Feingold syndrome: Report of a new family and review

Feingold syndrome (or oculodigitoesophagoduodenal syndrome; Microcephaly, Mesobrachyphalangy, Tracheo-esophageal fistula syndrome) is a dominantly inherited combination of hand and foot abnormalities, microcephaly, esophageal/duodenal atresia, short palpebral fissures and learning disabilities, first reported in 1975 (MIM 164280). We report on the seventh family with Feingold syndrome. The propositus is a male infant with esophageal and duodenal atresia, brachymesophalangy of the fifth fingers, bilateral syndactyly of toes 4-5 (and 2-3), relative microcephaly, and facial anomalies. His mother also has microcephaly, similar facial appearance, short fifth fingers with single flexion crease, syndactyly of toes 4-5, and learning disabilities. The maternal sister, brother, and grandmother of the propositus have the same phenotype. The 7 families with Feingold syndrome are reviewed. Intestinal (esophageal/duodenal) atresia/obstruction occurs in approximately ⅓ of the patients with Feingold syndrome. Am. J. Med. Genet. 73:55–60, 1997. © 1997 Wiley-Liss, Inc.     

A new dominant branchiogenic-deafness syndrome with internal auditory canal hypoplasia and abnormal extremities

Two sibs from one Lebanese family presented with congenital hearing loss, meatal atresia, preauricular tags and pits, branchial cysts or fistulae, strabismus, difficulty in opening the mouth wide enough, abnormal fifth fingers, somewhat short stature, and learning disability and patchy skin depigmentation in one. Temporal bone abnormalities identified on computed tomography included atresia of the external auditory canal with reduction in size of the middle ear, malformed ossicles, and unilateral internal auditory canal hypoplasia. Hand radiographs showed pointed phalanges of the 5th fingers with osseous erosions. Their father, his sister, and his half-brother had unilateral auricular pits and/or branchial cysts. Results of all laboratory investigations including sequencing of the EYA1 gene were normal. Differential diagnosis is discussed and the possibility of the report of a new autosomal dominant type of branchiogenic-deafness syndrome with variable expressivity is raised.     

Instability of lymphocyte chromosomes in a girl with Rothmund-Thomson syndrome.

Rothmund-Thomson syndrome is a rare autosomal recessive syndrome characterised by poikiloderma of the face and extremities, alopecia, short stature, and skeletal defects. We report a patient with the characteristic features of Rothmund-Thomson syndrome who also had lymphocyte chromosome abnormalities. She has a small flat face with short palpebral fissures and micrognathia together with severe skeletal abnormalities of the upper extremities with absence of both radii, short dysmorphic ulnae, a rudimentary right thumb, and aplasia of the left thumb. She also has anal atresia with a rectovaginal fistula. From the age of 3 months she developed poikiloderma skin changes on the face and extensor surfaces of the extremities. Mental development seems to be normal. Lymphocyte chromosomes in the neonatal period showed an unidentified marker chromosome in eight of a total of 32 cells. A repeat analysis at the age of 10 months showed three abnormal cells out of 100 analysed: 47,XX,-7,+i(7q),+7p, 46,XX,t(3;18)(p14.2;q22), and 49,XX,+del(3)(p11.2),+mar,+mar. A skin biopsy from an affected area showed poor growth and five of 48 cells analysed had structural abnormalities. The father had one of 48 cells with an additional marker chromosome and two cells with different 7;14 translocations. The abnormal chromosome complements in lymphocytes indicate that there may be in vivo chromosome instability in Rothmund-Thomson syndrome.     

Choanal atresia as a feature of ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome.

We report here a father and daughter with digital abnormalities, nasolacrimal duct obstruction, and variable alopecia. The father had a cleft lip and palate and the daughter had choanal atresia. We propose they both have the EEC syndrome and show the variable expressivity of this disorder. Choanal atresia has not been previously reported in this condition.     

