Factor VII deficiency and developmental abnormalities in a patient with partial monosomy of 13q and trisomy of 16p: case report and review of the literature
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Unbalanced chromosomal translocations may present with a variety of clinical and laboratory findings and provide insight into the functions of genes on the involved chromosomal segments.
A 9 year-old boy presented to our clinic with Factor VII deficiency, microcephaly, a seizure disorder, multiple midline abnormalities (agenesis of the corpus callosum, imperforate anus, bilateral optic nerve hypoplasia), developmental delay, hypopigmented macules, short 5th fingers, and sleep apnea due to enlarged tonsils. Cytogenetic and fluorescence in situ hybridization analyses revealed an unbalanced translocation involving the segment distal to 16p13 replacing the segment distal to 13q33 [46, XY, der(13)t(13;16)(q33;p13.3)]. Specific BAC-probes were used to confirm the extent of the 13q deletion.
This unique unbalanced chromosomal translocation may provide insights into genes important in midline development and underscores the previously-reported phenotype of Factor VII deficiency in 13q deletions.
KeywordsMicrocephaly Imperforate Anus Optic Nerve Hypoplasia Unbalanced Translocation Enlarge Tonsil
List of abbreviations
bacterial artificial chromosome
fluorescent in situ hybridization
intrauterine growth retardation
activated prothrombin time
partial thromboplastin time
single palmar crease
The identification of chromosomal breakpoints in association with variations in human phenotypes often leads to the discovery of novel genes or the characterization of the clinical importance of known genes. Patients who present with a known Mendelian disorder, but who also exhibit developmental delay or other, seemingly unrelated conditions, may harbor a chromosomal abnormality. We present the case of a child who presented with asymptomatic Factor VII deficiency at age 9 who was found to have an unbalanced 13;16 translocation associated with several other developmental abnormalities.
A 9 year-old male presented with Factor VII deficiency and multiple congenital abnormalities. Prior to her pregnancy with this child, his mother (currently 50 years old) had nine in vitro fertilization attempts that ended in miscarriage. One of these miscarriages was documented as trisomy 21 at 18 weeks gestation. This patient was one twin of a fraternal twin pregnancy conceived on the 10th round of in vitro fertilization. His sister was born healthy and her cytogenetic evaluation has not been performed. This twin pregnancy was complicated by premature labor requiring 13 weeks of maternal bed rest prior to delivery via C-section at 36 weeks gestation. The patient's birth weight was 3 lbs, 14.5 oz and his Apgar scores were 9 and 9 at 1 and 5 minutes, respectively.
At birth, the patient was noted to have an imperforate anus that was repaired with a colostomy at 15 days of life. An ultrasound of the brain showed agenesis of the corpus callosum, which was later confirmed on MRI. Both an echocardiogram and a renal ultrasound were normal.
For the first year of life, the patient failed to thrive. He underwent two successful operations for his imperforate anus at ages 9 and 11 months, after which he began to gain weight appropriately. Development was delayed; he sat at 9 months, pulled up at 11 months, walked at 22 months, and spoke single words at 15 months. His pediatricians noted "borderline microcephaly" and low muscle tone. He has been receiving speech therapy and physical therapy since age 1. At age 6 years, he developed grand mal seizures which have been successfully managed with medication. He had repeated upper respiratory infections and was noted to have enlarged tonsils that may have contributed to sleep apnea. As part of his pre-operative work-up for tonsillectomy, he was discovered to have elevated prothrombin and partial thromboplastin times of 21.3 seconds and 36.8 seconds, respectively. Factor VII deficiency (17% of normal) was subsequently diagnosed; Factor X levels were 54% of normal. The patient, however, has never had a severe bleeding disorder. It was the combination of Factor VII deficiency and multiple congenital malformations that prompted the genetics work-up, including karyotype. He had abnormal tooth eruption and required dental surgery and frenulectomy. Neither surgery required coagulation assistance.
The patient's parents are healthy, as is his fraternal twin sister and a younger brother, age 7. Review of systems was notable for chronic constipation requiring daily enemas. He is currently on Depakote 325 mg bid and has no known drug allergies.
On ophthalmologic examination, the patients best-corrected visual acuity is 20/50 OU with a +6.25 + 1.25 × 95 OD and +6.25 + 1.75 × 95 OS prescription. He has no measurable stereopsis. Color vision, ocular ductions, ocular alignment, pupillary examination, confrontational visual fields, and slit lamp examination were all normal. Dilated fundoscopic examination showed bilateral, mild optic nerve hypoplasia.
