Terminal Transverse Defects Research Articles

Hypothesis: Central digit hypoplasia.

Limb deficiencies are a common birth defect. A malformations surveillance program among many newborns, stillborn fetuses, and malformed fetuses in elective terminations can identify a sufficient number of infants with the same set of abnormalities to characterize a specific limb deficiency phenotype. The active malformations surveillance program was carried out among 289,365 births at Brigham and Women's Hospital in Boston over a 41-year period (1972-2012). The research assistants identified the affected infants and fetuses from reading the findings recorded in each newborn's medical record by the examining pediatricians and consultants and by the pathologists in autopsies. One hundred ninety-four newborn infants and fetuses were found to have a limb deficiency either as an isolated abnormality or as one of multiple malformations. We identified three phenotypes of limb deficiency. We present here the seventeen infants and fetuses with "central digit hypoplasia," a term we suggest for this phenotype: hypoplasia of the thumb and fifth finger with nubbins of soft tissue in place of fingers 2, 3, and 4 at the level of the metacarpal-phalangeal joint. Central digit hypoplasia is to be distinguished primarily from the terminal transverse limb defect that ends at the wrist. In symbrachydactyly, the middle and distal phalanges of the fingers and toes are hypoplastic. In addition, central digit hypoplasia should be distinguished from the amniotic band syndrome, the most common and incorrect diagnosis suggested by the pediatricians and the consultants in this survey. The affected infant and her/his parents benefit from more accurate and specific counseling.

Terminal transverse limb defects with "nubbins".

A terminal transverse limb defect with absence of the forearm and hand or just the hand is an uncommon limb deformity in an otherwise healthy newborn. Most of the affected infants also have tiny digit-like nubbins on the stump of the affected limb, a finding that could represent an attempt at regeneration following vascular obstruction in early limb development. One hundred ninety-four newborn infants with a limb deficiency were identified among 289,365 births in an active malformations surveillance program at Brigham and Women's Hospital in Boston, MA from 1972 to 2012. Twenty-eight infants with terminal transverse limb defects were identified. Twenty-four had tiny digit-like nubbins (0.5cm in length) on the stump at one of three levels: the proximal portion of the forearm, the wrist or the forefoot. The examination of the placentas of eight affected infants showed no evidence of amnion rupture. Three of these 28 infants had associate chromosome abnormalities: trisomy 21, chromosome 11q deletion and the deletion of 22q11.2. Terminal transverse limb defects reflect failure of early limb development. Awareness of this phenotype at birth, or when identified by ultrasound screening, can provide more accurate counseling than occurs with the more common misdiagnosis of "amniotic band syndrome."

Expanding the phenotype in Adams-Oliver syndrome correlating with the genotype.

Adams-Oliver syndrome (AOS) is a genetic disorder characterized by the association of aplasia cutis congenita (ACC), terminal transverse limb defect (TTLD), congenital cardiac malformation (CCM), and minor features, such as cutaneous, neurological, and hepatic abnormalities (HAs). The aim of the study is to emphasize phenotype-genotype correlations in AOS. We studied 29 AOS patients. We recorded retrospectively detailed phenotype data, including clinical examination, biological analyses, and imaging. The molecular analysis was performed through whole exome sequencing (WES). Twenty-nine patients (100%) presented with ACC, the principal inclusion criteria in the study. Seventeen of twenty-one (81%) had cutis marmorata telangiectasia congenita, 16/26 (62%) had TTLD, 14/23 (61%) had CCM, 7/20 (35%) had HAs, and 9/27 (33%) had neurological findings. WES was performed in 25 patients. Fourteen of twenty-five (56%) had alterations in the genes already described in AOS. CCM and HAs are particularly associated with the NOTCH1 genotype. TTLD is present in patients with DOCK6 and EOGT alterations. Neurological findings of variable degree were associated sometimes with DOCK6 and NOTCH1 rarely with EOGT. AOS is characterized by a clinical and molecular variability. It appears that degrees of genotype-phenotype correlations exist for patients with identified pathogenic mutations, underlining the need to undertake a systematic but adjusted multidisciplinary assessment.