Familial CHARGE syndrome because of CHD7 mutation: clinical intra- and interfamilial variability

CHARGE syndrome (OMIM #214800) is a multiple malformation syndrome with distinctive diagnostic criteria, usually because of CHD7 (chromodomain helicase DNA binding 7) haploinsufficiency. Familial occurrence of CHARGE syndrome is rare. We report six patients from two Caucasian families (both with one parent and two children) affected by mild to severe CHARGE syndrome. Direct sequencing of the CHD7 gene was performed in these two unrelated families. A mutation in exon 8 (c.2501C>T - p.S834F) in first chromodomain was found in family A and a nonsense mutation in exon 2 (c.469C>T - p.R157X) in family B. Both mutations are de novo in the parents. In family A, the elder son had bilateral cleft lip and palate, esophageal atresia with fistula, complex heart defect and vertebral abnormalities, while the younger had a posterior coloboma. Their mother had asymptomatic vestibular dysfunction and retinal coloboma, identified after the molecular diagnosis of her children. In family B, both affected children had severe expression of CHARGE syndrome. The father carrying the mutation only had asymmetric anomaly of the pinnae. These familial reports describe the intrafamilial variability of CHARGE syndrome, and underline the presence of CHD7 mutations in patients who do not fit the 'classical clinical criteria' for CHARGE syndrome.     

Oesophageal atresia, tracheo-oesophageal fistula, and the VACTERL association: review of genetics and epidemiology

Oesophageal atresia and/or tracheo-oesophageal fistula are relatively common malformations occurring in approximately 1 in 3500 births. In around half of the cases (syndromic oesophageal atresia), there are associated anomalies, with cardiac malformations being the most common. In the remainder (non-syndromic cases), oesophageal atresia/tracheo-oesophageal fistula occur in isolation. Data from twin and family studies suggest that genetic factors do not play a major role, and yet there are well-defined instances of this malformation where genetic factors clearly are important. This is highlighted by the recent identification of no fewer than three separate genes with a role in the aetiology of oesophageal atresia: those for Feingold syndrome (N-MYC), anophthalmia-oesophageal-genital (AEG) syndrome (SOX2), and CHARGE syndrome (CHD7). Additional support for genetic factors in this malformation comes from chromosomal studies and mouse models. This paper reviews current knowledge of the genetics and epidemiology of the different oesophageal atresia/tracheo-oesophageal fistula syndromes and associations.     

A newborn with overlapping features of AEC and EEC syndromes

Ectrodactyly, ectodermal dysplasia, clefting (EEC) syndrome is the prototype of several p63 conditions, which include ankyloblepharon, ectodermal dysplasia, clefting (AEC) syndrome, limb-mammary syndrome (LMS), Rapp-Hodgkin syndrome (RHS), ADULT syndrome, and others. All these disorders include combinations of ectodermal dysplasia, orofacial clefting and limb malformations in variable severity. A newborn patient is presented with diffuse erythematous and desquamating skin lesions and anal atresia. She also had sparse and lightly colored thin hair, deeply set eyes, hypoplastic alae nasi, and a short philtrum. Cleft lip/palate and ankyloblepharon were not present. Complete cutaneous syndactyly was present on both hands in between the third and fourth fingers. Mild ectrodactyly was evident on all four extremities in between first and second digits. There was post-axial polydactyly on both feet. Anal atresia was present and defecation occurred through a rectovaginal fistula. The patient represented an interesting overlapping clinical condition between AEC and EEC syndromes. Diffuse skin lesions with excoriation and desquamation suggest AEC syndrome, despite the absence of ankyloblepharon, however; ectrodactyly and polydactyly strongly suggest the EEC syndrome. C308Y mutation in exon 8 of TP63 gene was detected, which was previously described to lead only to EEC syndrome and not to any of the other allelic conditions. These data emphasize the large degree of clinical variability that may be seen for specific TP63 mutations.     

Oesophageal atresia in the South West of England.

