Tetraphocomelia and bilateral cleft lip in a historical case of Roberts syndrome [Virchow, 1898]

We discuss an unlabelled specimen of tetraphocomelia and bilaterally cleft lip from the former Virchow Museum of our Medical School. Identity of the subject with a case of what was later termed “Roberts syndrome” published by Rudolf Virchow in 1898 is demonstrated. Rediscovery of this important historical case is gratifying, since almost 95% of the specimens of Virchow's collection were lost during World War II. We have restudied Virchow's case. Recent CT scan images of the fetus are presented. We review data from the literature and present new clinical details. The fate of the original clinical data after passing through three reviews is documented briefly. We also reconstruct Virchow's view on phocomelia and its consequences for later research. Am. J. Med. Genet. 72:307–314, 1997. © 1997 Wiley-Liss, Inc.     

Roberts syndrome and SC phocomelia. A single genetic entity

A family with three siblings showing different manifestations of Roberts syndrome or SC phocomelia is described. With regard to previously published cases of familial Roberts syndrome and SC phocomelia we conclude that these two syndromes are one and the same genetic entity.     

Cytogenetic findings in Roberts-SC phocomelia syndrome(s)

Roberts syndrome and SC phocomelia syndrome are an autosomal recessive condition of prenatal and postnatal growth retardation, symmetrical limb reduction, and craniofacial abnormalities. A distinction has been made between the two syndromes on the basis of relative severity of these manifestations. Where chromosome studies have been carried out, most have been reported as normal. However, there have been two reports of consistent centromere abnormalities; one in a patient with SC phocomelia (pseudothalidomide syndrome), the other in a patient with Roberts syndrome. Four patients with similar phenotypic manifestations have recently been shown in our laboratory to have the same centromere puffing and splitting. These four patients had other clinical manifestations in common, including bilateral corneal opacities, microcephaly, absence of radii, limited extension at knees and elbows, apparent enlargement of the phallus, and survival beyond the neonatal period.     

A mild form of Roberts/SC phocomelia syndrome with asymmetrical reduction of the upper limbs

Roberts syndrome is a rare autosomal recessive condition characterized by growth retardation, cranio-facial abnormalities and symmetrical limb reduction of variable severity. Most patients with Roberts syndrome show a typical cytogenetic finding known as "Roberts syndrome effect". We describe a 4-month-old patient with a mild form of this syndrome, who presented with an asymmetrical reduction of the right upper limb.     

Lower limb anomalies in the thrombocytopenia absent-radius (TAR) syndrome

We report a case of the TAR syndrome with severe abnormalities of the lower limbs. The syndrome of thrombocytopenia and radial deformities occasionally presents diagnostic difficulties when severe limb anomalies are present. Based on this case and 2 additional cases from the literature, reduction anomalies of the lower limbs should be considered part of the TAR syndrome.     

Roberts-SC phocomelia syndrome: a case with additional anomalies

Roberts-SC phocomelia syndrome (RS) is an autosomal recessive disorder with symmetric limb defects, craniofacial abnormalities, pre- and postnatal growth retardation and mental retardation. Patients with RS were reported to have premature separation of heterochromatin of many chromosomes. We report an infant whose clinical, radiologic and chromosomal findings resemble those of RS, with rudimentary gallbladder and accessory spleen. This patient may represent a variant of RS.     

Cell proliferation rate and nuclear morphometry in Roberts syndrome

Roberts syndrome (RS) is a rare autosomal recessive disorder characterized primarily by symmetric reduction anomalies of all limbs, growth retardation and craniofacial abnormalities. Most RS patients are reported to present a typical abnormality of their constitutive heterochromatin, accompanied by abnormal cytological growth characteristics. We present an extremely severe case of an RS fetus, karyotypically documented, with a clinical presentation including growth deficiency, tetraphocomelia, frontal meningocele, craniofacial abnormalities and penile enlargement with hypospadias. Nuclear morphometrical analysis in tissues of various organs revealed a reduced nuclear size in RS as compared to normal controls, and statistically significant differences in morphometric parameters related to the nuclear shape. Immunohistochemical study of the same organs showed a reduced expression of proliferating cell nuclear antigen in the presented case, thus indicating a decreased cell proliferation rate in RS. Our results reconfirm previously reported findings in cultured fibroblasts of RS cases, thereby reinforcing on a histologic level, the hypothesis that reduced cell proliferation may be involved in the growth retardation and the reduction abnormalities observed in RS.     

Tri-amelia and phocomelia with multiple malformations resembling Roberts syndrome in a fetus: is it a variant or a new syndrome?

