Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging.

Genome sequencing has established clinical utility for rare disease diagnosis. While increasing numbers of individuals have undergone elective genome sequencing, a comprehensive study surveying genome-wide disease-associated genes in adults with deep phenotyping has not been reported. Here we report the results of a 3-y precision medicine study with a goal to integrate whole-genome sequencing with deep phenotyping. A cohort of 1,190 adult participants (402 female [33.8%]; mean age, 54 y [range 20 to 89+]; 70.6% European) had whole-genome sequencing, and were deeply phenotyped using metabolomics, advanced imaging, and clinical laboratory tests in addition to family/medical history. Of 1,190 adults, 206 (17.3%) had at least 1 genetic variant with pathogenic (P) or likely pathogenic (LP) assessment that suggests a predisposition of genetic risk. A multidisciplinary clinical team reviewed all reportable findings for the assessment of genotype and phenotype associations, and 137 (11.5%) had genotype and phenotype associations. A high percentage of genotype and phenotype associations (>75%) was observed for dyslipidemia (n = 24), cardiomyopathy, arrhythmia, and other cardiac diseases (n = 42), and diabetes and endocrine diseases (n = 17). A lack of genotype and phenotype associations, a potential burden for patient care, was observed in 69 (5.8%) individuals with P/LP variants. Genomics and metabolomics associations identified 61 (5.1%) heterozygotes with phenotype manifestations affecting serum metabolite levels in amino acid, lipid and cofactor, and vitamin pathways. Our descriptive analysis provides results on the integration of whole-genome sequencing and deep phenotyping for clinical assessments in adults.

Tocolysis in women with advanced preterm labor: a secondary analysis of a randomized clinical trial.

OBJECTIVE: To compare the efficacy of tocolytic treatment with indomethacin (I), magnesium sulfate (M) and nifedipine (N) for acute tocolysis in women with advanced cervical dilation (4-6 cm). METHODS: A single center, randomized trial was carried out involving patients in preterm labor (cervix 1-6 cm). Secondary analysis of women with advanced cervical dilation (cervix 4-6 cm) at 24-32 weeks' gestation who received intravenous M, oral N or I suppositories comprised this study population. RESULTS: Over 38 months, 92 women with advanced cervical dilation were randomized to one tocoloytic type. Days gained in utero (11.7) and percent remaining undelivered at 48 h (60.8%), 72 h (53.1%) and >7 days (38.3%) were similar regardless of tocolytic employed (p = 0.923, 0.968, 0.791, 0.802, respectively). Likewise, gestational age at delivery (30.7 ± 3.2) was similar between groups (p = 0.771). Finally, neonatal statistics were not different when stratified by tocolytic treatment. CONCLUSION: There were no statistical differences between tocolytics in treating women with advanced cervical dilation. All offered significant days gained in utero after therapy, a high percentage remaining undelivered after 48 or 72 h and after 7 days. It would appear from data that there may be advantages to tocolytic treatment even in women with advanced cervical dilation.

Effect and Tolerability of Agalsidase Alfa in Patients with Fabry Disease Who Were Treatment Naïve or Formerly Treated with Agalsidase Beta or Agalsidase Alfa.

OBJECTIVES: In a multicenter, open-label, treatment protocol (HGT-REP-059; NCT01031173), clinical effects and tolerability of agalsidase alfa (agalα; 0.2 mg/kg every other week) were evaluated in patients with Fabry disease who were treatment naïve or switched from agalsidase beta (switch). Over 24 months, data were collected on the safety profile; renal and cardiac parameters were assessed using estimated glomerular filtration rate (eGFR), left ventricular mass index (LVMI), and midwall fractional shortening (MFS). RESULTS: Enrolled patients included 71 switch (median [range] age, 46.6 [5-84] years; male to female [M:F], 40:31) and 29 treatment naïve (38.7 [12-74] years; M:F, 14:15). Adverse events (AEs) were consistent with the known safety profile of agalα. Two switch patients had hospitalization due to possibly/probably drug-related serious AEs (one with transient ischemic attack, one with infusion-related AEs). One switch and two treatment-naïve patients discontinued treatment because of AEs. Three patients (one each switch, treatment naïve, and previous agalα) died; no deaths were considered drug-related. There was no significant change from baseline in LVMI or MFS in either group. Similarly, eGFR remained stable; mean ± standard error annualized change in eGFR (mL/min/1.73 m(2)) was -2.40 ± 1.04 in switch and -1.68 ± 2.21 in treatment-naïve patients. CONCLUSIONS: This is the largest cohort of patients with Fabry disease who were started on or switched to agalα in an FDA-accepted protocol during a worldwide supply shortage of agalsidase beta. Because this protocol was primarily designed to provide access to agalα, there were limitations, including not having stringent selection criteria and the lack of a placebo group.