A retrospective anatomical and family study was made of 345 patients with oesophageal atresia who were born in the South West of England between 1942 and 1973. There were 186 males and 159 females. Twenty-one cases were stillborn. Eighty-five percent of the patients had a combination of oesophageal atresia with a tracheo-oesophageal fistula to the distal oesophageal segment, and 9 percent had atresia without a fistula. Fifty-five per cent of the patients had other congenital malformations and these tended to be multiple rather than single. Thirty-six per cent of singletons had unequivocal fetal growth retardation, and there is some evidence that nearly all cases have poor fetal growth. There appeared to be a maternal age effect, with an excess of mothers under 20 and over 35, and there was an unexplained excess of fathers employed in the Armed Forces. Ten per cent of the cases were illegitimate. There were 21 twins which is nearly three times the expected number; there were two pairs of twins concordant for oesophageal atresia, one being monozygotic and the other dizygotic. In one case there were two sibs with oesophageal atresia. Five out of 365 sibs had anencephaly. The blood group distributions of the patients and their mothers did not significantly differ from the expected distribution. Oesophageal atresia is aetiologically heterogenous. In this series there were at least five, and probably 10 cases of trisomy 18 and four cases of trisomy 21. Five mothers had overt diabetes, and there is some suggestion from other work that maternal diabetes or its treatment may be aetiologically important. Oesophageal atresia was part of a possibly recessively inherited malformation syndrome in two cases. A sibship with a case of rectal atresia, a case of Hirschprung's disease and a case of oesophageal atresia may represent the action of another recessive gene. It seems likely that oesophageal atresia is a rather non-specific consequence of several teratological processes.     

Possible Waardenburg syndrome with gastrointestinal anomalies.

We describe a patient with possible Waardenburg syndrome associated with anal atresia and oesophageal atresia with tracheooesophageal fistula. Three other published cases with atretic gastrointestinal anomalies associated with the Waardenburg syndrome are reviewed. We conclude that the association between atretic lesions of the gastrointestinal tract and the Waardenburg syndrome may be a significant one.     

Tracheoesophageal fistula, gastrointestinal abnormalities, hypospadias, and prenatal growth deficiency.

We studied 2 sibs, born to consanguineous parents, who presented with an MCA pattern which includes low birthweight, tracheoesophageal fistula, duodenal atresia, extrahepatic biliary atresia, hypoplastic pancreas, and hypospadias. This constellation of congenital anomalies appears to be a previously unreported autosomal recessive syndrome. A computerized search of the data files of the Spanish Collaborative Study of Congenital Malformations (ECEMC) identified 3 other unrelated infants with intestinal atresias, hypospadias, and low birth weight. These cases may represent a milder expression of the same syndrome.     

McKusick-Kaufman syndrome associated with esophageal atresia and distal tracheoesophageal fistula: A case report and review of the literature

A female infant with McKusick-Kaufman syndrome associated with esophageal atresia and distal tracheoesophageal fistula is presented. To the best of our knowledge, this is the second report in the literature of this association. © 1994 Wiley-Liss, Inc.     

Clinical and molecular analysis of Grebe acromesomelic dysplasia in an Omani family

Grebe syndrome is a rare autosomal recessive acromesomelic dysplasia. The syndrome was studied clinically, radiographically, and genetically in an Omani family with four affected children. The affected persons had normal axial skeletons, severely shortened, and deformed limbs with severity increasing in a proximo-distal gradient, and subluxated joints. The humeri and femora were hypoplastic with distal malformations. The radii/ulnae were shortened and deformed whereas carpal bones were invariably rudimentary or absent. The tibiae appeared rudimentary; fibulae were absent in two children, and some tarsal and metatarsal bones were absent. The proximal and middle phalanges were absent while the distal phalanges were present. The father and mother had short first metacarpal and middle phalynx of the fifth finger and hallux valgus respectively. Transition A1137G and deletion delG1144 mutations in the gene encoding the cartilage-derived morphogenetic protein-1 (CDMP-1) were identified in this family. The A1137G is a silent mutation coding for lysine, whereas the delG1144 predicts a frameshift mutation resulting in a presumable loss of the CDMP-1 biologically active carboxy-terminal domain. The affected siblings were homozygous for the delG1144 mutation while parents were heterozygous.     

Syndrome of microcephaly,facial and hand abnormalities,tracheoesophageal fistula,duodenal atresia,and developmental delay

We report on six new families (12 new patients) with the syndrome of microcephaly, facial and hand abnormalities, tracheoesophageal fistula, duodenal atresia, and developmental delay. The most common findings were hand abnormalities, microcephaly, short and/or narrow palpebral fissures, broad nasal bridge, anteverted nostrils, ear abnormalities, and micrognathia. Inheritance is autosomal dominant. There is a significant amount of intrafamilial variability especially as it relates to the gastrointestinal findings. Although the first patients reported, who were very young, did not exhibit any developmental delay, they subsequently did develop learning problems, and 87% of our 12 patients had mental retardation or learning difficulties. Am. J. Med. Genet. 69:245–249, 1997. © 1997 Wiley-Liss, Inc.     