Historical Perspectives: Perinatal Profile: Forrest Hood Adams, MD: Pediatric Polymath

Forrest Adams is a descendant of Presidents John Adams (1735–1826) and John Quincy Adams (1767–1848), both of whom had long lives for the era into which they were born, which may indicate the role of genetics in his longevity. Both his grandparents and great grandparents lived into their 80s and 90s. Even as a medical student, he became interested in hereditary disorders and wrote an article before graduation, which was published approximately 1 year later, as the first article in his extensive bibliography. Indeed, the hereditary disorder that he described now bears his name, being the description of what became known as the Adams-Oliver syndrome. (1) This has to be a rare distinction for one so young at the time. The disorder consists of aplasia cutis congenita, in association with terminal transverse defects of the limbs and (in the first case he saw) a skull defect. The limb defects are not dissimilar to those seen with amniotic band syndrome. It is fair to say that Forrest Adams was (and is) a polymath (“a person of great learning in several fields of study”). Not only did he continue to be interested in genetics, he then spent time investigating infectious diseases, before moving on to pediatric cardiology and later to pulmonary physiology. As I found out in a recent telephone conversation, Dr Adams, at the age of 94 (going on 95), remembers in considerable detail many of the circumstances that led to his important contributions.⇓ Photograph taken in 2009 when receiving the Harold S. Diehl Award for outstanding professional contributions, from the University of Minnesota Medical School. Forrest Adams was born (in 1919) and raised in Minneapolis, Minnesota, where he went to medical school and graduated in 1943. Soon after this, his eponymous article was published and shortly after that he …

Amniotic bands as a cause of congenital anterior staphyloma

Congenital anterior staphyloma is a rare, complex malformation syndrome of the anterior segment. Only a few reports on associated systemic malformations have been published. We herein present a rare manifestation of congenital anterior staphyloma (CAS) combined with amniotic band disruption syndrome (ABS). Shortly after birth, a massive enlargement of the left eye was observed in a female child. Furthermore, an extensive bilateral congenital cleft lip and cleft alveolar ridge with oblique facial cleft extending into the left medial canthal region, coloboma(s) of the left eyelids, extensive adhesions between lids and eye bulb, as well as circumferential grooves, clubfeet, and terminal transverse defects in both hands and feet were present. Due to severe progression of eye bulb protrusion with thinning of the sclera, enucleation of the left eye was performed at the age of 3 years in order to prevent complications including perforation of the globe and with the aim of improving cosmetic aspects. Histopathological examination of the enucleated eye disclosed findings typical of congenital anterior staphyloma, including massive corneal staphylomatic deformation with superficial vascularization and elapsed corneoscleral margin, destruction of Bowman's layer, absence of Descemet's layer, corneal endothelium, and angle structures. The lens was only partially formed, and had mainly dissolved. The neural retina appeared normal. The optic nerve disc revealed a pronounced excavation. Facial clefts, lid colobomas, congenital constriction bands, and amputation of distal limbs match ABS. This malformation complex develops in early pregnancy, probably prior to 35 days post conception. This is the first report on an association of these two rare complex congenital malformations, congenital anterior staphyloma and amniotic band syndrome. The anterior staphyloma was unilateral, and related to facial clefts and lid coloboma in the area adjacent to the anterior staphyloma. Furthermore, the systemic deformities are clearly due to the amniotic bands, and the timing of the development of both complex malformations seems to be similar. All findings suggest that the presence of amniotic bands is a causative factor for all observed abnormalities including anterior staphyloma.

Anatomic and etiological classification of congenital limb deficiencies

Limb deficiencies, the congenital absence or hypoplasia of a long bone and/or digits, vary greatly in their anatomy and etiology. Previous attempts to classify the range of possible phenotypes have not included all types of deficiencies. We present a new classification system, which includes all potential phenotypes. Infants with limb deficiencies were identified in the hospital-based Active Malformations Surveillance Program at Brigham and Women's Hospital in Boston, MA from the years 1972 to 1974 and 1979 to 2000. Affected infants were classified based on the anatomy and apparent cause of their deficiencies. The prevalence rate of all types of limb deficiency was 0.79/1,000. Upper limb deficiencies were significantly more common than lower limb deficiencies. There was no significant difference in frequencies between deficiencies on the left and right sides of the body. Longitudinal defects were more common than terminal transverse defects; intercalary defects were uncommon. Longitudinal defects were most likely to occur on the preaxial side of the limb. Almost half of affected infants had affected digits, with normal long bones. The most common apparent cause of limb deficiencies was vascular disruption defects (0.22/1,000), such as amniotic band-related limb deficiency. This new classification system includes deficiency of each long bone, as well as absence of any finger or toe. This system will make it possible to establish the prevalence of each specific phenotype. The large number of distinct apparent causes illustrates the marked etiologic heterogeneity of limb deficiencies.