Agalsidase alfa in pediatric patients with Fabry disease: a 6.5-year open-label follow-up study.

BACKGROUND: Signs and symptoms of the X-linked disorder, Fabry disease (FD), can occur early during childhood with heterogeneous clinical manifestations including potential cardiac and renal dysfunction. Several studies support the efficacy of the enzyme replacement therapy (ERT) agalsidase alfa, in adults with FD, though published data on the long-term safety and efficacy of agalsidase alfa in children are limited. As early treatment with ERT has the potential to reduce complications arising from disease progression, children in particular could benefit. The objective of this study was to evaluate the safety and efficacy of long-term agalsidase alfa ERT in children with FD. METHODS: TKT029 was a 6.5-year open-label, multicenter, extension study of children who completed TKT023 (26-week, open-label, every-other-week, intravenous 0.2 mg/kg agalsidase alfa). TKT029 was divided into two phases (before and after an agalsidase alfa manufacturing process change); only patients who participated in both phases were included in the analysis. Primary endpoints included safety, tolerability, and heart rate variability (HRV). Additional efficacy parameters included left ventricular mass index (LVMI), estimated glomerular filtration rate (eGFR), and plasma/urine globotriaosylceramide (Gb3). RESULTS: Eleven patients participated (phase 1 baseline median [range] age: 10.8 [8.6-17.3] years; 10 [90.9%] males). During TKT029 (6.5 years), all patients experienced ≥1 treatment-emergent adverse event (AE); eight patients had ≥1 possibly/probably drug-related AE. Six patients experienced infusion-related AEs, but none discontinued due to AEs. Eight serious AEs arose (two patients); none were deemed drug-related. No deaths occurred. Three patients developed anti-agalsidase alfa antibodies, with IgG antibodies in one patient that were agalsidase alfa neutralizing, but without apparent clinical impact. Renal (eGFR) endpoints remained generally in normal range. Cardiac endpoints remained stable within normal range for LVMI and a trend towards improved HRV, although some patients experienced a reduction in heart rate. Plasma and urinary Gb3 reductions were maintained. CONCLUSIONS: TKT029 represents the longest assessment of ERT in children with FD in a clinical trial setting. Overall, agalsidase alfa was well tolerated and demonstrated a stabilizing clinical effect. Agalsidase alfa may be a useful clinical therapeutic option for long-term treatment initiated during childhood in patients with FD. TRIAL REGISTRATION: http://ClinicalTrials.gov identifier NCT00084084 .

The use of 17-hydroxy progesterone in women with arrested preterm labor: a randomized clinical trial.

BACKGROUND: The use of 17-alpha-hydroxyprogesterone caproate (17 P) has been shown to reduce preterm delivery in women who have had a prior preterm birth. The role of 17 P in women with arrested preterm labor is less certain. AIMS: To compare the preterm birth rate and neonatal outcome in women with arrested preterm labor randomized to receive 17 P or placebo. MATERIALS AND METHODS: Women with arrested preterm labor were randomized to weekly injections of either 17 P (250 mg) or placebo. Maternal and neonatal outcome were evaluated. RESULTS: Forty-five singleton pregnancies were randomized after successful tocolysis; 22 received 17 P while 23 got placebo. Gestational age at delivery (p = 0.067) and the interval from treatment to delivery (p = 0.233) were not affected by 17 P. Significantly less women in the 17 P group delivered at <34 weeks (14 versus 21, p = 0.035). There was also a significant reduction in the risk of neonatal sepsis (p = 0.047) and gr III/IV intraventricular hemorrhage (IVH) (p = 0.022) in the 17 P group. CONCLUSION: In this study, 17 P did not delay the interval to delivery after successful preterm labor, but births <34 weeks as well as neonatal sepsis and IVH were reduced by 17 P treatment.

A comparison of three tocolytics for preterm labor: a randomized clinical trial.

