Erawati V. Bawle

Adult and two children with fetal methotrexate syndrome

The folic acid antagonists, methotrexate and aminopterin, are known to be teratogenic in humans. The critical period for their teratogenecity is suspected to be between 6 to 8 weeks post-conception. Fetal exposure from 10 to 32 weeks weeks post-conception to methotrexate alone or in combination with other anti-cancer drugs has not resulted in obvious teratogenic effects. Methotrexate is often used to treat cancers but is occasionally used as an abortifacient. The long-term outcome of the fetal aminopterin syndrome has been published in only four adults. We report on a 28-year-old man with fetal methotrexate syndrome and two children with mild manifestations of the syndrome. One child was inadvertently exposed to methotrexate from 7 1/2 through 30 weeks post-conception because his mother was receiving it for treatment of breast cancer. The other was exposed from 11 weeks and 5 days through 25 weeks in an attempt to induce abortion. The 28-year-old man has craniofacial and digital anomalies, growth retardation but normal intelligence as noted in the previously reported cases. These cases remind us of the teratogenicity of methotrexate and should serve as a warning that if methotrexate is used as an abortifaciant and an abortion does not ensue, there is a teratogenic risk.

Seven new cases of Cayler cardiofacial syndrome with chromosome 22q11.2 deletion, including a familial case.

Cayler cardiofacial syndrome comprises congenital unilateral hypoplasia of the depressor anguli oris muscle (HDAOM) and congenital heart defects [Cayler, 1969]. Hypoplasia of this muscle leads to failure of one corner of the mouth to move downward and outward while crying or grimacing and hence, is described as ‘‘asymmetric crying face.’’ Asymmetric facial expression is most noticeable in young babies and with age it becomes less distinct. The cause of Cayler syndrome is heterogeneous: It may be an autosomal dominant trait, occurring sporadically, or it can be seen in chromosome 22q11.2 deletions. Our clinical geneticist (E.V.B.) diagnosed 24 patients with 22q11.2 deletions in the last 2.5 years and found seven of them to have Cayler syndrome (29%). Their clinical findings are summarized in Table I. Six of the seven patients are shown in Figure 1. There was no correlation between the type of heart defect and the side of the HDAOM. All except one (who is too young to evaluate) had either a cleft palate or velopharyngeal incompetence, and six had a conotruncal cardiac malformation. The mother (Case 4) of Case 3 has normal cardiac structure on echocardiogram. Cases 3, 4, and 5 were erroneously suspected to have traumatic facial nerve paralysis neonatally. The HDAOM in Case 7 was barely noticeable at age 12 years but he had been evaluated at 18 months of age when the diagnosis of Cayler syndrome was made. Fluorescent in situ hybridization (FISH) studies were performed to determine the size and extent of the deletion in the affected mother (Case 4) and one of her sons (Case 3). Both individuals have an approximately 1.5-Mb deletion within the DiGeorge syndrome region and share similar proximal and distal deletion boundaries. The size of the deletion does not appear to differ from the common deletion seen in most patients with the 22q11.2 deletion syndrome. Giannotti et al. first reported Cayler syndrome in 5 of their 15 patients (33%) with chromosome 22q11.2 deletions [Giannotti et al., 1994]. However, in a large series of 558 patients with an interstitial deletion of chromosome 22q11.2 from 23 European centers, only 11 patients (2%) with unilateral HDAOM were reported [Ryan et al., 1997]. The frequency of Cayler cardiofacial syndrome (29%) among our patients with 22q11.2 deletion is comparable to that reported by Giannotti et al. (33%). Our Case 4 and the two patients reported by Stewart and Clayton Smith [1997] have HDAOM without a congenital heart defect. Cases of asymmetric crying face resulting from unilateral HDAOM with or without other defects showing autosomal dominant inheritance have been reported [Papadatos et al., 1974; Miller and Hall, 1979; Singhi et al., 1980; Silengo et al., 1986]. However, these reports predate the application of FISH to detect microdeletions of chromosomes. Therefore, the prevalence of 22q11.2 deletions in Cayler syndrome or in patients with only HDAOM is unknown. We think that this is the first report of autosomal dominant transmission of unilateral HDAOM due to 22q11.2 deletion. The face of the crying baby or child usually shows the asymmetric facies. However, HDAOM may not be noticeable in adults. Diagnoses in our Cases 4 and 7 were made based on their photographs taken during infancy. Therefore we recommend that infant photographs be examined. Our observations provide additional evidence that unilateral HDAOM is part of the spectrum of syndromes associated with 22q11.2 deletion, namely the velocardiofacial syndrome and DiGeorge syndrome. We recommend investigations for 22q11.2 deletion in all cases of unilateral HDAOM.