Roberts-SC phocomelia syndrome is a rare autosomal recessive disorder characterized by morphological anomalies such as limb defects and midfacial clefting, and by premature centromeric division in chromosomal study. Although it has been regarded as a single genetic entity and includes various morphologic defects, babies are being reported nowadays with severe facial defects, tetra-amelia, and pulmonary abnormality, yet with normal chromosomal findings. We have added a case resembling Roberts syndrome with various congenital anomalies. A gestation with a fetus was terminated at 24 weeks of gestational age because of multiple fetal anomalies. Postmortem examination revealed a severe mid-facial cleft, tri-amelia and phocomelia, multiple encephaloceles, protruding and hypoteloric eyes, low-set ears, atrial septal defect of ostium secundum type, patent ductus arteriosus, bilateral two-lobed lungs with incomplete location, multiple visceral anomalies, a penis without scrotum, abnormal dermoglyphics, and absence of nipples.     

MCA syndrome with renal‐hepatic‐pancreatic dysplasia,posterior fossa cyst,symmetrical limb deficiencies,cleft palate,cardiac and Müllerian duct anomalies

Angelman syndrome (AS) is a disorder of psychomotor development caused by loss of function of the imprinted UBE3A gene. Since the paternal UBE3A copy is regularly silent, only mutations inactivating the maternal copy cause AS. Among 1,272 patients suspected of AS, we found one with an isolated deletion of the UBE3A gene on the maternally inherited chromosome. Initial DNA methylation testing at the SNURF‐SNRPN locus in the patient revealed a normal pattern. The deletion was only detected through allelic loss at microsatellite loci D15S1506, D15S122, and D15S210, and confirmed with fluorescence in situ hybridization (FISH) using bacterial artificial chromosome (BAC) probes derived from the loci. It extends approximately 570 kilobase pairs (kbp), encompassing the UBE3A locus, and is flanked by loci PAR/SN and D15S986. The deletion is familial, and haplotype studies suggest that a great grandfather of the index patient already carried this deletion, and that it causes AS when inherited through the female germline but not Prader‐Willi syndrome (PWS) when paternally inherited. Our findings support the hypothesis that the functional loss of maternal UBE3A gene activity is sufficient to cause AS and that the deleted region does not contain genes or other structures that are involved in PWS. Finally, this case highlights that methylation tests can fail to detect some familial AS cases with a recurrence risk of 50%. © 2002 Wiley‐Liss, Inc.     

Roberts syndrome: A review of 100 cases and a new rating system for severity

Roberts syndrome (RS) is a rare genetic disorder characterized by pre- and postnatal growth retardation, limb defects, and craniofacial anomalies. Affected persons have varying degrees of malformations involving symmetric reduction in the number of digits, and length or presence of bones in the arms and legs. Craniofacial malformations involve hypertelorism, hypoplastic nasal alae, and a high incidence of cleft lip and palate. Familial and sporadic cases have been reported consistent with an autosomal recessive mode of inheritance. Mitotic cells from many individuals with RS display a characteristic cytogenetic phenomenon consisting of repulsion of heterochromatic regions near centromeres, particularly of chromosomes 1, 9, 16, and splaying of the short arms of the acrocentrics and of the distal Yq. Mitosis in RS cells is abnormal in metaphase duration and anaphase progression. Specifically, anaphase figures show a higher degree of chromosomes that are outlying, lagging, or prematurely advancing toward the poles compared to normal controls. RS cells have abnormal nuclear morphology and also show a higher frequency of micronucleation than normal cells, presumably as a result of the abnormal mitotic events during anaphase. Therefore, RS has been interpreted as a human mitotic mutation syndrome which leads to secondary developmental defects. This report reviews 100 cases of RS, summarizes the phenotypic, genetic, cytogenetic, and cell biology findings in Roberts syndrome, and introduces the RS Rating for quantitating severity. © 1993 Wiley-Liss, Inc.     

TAR syndrome: Clinical and molecular characterization of a cohort of 26 patients and description of novel noncoding variants of RBM8A

Thrombocytopenia‐absent radius (TAR) syndrome is characterized by radial defect and neonatal thrombocytopenia. It is caused by biallelic variants of RBM8A gene (1q21.1) with the association of a null allele and a hypomorphic noncoding variant. RBM8A encodes Y14, a core protein of the exon junction complex involved in messenger RNA maturation. To date, only two hypomorphic variants have been identified. We report on a cohort of 26 patients affected with TAR syndrome and carrying biallelic variants in RBM8A. Half patients carried a 1q21.1 deletion and one of the two known hypomorphic variants. Four novel noncoding variants of RBM8A were identified in the remaining patients. We developed experimental models enabling their functional characterization in vitro. Two variants, located respectively in the 5′‐untranslated region (5′‐UTR) and 3′‐UTR regions, are responsible for a diminished expression whereas two intronic variants alter splicing. Our results bring new insights into the molecular knowledge of TAR syndrome and enabled us to propose genetic counseling for patients' families.     

