eight patterns were studied and coded in the present study by types A-H. An exceptional variability in the occurrence of the secondary centers in lateral toes (II-V) was observed, and the classic pattern of phalangeal ossification was never observed. The absence of one or more secondary centers seems to be observed only in the human species, and we suggest that this could be a derived pattern specific to the human species, i.e., autapomorphic pattern. These results are of interest in the characterization and understanding of the reduction in size of the lateral toes which characterizes the specific evolution of the human foot.     

Novel deletion mutation of TRPS1 gene in a Chinese patient of trichorhinophalangeal syndrome type I

Tricho–rhino–phalangeal syndrome (TRPS) is a rare autosomal dominant disorder. Deletion or mutation of the TRPS1 gene leads to the tricho–rhino–phalangeal syndromes type I or type III. In this article, we describe a Chinese patient affected with type I TRPS and showing prominent pilar, rhinal and phalangeal abnormalities. Mutational screening and sequence analysis of TRPS1 gene revealed a previously unidentified four-base-pair deletion of nucleotides 1783–1786 (c.1783_1786delACTT). The mutation causes a frame shift after codon 593, introducing a premature stop codon after 637 residues in the gene sequence. This deletion is an unquestionable loss-of-function mutation, deleting all the functionally important parts of the protein. Our novel discovery indicates that sparse hair and metacarpal defects of tricho–rhino–phalangeal syndromes in this patient are due to this TRPS1 mutation. And this data further supports the critical role of TRPS1 gene in hair and partial skeleton morphogenesis.     

Anatomical features associated with preaxial duplication (pd): a recessive mutation in the rat

Preaxial polydactyly of the fore- and hindlimbs was found in Wistar-derived rats in 1978. Genetic analysis indicated that the polydactyly was due to the effects of an autosomal recessive gene (gene symbol; pd). Polydactylous homozygous rats had two or three pollices (six or seven digits) in the forelimbs and one to three preaxial extra digits (six to eight digits) in the hindlimbs. Skeletal examination revealed the presence of the extra carpal, metacarpal, and phalangeal bones that seemed to be complete or incomplete duplication of the navicular, greater multangular, first metacarpal, and phalanges of digit I in the forelimbs. In the hindlimbs, extra tarsal, metatarsal, and phalangeal bones were also observed preaxially. These extra elements seemed to be mirror-image duplications of the talus, navicular, second cuneiform, third cuneiform, cuboid, and metatarsals and phalanges of digits II-V with the absence of the first cuneiform, tibiale, first metatarsal, and phalanges of digit I. In addition, morphological changes were observed in the humerus, radius, and ulna in the forelimbs and femur, tibia, and fibula in the hindlimbs. Especially in the radius and tibia, thickening and bifurcation were found, indicating incomplete duplication of these bones. Based on these findings, the limb anomaly was classified as preaxial carpometacarpal/tarsometatarsal-type polydactyly with incomplete duplication of the radius and tibia. The mutant rats had other associated anomalies such as accessory spleens and cryptorchism. The males are sterile, whereas the females breed normally.