Analphoid 3qter markers

Two cases of marker chromosomes derived from a non-centromeric location were studied to determine the characteristics of these markers with respect to the presence of functional centromeres and whether an associated phenotype could be described. The markers were characterized by fluorescence in situ hybridization and centromeric protein studies. Assessments were done to identify clinical features. Case 1 is a girl referred at age 1.5 years with swirly areas of hyperpigmentation, bilateral preauricular pits, hypotonia, developmental delay, and seizures. Case 2 is a male first evaluated as a newborn and then later during the first year of life. He had streaky hypopigmentation, right preauricular pit, accessory nipples, postaxial polydactyly, asymmetric cerebral ventricles, duplicated right kidney, a right pulmonary artery stenosis, and seizures. Mosaicism for an extra marker from the 3qter region was present in both cases. Both markers had a constriction near one end and were C-band negative. Centromeric protein studies indicated absence of CENP-B, presence of CENP-C (data for case 1 only), and presence of CENP-E. Marker chromosomes were thus identified with a chromosomal origin far from their usual centromeric region and yet appeared to have functional centromeres. These two cases did not permit a specific clinical phenotype to be ascribed to the presence of tetrasomy for 3q26.2 approximately 3q27.2-->3qter.

Familial infantile olivopontocerebellar atrophy.

Infantile olivopontocerebellar atrophies are rare progressive, fatal, neurologic conditions characterized pathologically by loss of neurons and gliosis in the cerebellum, pons, and inferior olivary nuclei in early life. The clinical and pathologic features of 2 brothers who presented in early infancy with failure to thrive and neurologic deterioration leading to death by the age of 5 months are reported. Magnetic resonance imaging of the brain of Patient 1 disclosed progressive pontocerebellar atrophy. Both siblings had identical patterns of neuronal loss consistent with olivopontocerebellar atrophy at postmortem examination. Serum biochemical abnormalities of low thyroid binding globulin, hypoalbuminemia, and low cholesterol, suggestive of the carbohydrate-deficient glycoprotein syndrome, were also present in both patients.

Spontaneous Contraction of Leukodermic Patches in Waardenburg Syndrome

Waardenburg Syndrome is an autosomal dominantly inherited disorder with variable penetrance (1–5). It is a rare disorder with an estimated frequency of 1:20,000 in Kenya (East Africa) and 1:40,000, in the Netherlands presenting with or without deafness. The frequency with deafness is lower, estimated at 1:50,000 to 1:212,000 (1, 2). The major characteristic features are as follows, with reported incidences in parenthesis: 1) Dystopia canthorum (99%); 2) synophrys (17%–69%); 3) broad nasal root (78%); 4) depigmentation of hair, skin, or both (17%–58% with white forelock); 5) heterochromic or hypochromic irides (greater than 20%); 6) congenital deafness (9%–38%) (1–7). Genetic heterogeneity has led to classification of affected families as type I, with dystopia canthorum, or type II, without dystopia canthorum (2, 6). Piebaldism and Woolfs Syndrome can present with pigmentary changes which are similar to Waardenburg Syndrome (2, 3, 8). Woolfs Syndrome also includes deafness (9). However, the distinguishing structural ophthomologic abnormalities of dystopia canthorum, broad nasal root, and synophrys are not found in either piebaldism or Woolfs Syndrome (2, 3, 8, 9). The congenital patterns of leukoderma in both piebaldism and Waardenburg Syndrome has been believed to be stable throughout the lifetime of the affected individuals (2, 10). We report an otherwise typical family with Waardenburg Syndrome, type I, in which 2 members atypically demonstrate spontaneous pigmentation and contraction of congenital leukodermic patches. To our knowledge, this has not been previously reported in Waardenburg Syndrome (1, 2, 6, 10).

The genetic implication for preceding generations of the prenatal diagnosis of interrupted aortic arch in association with unsuspected DiGeorge anomaly

We present a case of prenatally diagnosed interrupted aortic arch with a ventricular septal defect in the presence of maternal congenital heart disease, which led to the detection of segmental monosomy of chromosome 22q11.2 in both patients. The implications of detecting a microdeletion and the importance of a multidisciplinary approach to prenatal diagnosis and counseling are discussed.

Microduplication of 4p16.3 Due to an Unbalanced Translocation Resulting in a Mild Phenotype

With the widespread clinical use of comparative genomic hybridization chromosomal microarray technology, several previously unidentified clinically significant submicroscopic chromosome abnormalities have been discovered. Specifically, there have been reports of clinically significant microduplications found in regions of known microdeletion syndromes. In general, these microduplications have distinct features from those described in the corresponding microdeletion syndromes. We present a 5½‐year‐old patient with normal growth, borderline normal IQ, borderline hypertelorism, and speech and language delay who was found to have a submicroscopic 2.3 Mb terminal duplication involving the two proposed Wolf–Hirschhorn syndrome (WHS) critical regions at chromosome 4p16.3. This duplication was the result of a maternally inherited reciprocal translocation involving the breakpoints 4p16.3 and 17q25.3. Our patients features are distinct from those described in WHS and are not as severe as those described in partial trisomy 4p. There are two other patients in the medical literature with 4p16.3 microduplications of similar size also involving the WHS critical regions. Our patient shows clinical overlap with these two patients, although overall her features are milder than what has been previously described. Our patients features expand the knowledge of the clinical phenotype of a 4p16.3 microduplication and highlight the need for further information about it.