OBJECTIVE: To compare the efficacy and maternal side effects of nifedipine (N), magnesium sulfate (M), and indomethacin (I) for acute tocolysis. METHODS: In this single center randomized trial, women in preterm labor 24-32 weeks' gestation received intravenous M, oral N, or I suppositories. The primary outcomes of interest were arrest of preterm labor (>48 h, ≥7 days), gestational age at delivery, and maternal side effects. RESULTS: Over a 38-month period, 301 women were allocated to receive M (90), N (114), or I (90). Gestational age at delivery (p = 0.551) or arrest of labor >48 h, >7 days were similar between the three groups (p = 0.199, 0.654). Hypotension and tachycardia were more common in N patients compared to women receiving M or I (p = 0.003, 0.009). Patients receiving I had more fetal ductal constriction or oligohydramnios compared to M or N (p = 0.001, 0.020) but, I women were tested more often. There was one case of pulmonary edema in the M group and one with plural effusion in the N group. CONCLUSION: There were no differences in efficacy or in major maternal safety issues between the three tocolytic agents. Since there is no FDA approved tocolytic to treat preterm labor, clinicians should use the tocolytic that has afforded them the best results with the least maternal/neonatal side effects.

Changes in plasma and urine globotriaosylceramide levels do not predict Fabry disease progression over 1 year of agalsidase alfa.

PURPOSE: Globotriaosylceramide concentrations were assessed as potential predictors of change from baseline after 12 months by estimated glomerular filtration rate and left-ventricular mass index using pooled data from three randomized, placebo-controlled agalsidase alfa trials and open-label extensions of patients with Fabry disease. METHODS: Males (aged 18 years or older) with Fabry disease received agalsidase alfa (0.2 mg/kg every other week for 12 months). A backward-elimination approach evaluated potential predictors (baseline estimated glomerular filtration rate and left-ventricular mass index; age at first dose; baseline and change from baseline at 12 months of globotriaosylceramide (urine, plasma); urine protein excretion; and systolic and diastolic blood pressure). Subgroups included patients randomized to placebo or agalsidase alfa (double-blind phase), then to agalsidase alfa (open-label extensions; placebo→agalsidase alfa or agalsidase alfa→agalsidase alfa, respectively) and stage 2/3 chronic kidney disease patients. RESULTS: Baseline estimated glomerular filtration rate, age at first dose, baseline urine globotriaosylceramide excretion, and baseline and change from baseline urine protein excretion significantly predicted change from baseline estimated glomerular filtration rate in the analysis population (N = 73; all P<0.05), although not in all subgroups. Change from baseline urine and plasma globotriaosylceramide (baseline and change from baseline) concentrations did not predict change from baseline estimated glomerular filtration rate. No predictors of left-ventricular mass index were significant. CONCLUSION: Changes in globotriaosylceramide concentrations do not appear to be useful biomarkers for prediction of Fabry disease-related changes in estimated glomerular filtration rate or left-ventricular mass index.

Postpartum thrombotic microangiopathic syndrome.

OBJECTIVE: Characterization of syndromes for patients with life-threatening, progressively worsening hemolysis-elevated-liver-enzymes-and-platelet (HELLP) syndrome-like diseases and with thrombotic microangiopathies. RETROSPECTIVE STUDY DESIGN: Patients who underwent postpartum plasma-exchange (PPEX) for preeclampsia-related, and microangiopathy/coagulopathy illnesses unresponsive to medical therapy between 1994 and 2008 in our center and elsewhere. RESULTS: Nine patients were treated with PPEX in our center with 78% maternal survival. Treatment with PPEX increased platelet levels (p=0.048), decreased serum lactic dehydrogenase (p=0.0012) and aspartate aminotransferase (p=0.0001). CONCLUSION: Nineteen patients from publications combined with our patients suggest five categories of postpartum thrombotic microangiopathy syndrome that exhibit HELLP syndrome criteria and respond to PPEX.

Effect of antenatal tocolysis on neonatal outcomes.