Autosomal dominant inheritance of the Kabuki make-up (Niikawa-Kuroki) syndrome

We report on three individuals (two sibs and their father) with the Kabuki make-up syndrome. The two sibs had congenital dislocation of the hips and all three individuals had short stature and the facial characteristics of the syndrome. To our knowledge this is the first report of familial occurrence of the Kabuki make-up syndrome.     

The Tel Hashomer camptodactyly syndrome in a consanguineous Brazilian family

We report on two Brazilian sibs whose parents are first cousins with clinical findings of the Tel Hashomer camptodactyly syndrome, namely, camptodactyly, muscle hypoplasia, skeletal abnormalities, and abnormal palmar creases. Both affected sibs have flat orbital roofs not described in previous cases and a high number of dermatoglyphic arches. The patient's father had camptodactyly of the fifth fingers, possibly a heterozygote manifestation.     

Vertebral anomalies in a new family with ODED syndrome

We report a new family with oculodigitoesophagoduodenal syndrome (ODED syndrome), which associates microcephaly, abnormalities of the hands and feet, shortened palpebral fissures, tracheoesophageal fistula and duodenal atresia. In addition, previously unreported vertebral anomalies are described. This report further delineates the clinical and radiographic spectrum of this syndrome, providing useful information for diagnosis and family counseling.     

Feingold syndrome: clinical review and genetic mapping

Feingold syndrome is characterized by autosomal dominant inheritance of microcephaly and limb malformations, notably hypoplastic thumbs, and clinodactyly of second and fifth fingers. Syndactyly frequently involves the second and third, as well as the fourth and fifth toes. Approximately one in three Feingold syndrome patients have esophageal or duodenal atresia or both. Anal atresia has been reported in a single case. At least 79 patients in 25 families have been reported. The syndrome has autosomal dominant inheritance with full penetrance, and variable expressivity. Vertebral anomalies, cardiac malformations, and deafness have been noted in a minority of patients. Here, we report a patient with hydronephrosis of one kidney and cystic dysplasia of the other, necessitating nephrectomy. The overall pattern of malformations in Feingold syndrome shows considerable overlap with the VATER/VACTERL association. The gene for Feingold syndrome maps to 2p23-p24, but remains to be identified. Comparison of the pattern of anomalies that occurs in the Feingold syndrome in humans and malformations that are present in mice with mutations of genes in the sonic hedgehog signaling pathway suggest, that the elusive Feingold syndrome gene may involve this signaling pathway as well.     

An autosomal dominant syndrome of renal and anogenital malformations with syndactyly.

We describe a family with autosomal dominant inheritance of anal anomalies, renal tract abnormalities, genital malformations, and syndactyly. These clinical manifestations do not clearly fall into any previously described syndrome. A mother and daughter had almost identical congenital malformations, short stature, and unusual facies. The proband was born with anal stenosis, a rectovaginal fistula, clitoral hypertrophy, a pelvic right kidney, and syndactyly of both feet. Her daughter had the same anal, clitoral, and foot anomalies, a solitary pelvic kidney, and no fistula. This family is likely to represent autosomal dominant inheritance of a new combination of malformations, which may overlap with the Townes-Brocks syndrome, but does not fall into a current diagnostic category.     

Change of blood group from A2 to Ax in a child with congenital abnormalities.

A blood group change from A2 to Ax is described in a boy who had Fallot's tetralogy, oesophageal atresia, and a tracheo-oesophageal fistula. The change of blood group created a transfusion problem. The unusual serology is discussed.     

A new autosomal dominant craniofacial deafness syndrome

A Jewish family is reported in which the proband and her father had congenital hearing loss and unusual facies consisting of facial asymmetry, temporal alopecia with frontal bossing, a broad nasal root and small nasal alae. In addition, both were born with a short frenulum of the tongue. We believe these findings represent a new autosomal dominant deafness syndrome with distinct craniofacial features.