Unusual retrospective prenatal findings in a male newborn with Timothy syndrome type 1.

Timothy syndrome 1 (TS1) is a multisystem disorder characterized by severe QT prolongation and potentially lethal ventricular arrhythmias in the first years of life, plus other cardiac and extracardiac manifestations caused by mutation in the CACNA1C gene, a CaV1.2 L-type calcium channel. Here, we report retrospectively an unusual fetal presentation on a second patient with TS1 with fetal hydrops due to a congenital AV block and its postnatal diagnosis by a marked prolongation of the corrected QTc interval of 570 ms and a missense mutation, p.Gly406Arg, in exon 8A of CACNA1C gene. The observed manifestations in our patient during fetal period indicate a severe form and they were probably exacerbated by the maternal use of amitriptyline during the first 4 months of pregnancy. Unfortunately, he died at 3 months-old due a ventricular tachycardia and fibrillation related to a septic event. Although difficult to diagnose, possibly most fetuses with TS1 have symptoms of long QT syndrome. Despite the fatal outcome for our patient, an early diagnosis of TS may help to prevent life-threatening events or early death in future patients, especially in developing countries where availability of therapies such as cardioverter defibrillator are very limited, or require time for its funding.

New ocular findings in two sisters with Yunis-Varón syndrome and literature review.

The Yunis-Varón syndrome (YVS) represents a rare autosomal recessive syndrome of easy recognition characterized by cleidocraneal dysplasia, absence of thumbs and halluces, distal aphalangia, ectodermal anomalies, and poor outcome. Here, we report two sisters with YVS who also had papillo-macular atrophic chorioretinopathy with "salt-and-pepper" appearance that could not be attributed to environmental or metabolic causes. Our best hypothesis is that the ocular findings in our two patients are part of the phenotypic manifestations of YVS. We suggest that an extensive ophthalmologic examination should be carried out in all children with YVS in order to define the frequency and nature of the ocular findings in these patients.

Holoprosencephaly and genitourinary anomalies in fetal methotrexate syndrome.

Prenatal exposure to methotrexate (MTX) in the first trimester may lead to fetal death, and surviving children have increased risks for cranial dysostosis, dysmorphic facies, skeletal malformations, limb defects, growth retardation, and, in some cases, developmental delay, a pattern of defects recognized as fetal MTX syndrome (FMS). We report on a male infant who, in addition to severe FMS, showed previously undescribed central nervous system (CNS) and genitourinary anomalies that contributed to the further delineation. The propositus was born to a G2, 20-year-old mother with an irregular menstrual history. The unplanned pregnancy was complicated by oral MTX treatment (5 mg/day) for suspected systemic lupus erythematosus for 14 days at the 5th week post-conception, as dated by the first trimester sonogram. In addition to the typical features of the FMS, our propositus exhibited congenital penile curvature, vesicoureteral reflux, hydronephrosis, and severe CNS anomalies including semilobar holoprosencephaly (HPE). A single previous report of lobar-type HPE in an infant with FMS led us to confirm that the HPE observed in the propositus is a feature attributable to MTX teratogenicity, although the exact mechanisms of the HPE production need to be further elucidated. Also, this case serves to highlight the presence of genitourinary anomalies in patients with FMS, a fact that requires intentional searches in future patients in order to confirm this as being characteristic of the entity.

Umbilical cord disruption sequence caused by long cord in two unrelated infants with amyoplasia.

Encirclement of a fetal body part by the umbilical cord with or without vascular obstruction in either the umbilical cord or the encircled fetal part is considered an umbilical cord loop (UCL). Significant disruption of the encircled fetal parts is recognized as the umbilical cord disruption sequence (UCDS). UCL around fetal parts is an occasional anomaly in infants with amyoplasia. We report on 2 patients with amyoplasia and damage to the fetal limbs caused by UCDS and a long umbilical cord. Patient 1 showed two deep constrictions on the left lower limb caused by UCL with an intact skin and a mild mark of constriction on the left wrist. The umbilical cord in patient 2 produced 5 entanglements around the left thigh which resulted in a deep groove extending down to the femur and also showed an exposed fracture and gangrene of the entire lower limb with an unusual congenital paraumbilical "stoma" that corresponded to the afferent loops of a jejunal atresia. The UCDS in infants with amyoplasia has been associated with short umbilical cords, whereas in patients without congenital contractures, the UCDS or UCL has been related to long umbilical cords. Our observations of UCDS in patients with amyoplasia but with long umbilical cords suggest the influence of both pathogenic factors or the existence of additional mechanisms. Evidence in patient 2 may support a vascular pathogenesis.