OBJECTIVE: Detail adverse neonatal effects in pregnancies treated with indomethacin (I), magnesium sulfate (M) or nifedipine (N). METHODS: Women in acute preterm labor with cervical dilatation 1-6 cm were randomized to receive one of three first-line tocolytic drugs. RESULTS: There were 317 neonates (I = 103, M = 95, N = 119) whose mothers were treated with tocolytic therapy. There was no difference in gestational age at randomization (average 28.6 weeks' gestation) or at delivery (31.6 weeks' gestation, p = 0.551), birth weight (p = 0.871) or ventilator days (p = 0.089) between the three groups. Neonatal morbidity was not different between the three groups; respiratory distress syndrome (p = 0.086), patent ductus arteriosus (p = 0.592), sepsis (p = 0.590), necrotizing enterocolitis (p = 0.770), intraventricular hemorrhage (p = 0.669) and periventricular leukomalacia (p = 0.124). CONCLUSIONS: There were no statistically significant differences between the three tocolytics as far as composite neonatal morbidity or mortality was concerned.

Prevention of ulceration, amputation, and reduction of hospitalization: outcomes of a prospective multicenter trial of tibial neurolysis in patients with diabetic neuropathy.

This is the first multicenter prospective study of outcomes of tibial neurolysis in diabetics with neuropathy and chronic compression of the tibial nerve in the tarsal tunnels. A total of 38 surgeons enrolled 628 patients using the same technique for diagnosis of compression, neurolysis of four medial ankle tunnels, and objective outcomes: ulceration, amputation, and hospitalization for foot infection. Contralateral limb tibial neurolysis occurred in 211 patients for a total of 839 operated limbs. Kaplan-Meier proportional hazards were used for analysis. New ulcerations occurred in 2 (0.2%) of 782 patients with no previous ulceration history, recurrent ulcerations in 2 (3.8%) of 57 patients with a previous ulcer history, and amputations in 1 (0.2%) of 839 at risk limbs. Admission to the hospital for foot infections was 0.6%. In patients with diabetic neuropathy and chronic tibial nerve compression, neurolysis can result in prevention of ulceration and amputation, and decrease in hospitalization for foot infection.

A positive Tinel sign as predictor of pain relief or sensory recovery after decompression of chronic tibial nerve compression in patients with diabetic neuropathy.

Predictive ability of a positive Tinel sign over the tibial nerve in the tarsal was evaluated as a prognostic sign in determining sensory outcomes after distal tibial neurolysis in diabetics with chronic nerve compression at this location. Outcomes were evaluated with a visual analog score (VAS) for pain and measurements of the cutaneous pressure threshold/two-point discrimination. A multicenter prospective study enrolled 628 patients who had a positive Tinel sign. Of these patients, 465 (74%) had VAS >5. Each patient had a release of the tarsal tunnel and a neurolysis of the medial and lateral plantar and calcaneal tunnels. Subsequent, contralateral, identical surgery was done in 211 of the patients (152 of which had a VAS >5). Mean VAS score decreased from 8.5 to 2.0 (p <0.001) at 6 months, and remained at this level for 3.5 years. Sensibility improved from a loss of protective sensation to recovery of some two-point discrimination during this same time period. It is concluded that a positive Tinel sign over the tibial nerve at the tarsal tunnel in a diabetic patient with chronic nerve compression at this location predicts significant relief of pain and improvement in plantar sensibility.

Women with preterm premature rupture of the membranes do not benefit from weekly progesterone.

OBJECTIVE: We sought to determine if 17-alpha-hydroxyprogesterone (17P) extends gestation vs placebo in women with preterm premature rupture of the membranes (PPROM). STUDY DESIGN: Women with vertex presentations with PPROM, 20-30 weeks' gestation, were randomized to receive weekly 17P or placebo in an attempt to prolong the pregnancy. A total of 69 patients (17P, n = 33; placebo, n = 36) were randomized into this study. RESULTS: Initial cervical dilatation, gestational age at enrollment, and interval to delivery were not different between the 2 groups (P = .914, .424, and .146, respectively). Time of randomization to delivery (P = .250), mode of delivery (relative risk, 1.16; 95% confidence interval, 0.66-2.06), and the neonatal outcome statistics of morbidity (P = .820) and mortality (relative risk, 1.28; 95% confidence interval, 0.59-2.75) were similar between the 2 groups. CONCLUSION: In patients with PPROM, 17P did not extend gestation vs placebo and cannot be recommended for treatment in such women.

Prediction of placenta accreta by ultrasonography and color Doppler imaging.

