Identification of proximal 1p36 deletions using array-CGH: a possible new syndrome.

Monosomy 1p36 is the most common terminal deletion syndrome with an estimated occurrence of 1:5000 live births. Typically, the deletions span <10 Mb of 1pter-1p36.23 and result in mental retardation, developmental delay, sensorineural hearing loss, seizures, cardiomyopathy and cardiovascular malformations, and distinct facies including large anterior fontanel, deep-set eyes, straight eyebrows, flat nasal bridge, asymmetric ears, and pointed chin. We report five patients with 'atypical' proximal interstitial deletions from 1p36.23-1p36.11 using array-comparative genomic hybridization. Four patients carry large overlapping deletions of approximately 9.38-14.69 Mb in size, and one patient carries a small 2.97 Mb deletion. Interestingly, these patients manifest many clinical characteristics that are different from those seen in 'classical' monosomy 1p36 syndrome. The clinical presentation in our patients included: pre- and post-natal growth deficiency (mostly post-natal), feeding difficulties, seizures, developmental delay, cardiovascular malformations, microcephaly, limb anomalies, and dysmorphic features including frontal and parietal bossing, abnormally shaped and posteriorly rotated ears, hypertelorism, arched eyebrows, and prominent and broad nose. Most children also displayed hirsutism. Based on the analysis of the clinical and molecular data from our patients and those reported in the literature, we suggest that this chromosomal abnormality may constitute yet another deletion syndrome distinct from the classical distal 1p36 deletion syndrome.

Sudden death caused by pulmonary thromboembolism in Proteus syndrome.

We report 3 patients with Proteus syndrome (PS) who died suddenly from pulmonary embolism (PE). The first patient was a male diagnosed with PS at 12 years who had varicose veins, portal vein thrombosis, right iliac vein occlusion and recurrent PE. At age 25 years, he was admitted to the hospital with a severe headache. Despite therapeutic doses of warfarin, investigations for an acute episode of breathlessness showed PE and he was unable to be resuscitated. The second case was a 9-year-old male with PS who collapsed at home and could not be revived. Autopsy revealed that the cause of death was a PE associated with thrombosis of the deep veins (DVT). The third patient was a 17-year-old female undergoing inpatient treatment for sinusitis when she unexpectedly arrested. She could not be revived and a full autopsy revealed a large PE with no identified DVT. We conclude that PE is a serious complication of PS and recommend vigilance concerning the signs and symptoms of thrombosis and PE in individuals with PS, including children. Aggressive evaluation and treatment should be considered urgently in patients with PS and signs or symptoms of DVT.

Discordance of oral-facial-digital syndrome type 1 in monozygotic twin girls.

The oral-facial-digital syndrome type 1 (OFD1) includes limb, facial, intraoral malformations and the gene for the disorder was recently mapped to Xp22.3-p22.2. We report on monozygotic twin girls discordant for OFD1. Monozygosity is supported by placental pathology (monochorionic diamniotic) and molecular studies with probability of dizygosity <1 x 10(-6). The affected twin has oral cavity abnormalities including median cleft lip, cleft palate, lobulated hamartomatous tongue, aberrant hyperplastic oral frenula, alveolar notches, and absent lateral incisors. Facial manifestations include telecanthus, hypoplastic alae nasi, and transient neonatal facial milia. The patient also has short and deviated fingers with partial cutaneous syndactyly. At 10 years, she has not had central nervous system or kidney problems. X-inactivation study revealed similar X-inactivation patterns in the lymphoblasts of both twins. We conclude that skewed X-inactivation is an unlikely cause for the discordance, which is more likely due to a postzygotic mutation in the affected twin.

Identification of a growth arrest specific (gas 5) gene by differential display as a candidate gene for determining susceptibility to hyperthermia-induced exencephaly in mice.

Neural tube defects (NTDs) are among the most common congenital malformations, affecting approximately 1 per 1,000 liveborn infants in the United States [Nakano, 1973; Richards et al., 1972]. Maternal exposure to hyperthermia, either through recreational sources or due to an infectious agent, is thought to account for approximately 10% of observed NTD cases. The specific genes conferring susceptibility or resistance to hyperthermia-induced NTDs have not been identified. This study used differential display-polymerase chain reaction (DD-PCR) to characterize alterations in gene expression in the anterior embryonic neural tube of two highly inbred murine strains (SWV/Fnn, LM/Bc/Fnn) known to differ in their genetically determined susceptibility to heat-induced NTDs. Herein, we report the neural tube-specific differential expression of the growth arrest specific (gas 5) gene in the highly susceptible SWV/Fnn strain during neural tube closure (NTC). Although the expression of gas 5 did not appear to be altered by the teratogenic heat treatment, its spatial and strain-specific pattern of expression makes it an excellent candidate gene responsible for the observed genetic differences in NTD susceptibility between these two inbred murine strains.