Abnormal oral-pharyngeal swallowing as cause of morbidity and early death in Stüve-Wiedemann syndrome.

Stüve-Wiedemann syndrome (SWS) is an autosomal recessive bone dysplasia (OMIM #601559) characterized by bowing of long bones, camptodactyly, respiratory insufficiency, hyperthermic episodes, and neonatal death from hyperthermia or apnea. We describe two female siblings with SWS born from consanguineous Gypsy parents. For a further delineation of SWS, we report hypothyroidism and ectopic thyroid as part of its phenotypic spectrum. Molecular study in the leukemia inhibitory factor receptor (LIFR) gene (OMIM *151 443) demonstrated the presence of a mutation. We observed that in one of our patients, oropharyngeal disruption in the swallowing process caused repetitive aspiration pneumonias, life-threatening events, and finally death. We emphasize that these features represent dysautonomic manifestations of SWS, and are probably related to pharyngoesophageal dyskinesia due to abnormal autonomic control of the anterior rami of cervical roots C1-C5.

Mental retardation in a boy with anterior cervical hypertrichosis.

Anterior cervical hypertrichosis (ACH) is a rare form of localized hypertrichosis with 15 previously reported cases. ACH has been considered to be a dominant phenotype, either X-linked or autosomal [OMIM 600457]. ACH was associated with hereditary motor and sensory neuropathy (HMSN) in one family, in which the proband also exhibited severe chorioretinal degeneration and optic atrophy, probably as a different entity [OMIM 239840]. A Mexican boy with congenital ACH associated with moderate mental retardation, abnormal EEG, mild microcephaly, hypertrichosis on the back, and hallux valgus is presented here. An equal sex ratio found in 16 reported cases as well as the suggestion of a paternal age effect in one report appear most consistent with an autosomal dominant mode of inheritance for this trait. It remains unclear if isolated ACH, ACH-HMSN, or other associated findings reported in patients with ACH, including unusual features found in our case, are part of ACH or fortuitous associations, due to the small number of affected patients and different ascertainment biases present in previous reports.

Chromosome instability induced in vitro with mitomycin C in five Seckel syndrome patients.

Seckel syndrome (SS) is an autosomal recessive entity characterized by proportionate pre- and post-natal growth retardation, microcephaly, typical facial appearance with beak-like protrusion, and severe mental retardation. A heterogeneous basis for SS was proposed since around 25% of SS patients have hematological anomalies, suggesting a subgroup of SS with chromosome instability and hematological disorders. Chromosome instability induced by mitomycin C (MMC) has been observed in previous reports. The purpose of this study is to report cytogenetic features in five patients with SS. The patients had low birth weight (mean 1,870 g), short stature (SD = 6.36), microcephaly (OFC, SD = 8.1), typical facial appearance, and multiple articular dislocations. None of them had anemia at the time of examination. In all cases their parents were healthy and non-consanguineous. Lymphocytes of SS patients and a control group (n = 9) matched by age and sex were cultured with and without MMC, and harvested at 72 and 96 hr. Chromosomal aberrations (chromatid and chromosomal gaps and breaks, deletions, fragments, and exchanges) were scored in 100 metaphases per culture. A statistical increase of chromosomal aberrations was observed in 96 hr MMC cultures in all patients (40.2% vs. 2.8%). Sister chromatid exchanges were also performed with no differences between groups. Clinical and cytogenetic findings support the idea that SS may correspond to a chromosome instability syndrome.

Atypical parasitic ischiopagus conjoined twins.

Occurrence of asymmetrical or parasitic conjoined twins (CT) is rare, and currently they are classified analogically to the common unions of symmetrical CT. The authors report on an infant with a parasitic third limb attached to the left lateral aspect of the autosite trunk, in whom male gonadal tissue was found histologically. Parasite parts included complete left lower limb, hemipelvis, lumbosacral vertebral column, spinal cord, and one kidney with ureter and adrenal gland. Autosite anomalies comprised a small left diaphragmatic defect, omphalocele, exstrophy of cloaca, and lumbar meningomyelocele. The authors considered this case to be a rare atypical parasitic ischiopagus CT. The differential diagnosis of the type of twining and other entities with caudal duplications is analyzed briefly.