OBJECTIVE: To determine the accuracy of ultrasound and color flow Doppler to diagnose placenta accreta. METHODS: Respectively, ultrasound images consistent with signs of placenta accreta (concomitant previa, numerous vascular lacunae, absent lower uterine segment between bladder-placenta, turbulent or complicated blood flow at the uteroplacental interface) were correlated with findings at the time of surgery and pathologic examination. RESULTS: Over 64 months, 12 cases with suspected placenta accreta by ultrasound were studied. The median gestational age at first diagnosis was 25 weeks and 92% had a previa while all had at least one previous cesarean delivery. At surgery, 83% (10/12) had an adherent placenta requiring hysterectomy (eight accreta, one increta, and one percreta). There were two false positives (one complete previa, one low-lying placenta with vasa previa). Nine of 12 women (75%) required blood transfusions due to a mean hematocrit nadir of 22.7 ± 4.6%. The mean number of packed red blood cell units transfused was 4.9 ± 4.7 units (range 2-17 units). CONCLUSION: Sonography coupled with color-flow Doppler appears helpful in allowing antenatal diagnosis of accreta.

Long-term, open-labeled extension study of idursulfase in the treatment of Hunter syndrome.

PURPOSE: This study evaluated the safety and effectiveness of long-term enzyme replacement therapy with idursulfase (recombinant human iduronate-2-sulfatase) in patients with Hunter syndrome. METHODS: All 94 patients who completed a 53-week double-blinded study of idursulfase enrolled in this open-labeled extension study and received intravenous idursulfase at a dose of 0.5 mg/kg weekly for 2 years, and clinical outcomes and safety were assessed. RESULTS: No change in percent predicted forced vital capacity was seen, but absolute forced vital capacity demonstrated sustained improvement and was increased 25.1% at the end of the study. Statistically significant increases in 6-minute walking test distance were observed at most time points. Mean liver and spleen volumes remained reduced throughout the 2-year extension study. Mean joint range of motion improved for the shoulder and remained stable in other joints. Both the parent- and child-assessed Child Health Assessment Questionnaire Disability Index Score demonstrated significant improvement. Infusion-related adverse events occurred in 53% of patients and peaked at Month 3 of treatment and declined thereafter. Neutralizing IgG antibodies were detected in 23% of patients and seemed to attenuate the improvement in pulmonary function. CONCLUSIONS: Weekly infusions of idursulfase result in sustained clinical improvement during 3 years of treatment.

Four-year prospective clinical trial of agalsidase alfa in children with Fabry disease.

OBJECTIVES: To investigate a 4-year prospective clinical trial of agalsidase alfa in children with Fabry disease, an X-linked metabolic disorder caused by a deficiency of the lysosomal enzyme alpha-galactosidase A. STUDY DESIGN: Seventeen (16 boys, 1 girl; age range, 7.3 to 18.4 years) of the 24 children who completed a 6-month, open-label agalsidase alfa study enrolled in a 3.5-year extension study that investigated the safety and potential efficacy of long-term treatment. All 17 patients completed the initial 6-month study, and 10 patients (9 boys) completed the extension study. RESULTS: Agalsidase alfa was well tolerated. In treated boys, there were sustained, statistically-significant improvements in the clinical features of Fabry disease, including reduced plasma globotriaosylceramide levels, reduced pain severity assessed by the Brief Pain Index, and improved heart rate variability. Mean urine globotriaosylceramide levels were reduced to normal range (P < .05 compared with baseline during 1.5 to 4 years). Kidney function and left ventricular mass indexed to height remained stable throughout. CONCLUSIONS: This clinical trial demonstrates that treatment with agalsidase alfa was well tolerated and associated with improvement of Fabry disease-related features.

Whorl patterns on the lower lip are associated with nonsyndromic cleft lip with or without cleft palate.

Nonsyndromic cleft lip with or without cleft palate (CL/P) is a common birth defect due to both genetic and environmental factors. Whorl lip print patterns are circular grooves on the central upper lip and/or the left and right lower lip. To determine if whorls are more common in families with CL/P than in controls, the Pittsburgh Orofacial Cleft Study collected lip prints from over 450 subjects, that is, individuals with CL/P, their relatives, and unrelated controls-from the U.S., Argentina, and Hungary. Using a narrow definition of lower-lip whorl, the frequency of whorls in the U.S. sample was significantly elevated in cleft individuals and their family members, compared to unrelated controls (14.8% and 13.2% vs. 2.3%; P = 0.003 and 0.001, respectively). Whorls were more frequent in CL/P families from Argentina than in CL/P families from the U.S. or Hungary. If these results are confirmed, whorl lip print patterns could be part of an expanded phenotypic spectrum of nonsyndromic CL/P. As such, they may eventually be useful in a clinical setting, allowing recurrence risk calculations to incorporate individual phenotypic information in addition to family history data.