Amniotic Band Sequence

After completing this article, readers should be able to: 1. Identify the clinical spectrum of defects seen in amniotic band sequence. 2. Describe possible mechanisms involved in the formation of defects. 3. Formulate a differential diagnosis for amniotic band sequence. Amniotic band sequence (OMIM #217100) comprises a broad clinical spectrum of defects that includes disruptions, deformations, and malformations. Disruptions may be caused by adhesions or constrictions by amniotic bands of structures programmed to develop normally. Deformations may result from distortion of embryologically normal structures. Amnion rupture may lead to oligohydramnios, which results in fetal constraint and tethering of fetal parts that may cause vascular engorgement, hemorrhage, edema, and tissue necrosis. Malformations may result from the presence of amniotic bands in the early embryonic period that interfere with normal embryogenesis. Amniotic band sequence is also known as amnion rupture sequence, ADAM complex (amniotic deformities/adhesions/mutilations), amniotic band disruption complex, congenital constricting bands, terminal transverse defects, and Streeter anomaly. Amnion rupture sequence has been described clinically as rupture of the amnion followed by encircling of developing structures by strands of amnion. These may vary from constricting bands to limb reduction defects. In addition, deformational defects such as scoliosis or talipes equinovarus may seen. Thoracoabdominoschisis, facial clefts, and encephaloceles also may be associated with amniotic adhesions, ruptured amnion, and amputation defects, and this has been referred to as the Limb Body Wall Complex (LBWC). Several reports regarding the incidence of amniotic band sequence have been cited in the literature. A frequency of 1 in 1,000 for congenital ring constrictions and amputations was reported by Baker and Rudolf. (1) The frequency of amniotic bands has been estimated to range from 1 in 1,234 to 15,000 live births, (2) but may be up to 1 in 56 in previable fetuses. (3) The incidence …

A morpho-etiological description of congenital limb anomalies

BACKGROUNDLimb anomalies rank behind congenital heart disease as the most common birth defects observed in infants. More than 50 classifications for limb anomalies based on morphology and osseous anatomy have been drafted over the past 150 years. The present work aims to provide a concise summary of the most common congenital limb anomalies on a morpho-etiological basis.PATIENTS AND METHODSIn a retrospective study, 70 newborns with anomalies of the upper and/or lower limbs were ascertained through clinical examination, chromosomal analysis, skeletal surveys and other relevant investigations.RESULTSFetal causes of limb anomalies represented 55.8% of the cases in the form of 9 cases (12.9%) with chromosomal aberrations (trisomy 13, 18 and 21, duplication 13q and deletion 22q) and 30 cases (42.9%) with single gene disorders. An environmental etiology for limb anomalies was diagnosed in 11 cases (15.7%) as amniotic band disruption, monozygotic twin with abnormal circulation, vascular disruption (Poland sequence, sirenomelia and general vascular disruption) and an infant with a diabetic mother. Twenty cases (28.5%) had limb anomalies as part of sporadic syndromes of unknown etiology.CONCLUSIONSThe morpho-etiological work-up of limb anomalies adopted in the present study is valuable for detecting the cause of the anomaly and is crucial for its prevention. Prevention can be achieved by proper genetic counseling, which includes recurrence risk estimation and prenatal diagnosis.

Mosaic trisomy 22 in a boy with a terminal transverse limb reduction defect

A terminal transverse limb reduction defect is a relatively common congenital malformation that most often occurs unilaterally and in isolation. A mildly mentally disabled boy is described with an absent left hand, a congenital cardiac defect, short stature, facial dysmorphism and skin pigmentary anomalies. Karyotyping of fibroblasts revealed mosaic trisomy 22. Most of the clinical features of our patient are consistent with the phenotype of mosaic trisomy 22, however, a terminal transverse reduction defect has until now never been reported in association with this chromosomal aberration.

Unilateral Transverse Arm Defect with Subterminal Digital Nubbins

We present a case of unilateral terminal transverse forearm deficiency with subterminal digit-like nubbins, identified in a fetus from a pregnancy terminated electively in the second trimester because the distal right arm and hand could not be seen by ultrasound and were presumed to be absent. Pathologic evaluation showed distal transverse shortening, tapering to a point in the mid-forearm. Five primitive digital nubbins were present, located just proximal to the tapered point. The arm vessels appeared normal histologically, and the amnion showed no evidence of intrauterine disruption. Histologic examination of the nubbins revealed osteocartilaginous tissue, never described previously within digital nubbins. This fetus has the rare phenotype of terminal transverse limb defects with residual nubbins, but differs in that the nubbins are not at the tip of the terminal transverse limb defect.

