Chromosome 19p13.13 Deletion Syndrome

A number sign (#) is used with this entry because of evidence that this disorder is a contiguous gene deletion syndrome (Chr19:12.79-13.10 Mb, NCBI36).

Clinical Features

Deletion Patients

Dolan et al. (2010) identified 4 patients with a deletion within 19p13.13. Patients were first seen at ages ranging from 0.5 years to 2 years. At time of first exam all had macrocephaly with an occipitofrontal head circumference (OFC) greater than the 95th percentile, with 3 of the 4 at the 98th percentile or higher. Facial features included frontal bossing and downslanting palpebral fissures in 2. All had strabismus. Two had nystagmus and 3 had optic nerve hypoplasia or atrophy. Three of the 4 had gastrointestinal complaints, including diarrhea, poor feeding, abdominal pain, and vomiting. One had a normal brain MRI; 1 had a Chiari I malformation with syrinx; 1 had mild atrophy of the frontal lobes; and 1 had absent rostral corpus callosum with cystic lesion. Two of 4 had seizures; 3 of 4 had hypotonia; all had moderate to severe mental retardation with moderate to significant speech delay. Ages at most recent exam ranged from 3 years to 14.5 years. All still had macrocephaly at that time, but only the youngest, at 3 years of age, still had persistent linear overgrowth.

Dolan et al. (2010) compared their 4 deletion patients with 4 others reported by Lysy et al. (2009), Auvin et al. (2009), Jensen et al. (2009), and Engels et al. (2007). In these 4 reports, the deletion ranged from 0.6 Mb to 2.9 Mb. Two of the 4 had microcephaly and 1 had macrocephaly. Two were reported to have had strabismus. One child had constipation. Two of the 4 had normal brain imaging studies; 1 had moderate ventriculomegaly; and 1 had mild hypoplasia of the corpus callosum and cerebellar vermis. Seizures were reported in 1 of the 4. Three of the 4 had hypotonia. All had moderate mental retardation. At the most recent examination, 1 patient had microcephaly (Engels et al., 2007), 1 had macrocephaly, and 1 had normal head circumference.

Dolan et al. (2010) concluded that the clinical findings in patients with a deletion in 19p13.13 are notable for a constellation of 3 recurring abnormalities. The first is overgrowth. Patients 1 to 4 and those of Auvin et al. (2009) were macrocephalic with frontal bossing; height and weight were concordant with the craniofacial size because these patients were large for age. Dolan et al. (2010) noted that patients 2 and 3 in their study and the patient of Auvin et al. (2009) had undergone NSD1 (606681) testing to rule out Sotos syndrome (117550), which was negative. The second clinical manifestation includes ophthalmologic abnormalities such as strabismus and optic nerve atrophy or hypoplasia. Dolan et al. (2010) suggested that all patients identified with 19p13.13 microdeletions should have formal brain MRI to fully evaluate the optic nerves. The third recurring clinical manifestation is gastrointestinal symptomatology, particularly abdominal pain and vomiting.

Duplication Patients

Dolan et al. (2010) described 1 patient with a microduplication in 19p13.13. This patient was born at 36 weeks' gestation and presented at 2 months of age with feeding problems, constipation, frequent vomiting, and marked irritability. At 14 months his weight, length, and OFC were all below the 5th percentile. Other clinical findings included sloping forehead, narrow alae nasi, inverted nipples, and an unusual fat distribution over the buttocks. He had a seizure disorder, with 4 to 5 seizures daily originating in a left frontotemporal focus. Ophthalmologic examination showed horizontal nystagmus. By 3 years of age his head circumference remained below the 5th percentile, and developmental delay was noted. Neuropsychologic testing at 4.5 years showed an age equivalent of 21 to 29 months with hyperactivity, sleep disruption, and obsessional and self-injurious behaviors. The patient's father had nystagmus and reported learning difficulties. Dolan et al. (2010) remarked on the striking difference in head circumference between patients with a 19p13.13 deletion, who were macrocephalic, and their patient with a duplication, who was microcephalic; this was also true for the duplication reported by Stratton et al. (1995). Some clinical findings (ocular findings, gastrointestinal symptoms, seizures) were present among the 19p cases regardless of deletion or duplication status.

Cytogenetics

Deletion

Among the 4 deletion patients identified by Dolan et al. (2010), the smallest region of overlap (SRO) encompassed approximately 311 kb (maximum 340 kb) within 19p13.13 (12,793,474 to 13,104,643, NCBI36). This SRO encompasses 16 genes involved in diverse processes including transcription, DNA repair, and hematopoiesis; candidate genes include MAST1 (612256), NFIX (164005), and CALR (109091).

The patients of Auvin et al. (2009) (740 kb) and Lysy et al. (2009) (3 Mb) had deletions that encompass the SRO delineated by Dolan et al. (2010). Dolan et al. (2010) noted that the patients of their study and the patient reported by Auvin et al. (2009) showed consistent phenotypic correlations, while the patient of Lysy et al. (2009) diverged significantly in phenotype; the deletion in this latter patient extended almost 3 Mb telomeric to those in the report of Dolan et al. (2010), and was almost 3 times larger than the largest deletion and 10 times larger than the critical region.

Duplication

The duplication in the patient described by Dolan et al. (2010) was of approximately 1.9 Mb within chromosome 19p13.2-p13.12 (minimum breakpoints 12,601,112 to 14,488,238, NCBI36).

Inheritance

Other reported cases with 19p13.13 deletions all occurred as de novo events (Dolan et al., 2010).