Endocrine studies, including a thyroid panel, a random cortisol, prolactin, and follicle-stimulating were within normal limits. The patient's bone age is at the upper limits of normal by Pyles and Greulich critreria.
Summary of cases with relatively isolated monosomy 13q33-qter.
46, XY, del(13)(q33.3)
IUGR; microcephaly; SS; hypotonia; large, low-set ears; hypertelorism; small chin; high/ broad forehead; SPC; mild psychomotor delay
46, XY, del(13)(q33.2)
IUGR; microcephaly; SS; psychomotor delay; reduced factors VII and X; MR; SS; high nasal bridge; large ears; stiff thumbs; language delay
46, XY, del(13)(q33.2)
IUGR; microcephaly; SS; speech delay; tapering fingers; transverse palmar crease; high nasal bridge; mild anal prolapse; reduced factors VII and X
46, XY, del (13)(q33)
Growth and psychomotor retardation; microcephaly; brachycephaly; facial asymmetry; ear anomalies; hypospadias
46, XX, del(13)(q33)
Psychomotor retardation; hypertelorism; upslanting PF; ear anomalies
46, XY, del(13)(q33.2)
Lumbosacral myelomeningocele; bilateral cryptorchidism; ambiguous genitalia; microcephaly; telecanthus; short PF; large ears; broad nasal bridge; short philtrum; enamel defects; short neck;
46, XX, del(13)(q33)
IUGR; growth and psychomotor retardation; microcephaly; hypertelorism; high nasal bridge; ear anomalies
46, XY, del(13)(q32.3q33.2)
Hirschspring disease; psychomotor retardation; ear anomalies
Summary of cases with relatively isolated trisomy 16p13.
46, XY, der(1), ins(1;16)(q24;p13.1p13.3)pat
MR, SS, microcephaly, mildly dysmorphic faces, proximally inserted thumbs, flexion contractures of PIP joints, deep-set nails, genu valga
46, XY, dup(16)(p13.1→pter)
autism, Tourette's syndrome, SS, prominent chin, elongated face, hi-arched palate, small penis/scrotum, poor fine and gross motor movements; slow basal activity on EEG
46, XY, add(16)(p16.3)
microcephaly; short neck, sparse har, hypertelorism, narrow PF, low set ears; bilateral CL/P; club feet/hands; tracheomalacia; VSD, ASD; hypoplastic aorta
Factor VII is a vitamin-K dependent clotting factor in the extrinsic pathway that – when deficient – is inherited as an autosomal recessive trait and produces an elevated partial thromboplastin time (PTT) in the face of a normal activated prothrombin time (PT); hemarthrosis; intracranial hemorrhage; hematuria; spontaneous epistaxis and bruising; and genitourinary and gastrointestinal bleeding. Although levels of activity correlate imprecisely with symptoms, it is likely that levels below 2% of normal are required before major symptoms develop. The Factor VII gene maps to 13q34, is alternatively spliced, and has multiple poly-adenylation signals. Pfeiffer et al. describe two cases of sub-clinical factor VII deficiency associated with a 46, XY, t(13;Y)(q11;q34) translocation and probable deletion of a terminal segment of 13q that manifested as elevated PTT. Hewson and Carter described severe Factor VII deficiency in a case of 13q deletion syndrome; while Fukushima et al. found approximately 50% factor V activity in two of three patients with terminal 13q deletions and normal levels in a patient with trisomy 13. Our patient would be predicted to be monosomic for 13q34. The fact that he exhibits less than 50% activity may be related to a polymorphism on his remaining allele causing slightly reduced activity or reduced levels of protein expression. Factor VII activity was not assayed in his parents.
Bilateral optic nerve hypoplasia is sometimes accompanied by midline anomalies of the central nervous system, such as absent corpus callosum, absent septum pellicidum, and pituitary insufficiency. None of the three genes known to produce this phenotype in animal models – namely netrin (17p13-p12), Hesx1 (3p21), and DCC (18q21.3) – map to either chromosome 13 or 16, suggesting an uncharacterized regulatory gene for midline CNS development in the abnormal regions. Of note, netrin-2 -like gene is located on 16p13. Several other zinc-finger containing proteins of unknown function also map to this region. A three-generation family with dominant congenital cataract and microphthalmia co-segregates with a t(2;16)(p22.3;p13.3) translocation in four balanced carriers and three with monosomy of 16p13.3, suggesting that an important eye developmental gene resides at or near this breakpoint.
Written consent was obtained from the patient's mother for the publication of this study.
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