Natural history of the Adams-Oliver Syndrome: A report of progressive Central and Peripheral nervous system involvement in a mother and son

The association of aplasia cuds congenita of the scalp with terminal transverse defects of the limbs has been described in 1945 by Adams and Oliver. This predominately autosomal dominant syndrome displays a wide phenotypic variation. Limb and cranial malformations may be associated with cutis mamorata and tortuous dilated scalp veins. Up to 20% of these patients have associated cardiovascular malformations. A variety of brain and cranial malformations have been reported in AOS and dysplasia of the cerebral cortex has been only recently reported in one case. We report on a 27 year old man who was diagnosed by us (NS) at the age of 3 years with typical findings of AOS. At that time, his mother was found to have only subtle distal phalangeal hypoplasia. A maternal aunt and her daughter were more typically affected. Our patient was a physically active young child. Cognitive evaluation at school age revealed borderline to mild mental retardation. He attended school through his late teens and worked until the age of 24 years. He then experienced progressive asymmetrical spastic weakness making him wheelchair dependent and developed dysphasia to the point that his speech became unintelligible. At his most recent admission to the hospital he exhibited severe spasticity in the legs and weakness in the arms involving the left side more than the right side. Vocal cord motion was normal, but swallowing was poorly coordinated with weak lingual, buccal and pharyngeal motion. Brain MRI showed pronounced asymmetrical cerebral atrophy and asymmetrical cerebral hypoplasia. His mother's recent examination revealed dysarthrta. weakness with wheelchair dependence and mild spasticity, which she experienced over a 10 year interval. Her brain MRI revealed very similar findings to those described in her son. Additional results of studies done on both patients will be presented as well as a review of the literature.

Aplasia Cutis Congenita: A Report of Five Cases in Riyadh

Aplasia Cutis Congenita: A Report of Five Cases in Riyadh

A changing pattern in the association of oral contraceptives and the different groups of congenital limb deficiencies

A case-control study on different groups of isolated congenital limb deficiency was performed in a ten-year population-based and revised Hungarian data set. A higher rate of one contraceptive pill type with relatively high dose (ethynodiol diacetate 1.0 mg + ethinyloestradiol 0.05 mg) used in the periconceptional period was found in the mothers of cases with terminal transverse defect (adjusted relative odds 1.9 with 95% confidence interval of 1.1–3.4). This risk is minimised by the use of recent low-dose pills.

Soft tissue calcification in children with terminal transverse defects of the upper limb — is it tumoral calcinosis?

We report five children with tranverse defects of the upper limb who developed calcified deposits at the distal end of the limb. The lesions were excised from two children and had the typical histological appearance of tumoral calcinosis but on clinical grounds it is unlikely that this is the same condition as that previously described as tumoral calcinosis.

Two isolated cases with symmetrically absernt hands and feet

We describe two unrelated boys with similar bilateral terminal transverse defects of the upper and lower limbs without other anomalies. Review of the literature did not reveal another report of this distinctive type of malformation.

Smoking during pregnancy and congenital limb deficiency.

To examine genetic and environmental factors in the origin of isolated congenital limb deficiencies. Case-control study with questionnaire at a family interview of cases of isolated congenital limb deficiencies (six types), negative controls (matched for age, sex, and place of residence), and positive controls (cases of sentinel anomalies). The database of the Hungarian Congenital Abnormality Registry, 1975-84, complemented by three other sources of ascertainment (1,575,904 births). 537 case-control pairs; 392 positive controls. Smoking during pregnancy, congenital limb deficiencies. The adjusted rate of smoking during pregnancy was significantly higher in the mothers of cases of terminal transverse defect (relative odds 1.48; 95% confidence interval 0.98 to 2.23; P = 0.017). This finding supports the hypothesis of vascular disruption as a cause of congenital limb deficiency. Maternal smoking during pregnancy raises the relative odds for terminal transverse limb deficiencies.

Congenital defects of the limbs and alcohol exposure in pregnancy: data from a population based study.