Progesterone does not prevent preterm births in women with twins.

OBJECTIVE: To compare preterm birth rate and neonatal outcome in twin gestations randomized to either 17 alpha-hydroxyprogesterone caproate (17P) or placebo. MATERIALS AND METHODS: Women with twin gestations between 20-30 weeks were randomized to receive weekly injections of either 250 mg 17P injection (Group I), or placebo (Group II). Maternal and neonatal outcome data was recorded. RESULTS: Thirty twin intrauterine pregnancies were randomized; 16 received 17P and 14 received placebo. Demographic data as well as past history and gestational age at randomization were equivalent between groups (P = 0.286-0.847). All patients in both groups were Medicaid recipients. The incidence of preterm labor (P = 0.980), and premature rupture of the membranes (P = 0.525) were the same between groups. Gestational age at delivery was also similar between 17P (33.9 weeks) versus placebo (33.1 weeks, P = 0.190) as was the incidence of preterm birth <35 weeks (44% vs 79%, P = 0.117). Infant weight (P = 0.641), Apgar score at 5 minutes (P = 0.338) as well as neonatal morbidity such as respiratory distress syndrome (P = 0.838), patent ductus arteriosus (P = 0.704), intraventricular hemorrhage (P = 0.851) and necrotizing enterocolitis (P = 0.946) showed no difference. Days spent in the NICU among 17P (18.4) versus placebo (17.3, P = 0.155), neonatal death (P = 0.359) and those infants discharged with neurologic handicap (P = 0.594) were not different between groups. CONCLUSION: Amongst this group of twin gestations weekly 17HP injections did not reduce the incidence of preterm birth or the complications associated with prematurity.

Diagnostic criteria and tumor screening for individuals with isolated hemihyperplasia.

Isolated hemihyperplasia, formerly termed isolated hemihypertrophy, is a congenital overgrowth disorder associated with an increased risk for embryonal tumors, mainly Wilms tumor and hepatoblastoma. This practice guideline will set forth the diagnostic criteria and tumor screening recommendations for children with isolated hemihyperplasia, based on the best information available. There is clinical overlap between isolated hemihyperplasia with Beckwith-Wiedemann syndrome. The majority of Beckwith-Wiedemann syndrome patients have a molecular abnormality involving the imprinted cluster of genes at 11p15.5. In contrast, the preponderance of isolated hemihyperplasia patients studied have no identified etiology. Tumors have developed in isolated hemihyperplasia patients with and without molecular abnormalities. For this reason, molecular diagnostics are not helpful in identifying the subset of isolated hemihyperplasia patients with tumor risk and all isolated hemihyperplasia patients should undergo tumor screening.

AXIS inhibition protein 2, orofacial clefts and a family history of cancer.

BACKGROUND: Cancer and congenital malformations occasionally may have a common etiology. The authors investigated whether families with one or more members affected by orofacial clefts (that is, families segregating orofacial clefts) had an increased cancer incidence when compared with control families. METHODS: The authors assessed 75 white families with nonsyndromic cleft lip with or without cleft palate (CL/P) and 93 white control families regarding a history of cancer. They used chi(2) and Fisher exact tests to determine significant differences. They then performed molecular studies with genes in which mutations have been independently associated with both cancer and craniofacial anomalies in a total of 111 families with CL/P. RESULTS: The families with CL/P reported a family history of cancer more often than did control families (P <.001), and they had higher rates of specific cancer types: colon (P <.001), brain (P = .003), leukemia (P = .005), breast (P = .009), prostate (P = .01), skin (P = .01), lung (P = .02) and liver (P = .02). The authors detected overtransmission of AXIS inhibition protein 2 (AXIN2) in CL/P probands (P = .003). CONCLUSION: Families segregating CL/P may have an increased susceptibility to cancer, notably colon cancer. Furthermore, AXIN2, a gene that when mutated increases susceptibility to colon cancer, also is associated with CL/P. CLINICAL IMPLICATIONS: People who are at a higher risk of developing disease need to adopt a healthier lifestyle, including avoiding exposure to risk factors that may interact with their genotypes.