PHAVER syndrome: An autosomal recessive syndrome of limb pterygia,congenital heart anomalies,vertebral defects,ear anomalies,and radial defects

We have studied 2 sibs with vertebral, radial, congenital heart, and ear defects. The second patient also had limb pterygia and meningomyelocele. The abnormalities in these two sibs are seen in the VATER association; however, distinguishing these cases from the VATER association are the findings of pterygia, meningomyelocele, and probable autosomal recessive inheritance. We propose the acronym PHAVER syndrome for limb pterygia, heart defects, autosomal recessive inheritance, vertebral defects, ear anomalies and radial defects. This represents an new autosomal recessive disorder with phenotypic variability. © 1993 Wiley-Liss, Inc.     

Cleft lip/palate-oligodontia-syndactyly-hair alterations,a new syndrome: Review of the conditions combining ecodermal dysplasia and cleft lip/palate

We report on a noninbred girl with cleft lip and palate, complete absence of deciduous teeth, hypodontia of permanent teeth, hair alterations, hypertelorism, midface hypoplasia, abnormal EEC, syndactyly, and other findings. Her mother had minor anomalies which could represent the mild expression of a gene. A review on the conditions combining ectodermal dysplasia and cleft lip/palate is presented.     

Sacral protuberance with cleft lip and palate: Prenatal presentation of 3MC syndrome

3MC syndromes are rare heterogeneous autosomal recessive conditions previously designated as Mingarelli, Malpuech, Michels, and Carnevale syndromes, characterized by dysmorphic facial features, facial clefts, growth restriction, and intellectual disability. 3MC is secondary to mutations in the MASP1, MASP3, COLEC11, and COLEC10 genes. The number of patients with 3MC syndrome with known mutations in the COLEC11 or MASP1 is, to date, less than 50. At the time this case presented (2015), the only gene identified in Online Mendelian Inheritance in Man to be associated with 3MC syndrome was MASP1. We present, to the best of our knowledge, the first prenatal report of 3MC syndrome, secondary to a homozygous variant in MASP1. Fetal findings included bilateral cleft lip and palate, abnormality of the sacral spine, a right echogenic pelvic kidney, and brachycephaly. 3MC syndrome should be considered as part of the differential diagnosis when fetal ultrasound detects facial clefts and spinal defects, as the risk of recurrence is significant and a molecularly confirmed diagnosis allows for alternate reproductive options.     

Renal tubular dysgenesis,absent nipples,and multiple malformations in three brothers: A new,lethal syndrome

We report on three brothers with renal tubular dysgenesis and absent nipples, each also had other malformations including preauricular pits and a preauricular tag, branchial clefts, choanal atresia, pulmonary lobation anomaly, ventricular septal defect, type IIB interrupted aortic arch, absent gallbladder, absent thymus, parathyroid gland, accessory spleen, imperforate anus, clinodactyly, and broad digits and small nails. All three infants died neonatally. This pattern of clinical malformations appears to be a previously unreported syndrome. Am. J. Med. Genet. 80:335–342, 1998. © 1998 Wiley-Liss, Inc.     

Hardikar syndrome: A new syndrome with cleft lip/palate,pigmentary retinopathy and cholestasis

We present a child with a remarkable constellation of abnormalities comprising cleft lip and palate, pigmentary retinopathy, hydronephrosis, malrotation of the gut and obstructive liver disease. This patient, together with two other reported cases, seems to represent a new syndrome with some similarities to the Kabuki syndrome. Am. J. Med. Genet. 71:472–474, 1997. © 1997 Wiley-Liss, Inc.     

A dominantly inherited malformation syndrome with short stature,upper limb anomaly,minor craniofacial anomalies,and absence of TBX5 mutations: Report of a Thai family

We report on a Thai family with dominantly inherited malformation syndrome with upper limb anomalies, short stature, quadricuspid aortic valve, and minor craniofacial anomalies. The affected individuals comprised a mildly affected mother, a moderately affected daughter, and a most severely affected son. The daughter and son had short stature. The craniofacial abnormalities comprised frontal bossing, hypoplastic nasal bones, depressed nasal bridge, and broad nasal alae. The upper limb defects varies among the patients, ranging from radial ray defects in the mother through radial and ulnar ray defects with unilateral humeral hypoplasia in the daughter to radial ray defects with severe oligodactyly and bilateral humeral hypoplasia in the son. All patients in this family had hypoplasia of the shoulder girdle and resembled what is observed in many families with Holt‐Oram syndrome. Moreover, the son showed quadricuspid aortic valve with mild aortic regurgitation. However, the present family did not show any mutation of the TBX5 gene, a disease‐causing gene of Holt‐Oram syndrome. The present family deserves further investigation on other genes that play a role in the development of the upper limbs, particularly of radial rays. © 2002 Wiley‐Liss, Inc.     

Ocular hypotelorism,submucosal cleft palate,and hypospadias: A new autosomal dominant syndrome

A syndrome characterized by ocular hypotelorism, submucosal cleft palate, and hypospadias in males was found in ten relatives over five generations of a family. Other anomalies are blepharophimosis, upslant of palpebral fissures, and a tendency to cutaneous syndactyly of 3rd and 4th fingers as well as 2nd and 3rd toes. Autosomal dominant inheritance is likely.