Limb deficiency may occur in offspring prenatally exposed to alcohol. In a study on limb deficiency occurring in 1,213,913 consecutive liveborn infants in British Columbia, born in the years 1952-1984, a total of 659 cases with limb deficiency was identified. Cases with documented maternal alcohol abuse in pregnancy in this group were analyzed separately. We found eight cases with severe prenatal alcohol exposure (6 F, 2 M). In six of the eight cases a terminal transverse defect of the forearm or hand was present. In the remaining two cases ulnar defects were identified. These observations give further support to the hypothesis that intrauterine alcohol exposure may cause limb defects. This has also been demonstrated in experimental animals. Terminal transverse defects made up a larger proportion of cases with known alcohol exposure (6/8) than of cases where alcohol exposure was not noted (217/651) (chi 2 = 6.13; P < 0.025) in this study. The defects primarily involved the right hand and forearm. This suggests a vascular origin of the limb defects after intrauterine alcohol exposure.

Limb reduction defects in over one million consecutive livebirths.

Limb reduction defects occurring among 1,213,913 consecutive livebirths in British Columbia during the period 1952-1984 inclusive were reviewed. A total of 659 cases of limb reduction defects were identified, 393 of them involving the long bones and 190 of them more than one limb. The time period 1966-1984, during which ascertainment was consistent, was evaluated, and an incidence of 5.97 per 10,000 livebirths (1 in 1,692 live births) was found. The data were evaluated for trends over time, sex ratio, and regional and ethnic distribution. Associated anomalies of other organ systems in these cases were analyzed, and overall about one-half of the cases have additional defects. The majority of these additional defects affect the musculoskeletal system and include such entities as clubfoot, hip dislocation, and congenital contractures. Defects are also frequent in other organ systems, such as the cardiovascular, gastrointestinal, and genitourinary systems. By far the most common limb defects are terminal longitudinal defects then terminal transverse defects. Of all cases of limb defects, 75% are upper limb and 25% lower limb. We found no evidence that one side is affected more frequently. About 6.5% of cases had another family member registered with a skeletal defect; 12.9% of cases died within the first year of life, the majority (85%) of those dying having additional defects. Etiological considerations are discussed for some subgroups.(ABSTRACT TRUNCATED AT 250 WORDS)

Dominantly Inherited Unilateral Terminal Transverse Defects of the Hand (Adactylia) in Twin Sisters and One Daughter

Most previous cases of unilateral terminal transverse defects of the hand have not been familial. Several previously reported cases of apparent autosomal dominant inheritance of such defects have subsequently been reclassified as type B brachydactyly. We report a pair of adult twin women with unilateral terminal transverse defects affecting the left hand in one woman and the right hand in the other woman. The latter woman has one daughter with a unilateral terminal transverse defect affecting the left hand. The hand anomaly is characterized by absence of the terminal portions of digits 2 to 5 with a mildly hypoplastic thumb (adactylia). Tiny nail remnants are evident on the remaining digital stumps, and no soft tissue syndactyly is apparent. At 2 years of age, the daughter has hypoplastic first, fourth, and fifth metacarpals with no ossification of the second or third metacarpals or any of the phalanges. The affected mother has hypoplastic metacarpals for digits 2 to 4 and a vestigial fifth proximal phalanx on the affected hand, with no other phalanges evident by roentgenogram other than those of the thumb. The mother's twin sister has similar findings, except the ossified phalangeal remnant is on her second and third fingers rather than her fifth finger. Doppler flow arterial patterns appeared normal in each hand of affected family members. The other hand and both feet are clinically and radiologically normal in each case, and the family history is negative for any other individuals with limb anomalies. A review of the literature suggests that this family may very well be unique.

Genetics and Limb Deficiencies

The majority of cases of limb deficiencies are sporadic with no recurrence risk. This is particularly true for terminal transverse defects. Some terminal transverse defects, such as acheiropody, however, are part of genetic syndromes. There is a variety of radial defects, some of them autosomal dominant, some autosomal recessive, some due to chromosomal aberrations, and some sporadic. It is usually possible to indicate the mode of inheritance of radial defects by paying close attention to morphologic details of the limb malformation and to accompaying malformations. Most ulnar and fibular defects are sporadic, yet there are some genetic syndromes in which absence of ulna or fibula may occur. There are several domonant types of splithand-splitfoot. Classification is difficult, however, because of the great intrafamilial variability. Atypical nonhereditary splithand is usually unilateral. Most cases of unilateral total syndactyly probably belong to the same category.